METHODS FOR PREDICTING CANCER-ASSOCIATED VENOUS

THROMBOEMBOLISM USING CIRCULATING TUMOR DNA

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63/424,813, filed November 11, 2022, and U.S. Provisional Patent Application No. 63/507,399, filed June 9, 2023, the entire contents of which are incorporated herein by reference.

TECHNICAL FIELD

[0002] The present technology relates generally to methods for accurately predicting the risk of cancer-associated venous thromboembolism (CAT) and/or preventing CAT in cancer patients using ctDNA as a biomarker.

BACKGROUND

[0003] The following description of the background of the present technology is provided simply as an aid in understanding the present technology and is not admitted to describe or constitute prior art to the present technology.

[0004] Cancer associated thromboembolism (CAT) is a frequent complication of cancer with high morbidity. Biomarkers that effectively predict which patients are at highest risk of developing CAT are needed to assess which patients might benefit from prophylactic anti coagulation and further monitoring. The Khorana score, based on cancer type, prechemotherapy platelet and leukocyte count, hemoglobin, and body-mass index (BMI) is one such validated means of risk-stratifying patients for CAT (Khorana et al Blood 2008); it has been shown that patients with a high Khorana score are at high risk for CAT but that risk may be lowered by prophylactic anti coagulation (Khorana et al NEJM 2019, Carrier et al NEJM 2019). However, new molecular biomarkers may possess prognostic information not captured in laboratory, histopathologic, radiologic, or clinical variables (Jee et al ASCO 2021, ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.9009). SUMMARY OF THE PRESENT TECHNOLOGY

[0005] In one aspect, the present disclosure provides a method for preventing cancer associated thromboembolism (CAT) in a cancer patient in need thereof comprising (a) detecting ctDNA molecules in a biological sample obtained from the cancer patient, wherein the ctDNA molecules are detected at a variant allele fraction (VAF) detection limit of at least 0. l%-0.5% and (b) administering to the cancer patient an effective amount of anticoagulant therapy.

[0006] In another aspect, the present disclosure provides a method for preventing cancer associated thromboembolism (CAT) in a cancer patient in need thereof comprising administering to the cancer patient an effective amount of anticoagulant therapy, wherein a biological sample obtained from the cancer patient comprises detectable ctDNA molecules, wherein the ctDNA molecules are detected at a variant allele fraction (VAF) detection limit of at least 0. l%-0.5%.

[0007] Additionally or alternatively, in some embodiments of the methods disclosed herein, the ctDNA molecules are detected at a VAF detection limit of from about 0.1% to about 0.5%, from about 0.5% to about 2%, from about 2% to about 10% or from about 10% to about 99%. In certain embodiments, the ctDNA molecules are detected at a VAF detection limit of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%.

[0008] In any of the preceding embodiments of the methods disclosed herein, the cancer patient is diagnosed with or suffers from a cancer selected from the group consisting of nonsmall cell lung cancer, breast cancer, pancreatic cancer, melanoma, retinoblastoma, prostate cancer, esophagogastric cancer, histiocytosis, germ cell tumor, endometrial cancer, small cell lung cancer, soft tissue sarcoma, Gastrointestinal Stromal Tumor, ovarian cancer, mature B-Cell neoplasms, small bowel cancer, renal cell carcinoma, thyroid cancer, ampullary cancer, appendiceal cancer, sellar tumor, uterine sarcoma, bone cancer, nonmelanoma skin cancer, cervical cancer, mesothelioma, glioma, thymic tumor, gastrointestinal neuroendocrine tumor, salivary gland cancer, sex cord stromal tumor, anal cancer, mature T and NK neoplasms, peritoneal cancer, Head and neck cancer, choroid plexus tumor, leukemia, primary CNS melanocytic tumors, Myelodysplastic Syndromes, Peripheral Nervous System, mastocytosis, Wilms tumor, lymphatic cancer, vaginal cancer, Hodgkin lymphoma, adrenocortical carcinoma, brain tumors, embryonal tumors and NonHodgkin lymphoma. The cancer may be a Stage 1, Stage 2, Stage 3, or Stage 4 cancer. Additionally or alternatively, in some embodiments, the cancer patient has a Khorana Score > 2 or < 2 and/or has one or more organ sites of metastasis.

[0009] Additionally or alternatively, in some embodiments of the methods disclosed herein, the ctDNA molecules comprise one or more mutations (e.g., SNVs) in at least one cancer associated gene selected from the group consisting of AKT1, ALK, APC, AR, ARAF, ARID1 A, ARID2, ATM, B2M, BCL2, BCOR, BRAF, BRCA1, BRCA2, CARD11, CBFB, CCND1, CDH1, CDK4, CDKN2A, CIC, CREBBP, CTCF, CTNNB1, DICER1, DIS3, DNMT3A, EGFR, EIF1AX, EP300, ERBB2, ERBB3, ERCC2, ESRI, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, FOXA1, FOXL2, FOXO1, FUBP1, GATA3, GNA11, GNAQ, GNAS, H3F3A, HIST1H3B, HRAS, IDH1, IDH2, IKZF1, INPPL1, JAK1, KDM6A, KEAP1, KIT, KNSTRN, KRAS, MAP2K1, MAPK1, MAX, MED12, MET, MLH1, MSH2, MSH3, MSH6, MTOR, MYC, MYCN, MYD88, MYODI, NF1, NFE2L2, NOTCH1, NRAS, NTRK1, NTRK2, NTRK3, NUP93, PAK7, PDGFRA, PIK3CA, PIK3CB, PIK3R1, PIK3R2, PMS2, POLE, PPP2R1A, PPP6C, PRKCI, PTCHI, PTEN, PTPN11, RAC1, RAFI, RBI, RET, RHOA, RIT1, ROS1, RRAS2, RXRA, SETD2, SF3B1, SMAD3, SMAD4, SMARCA4, SMARCB1, S0S1, SPOP, STAT3, STK11, STK19, TCF7L2, TGFBR1, TGFBR2, TP53, TP63, TSC1, TSC2, U2AF1, VHL, XP01, and TERT. In certain embodiments, the ctDNA molecules comprise 2-20 mutations in the at the least one cancer associated gene.

[0010] In any and all embodiments of the methods disclosed herein, the ctDNA molecules comprise one or more rearrangements in at least one cancer associated gene selected from the group consisting of ALK, BRAF, EGFR, ETV6, FGFR2, FGFR3, MET, NTRK1, RET and ROSE The one or more rearrangements may comprise indels, CNVs, and/or gene fusions. Additionally or alternatively, in some embodiments, the ctDNA molecules comprise 2-20 rearrangements in the at the least one cancer associated gene.

[0011] In any of the preceding embodiments of the methods disclosed herein, the biological sample is whole blood, serum or plasma. In some embodiments, the biological sample has a cfDNA concentration ranging from about 3 pg/pL to 5.5 ng/pL. In some embodiments, the biological sample has a cfDNA concentration of about 3 pg/pL, about 4 pg/pL, about 5 pg/pL, about 6 pg/pL, about 7 pg/pL, about 8 pg/pL, about 9 pg/pL, about 10 pg/pL, about 15 pg/pL, about 20 pg/pL, about 25 pg/pL, about 30 pg/pL, about 35 pg/pL, about 40 pg/pL, about 45 pg/pL, about 50 pg/pL, about 55 pg/pL, about 60 pg/pL, about 65 pg/pL, about 70 pg/pL, about 75 pg/pL, about 80 pg/pL, about 85 pg/pL, about 90 pg/pL, about 100 pg/pL, about 125 pg/pL, about 150 pg/pL, about 175 pg/pL, about 200 pg/pL, about 225 pg/pL, about 250 pg/pL, about 275 pg/pL, about 300 pg/pL, about 325 pg/pL, about 350 pg/pL, about 375 pg/pL, about 400 pg/pL, about 425 pg/pL, about 450 pg/pL, about 475 pg/pL, about 500 pg/pL, about 525 pg/pL, about 550 pg/pL, about 575 pg/pL, about 600 pg/pL, about 625 pg/pL, about 650 pg/pL, about 675 pg/pL, about 700 pg/pL, about 725 pg/pL, about 750 pg/pL, about 775 pg/pL, about 800 pg/pL, about 825 pg/pL, about 850 pg/pL, about 875 pg/pL, about 900 pg/pL, about 925 pg/pL, about 950 pg/pL, about 975 pg/pL, about 1 ng/pL, about 1.25 ng/pL, about 1.5 ng/pL, about 1.75 ng/pL, about 2 ng/pL, about 2.25 ng/pL, about 2.5 ng/pL, about 2.75 ng/pL, about 3 ng/pL, about 3.25 ng/pL, about 3.5 ng/pL, about 3.75 ng/pL, about 4 ng/pL, about 4.25 ng/pL, about 4.5 ng/pL, about 4.75 ng/pL, about 5 ng/pL, about 5.25 ng/pL, or about 5.5 ng/pL.

[0012] Additionally or alternatively, in some embodiments, the anticoagulant therapy comprises one or more of apixaban, betrixaban, dabigatran, edoxaban, fondaparinux, heparin, rivaroxaban, warfarin, Xa inhibitors, statins, or enoxaparin. Examples of statins include, but are not limited to atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0013] In any of the foregoing embodiments of the methods disclosed herein, the cancer patient is chemotherapy-naive or has received/is receiving systemic chemotherapy. Systemic chemotherapy may comprise one or more of alkylating agents, antibiotics, antimetabolites, antimitotics, cyclin-dependent kinase inhibitors, epidermal growth factor receptor inhibitors, multikinase inhibitors, PARP inhibitors, platinum-based agents, selective estrogen receptor modulators (SERM), or VEGF inhibitors. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents, platinum agents, taxanes, vinca agents, anti-estrogen drugs, aromatase inhibitors, ovarian suppression agents, VEGF/VEGFR inhibitors, EGFZEGFR inhibitors, PARP inhibitors, cytostatic alkaloids, cytotoxic antibiotics, antimetabolites, endocrine/hormonal agents, bisphosphonate therapy agents and targeted biological therapy agents (e.g., therapeutic peptides described in US 6306832, WO 2012007137, WO 2005000889, WO 2010096603 etc.). In some embodiments, the at least one additional therapeutic agent is a chemotherapeutic agent. Specific chemotherapeutic agents include, but are not limited to, cyclophosphamide, fluorouracil (or 5 -fluorouracil or 5-FU), methotrexate, edatrexate (10-ethyl-10-deaza- aminopterin), thiotepa, carboplatin, cisplatin, taxanes, paclitaxel, protein-bound paclitaxel, docetaxel, vinorelbine, tamoxifen, raloxifene, toremifene, fulvestrant, gemcitabine, irinotecan, ixabepilone, temozolmide, topotecan, vincristine, vinblastine, eribulin, mutamycin, capecitabine, anastrozole, exemestane, letrozole, leuprolide, abarelix, buserlin, goserelin, megestrol acetate, risedronate, pamidronate, ibandronate, alendronate, denosumab, zoledronate, trastuzumab, tykerb, anthracyclines (e.g., daunorubicin and doxorubicin), bevacizumab, oxaliplatin, melphalan, etoposide, mechlorethamine, bleomycin, microtubule poisons, annonaceous acetogenins, or combinations thereof.

[0014] Additionally or alternatively, in some embodiments of the methods disclosed herein, the cancer patient is immunotherapy-naive or has received/is receiving immunotherapy. Examples of immunotherapy include, but are not limited to, anti-PD-1 antibody, anti-PD-Ll antibody, anti-PD-L2 antibody, anti-CTLA-4 antibody, anti-TIM3 antibody, anti-4-lBB antibody, anti-CD73 antibody, anti-GITR antibody, and anti-LAG-3 antibody. [0015] Additionally or alternatively, in certain embodiments of the methods disclosed herein, the cancer patient is radiotherapy-naive or has received/is receiving radiotherapy. The radiotherapy may comprise external radiotherapy, radiotherapy implants (brachytherapy), pre-targeted radioimmunotherapy, radiotherapy injections, radioisotope therapy, or intrabeam radiotherapy.

[0016] In any and all embodiments of the methods disclosed herein, the CAT is pulmonary embolism or lower extremity deep vein thrombosis (DVT). In some embodiments, lower extremity DVT includes thrombi involving a common iliac vein, an external iliac vein, a common femoral vein, a superficial femoral vein, a deep femoral vein, a popliteal vein, a peroneal vein, an anterior tibial vein, a posterior tibial vein, or a deep calf vein.

[0017] In one aspect, the present disclosure provides a method for preventing cancer associated thromboembolism (CAT) in a lung cancer patient in need thereof comprising detecting ctDNA molecules in a biological sample obtained from the lung cancer patient, wherein the ctDNA molecules comprise at least one alteration in at least one cancer- associated gene selected from the group consisting of AKT1, ALK, B2M, BRAF, EGFR, ERBB2 (HER2), FGFR2, FGFR3, KEAP1, KRAS, MAP2K1 (MEK1), MET, NRAS, PIK3CA, RET, ROS1, STK11, TP53, NTRK1, FGFR1, MYC, PTEN, and RICTOR; and administering to the lung cancer patient an effective amount of anticoagulant therapy. The lung cancer may be non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). In some embodiments, the lung cancer is Stage 1, Stage 2, Stage 3, or Stage 4.

[0018] In another aspect, the present disclosure provides a method for preventing cancer associated thromboembolism (CAT) in a lung cancer patient in need thereof comprising administering to the lung cancer patient an effective amount of anticoagulant therapy, wherein a biological sample obtained from the lung cancer patient comprises detectable ctDNA molecules comprising at least one alteration in at least one cancer-associated gene selected from the group consisting of AKT1, ALK, B2M, BRAF, EGFR, ERBB2 (HER2), FGFR2, FGFR3, KEAP1, KRAS, MAP2K1 (MEK1), MET, NRAS, PIK3CA, RET, ROS1, STK11, TP53, NTRK1, FGFR1, MYC, PTEN, and RICTOR. The lung cancer may be non- small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). In certain embodiments, the lung cancer is Stage 1, Stage 2, Stage 3, or Stage 4. [0019] Additionally or alternatively, in some embodiments, the anticoagulant therapy comprises one or more of apixaban, betrixaban, dabigatran, edoxaban, fondaparinux, heparin, rivaroxaban, warfarin, Xa inhibitors, statins, or enoxaparin. Examples of statins include, but are not limited to atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0020] In any of the preceding embodiments of the methods disclosed herein, the lung cancer patient has a Khorana Score < 2 or > 2. Additionally or alternatively, in certain embodiments, the at least one alteration is a SNV, an indel, a CNV, or a gene fusion.

[0021] Additionally or alternatively, in some embodiments of the methods disclosed herein, the at least one alteration is detected at a variant allele fraction (VAF) detection limit of 0. l%-0.5%. In certain embodiments, the detected ctDNA molecules comprise one alteration in the at the least one cancer associated gene. In other embodiments, the detected ctDNA molecules comprise 2-20 alterations in the at the least one cancer associated gene. Additionally or alternatively, in some embodiments of the methods disclosed herein, the ctDNA molecules are detected via polymerase chain reaction (PCR), real-time quantitative PCR (qPCR), droplet digital PCR (ddPCR), Reverse transcriptase-PCR (RT-PCR), microarray, RNA-Seq, or next-generation sequencing. In any of the preceding embodiments of the methods disclosed herein, the biological sample is whole blood, serum or plasma.

[0022] In any of the foregoing embodiments of the methods disclosed herein, the lung cancer patient is chemotherapy-naive or has received/is receiving systemic chemotherapy. Examples of systemic chemotherapy include, but are not limited to, alkylating agents, antibiotics, antimetabolites, antimitotics, cyclin-dependent kinase inhibitors, epidermal growth factor receptor inhibitors, multikinase inhibitors, PARP inhibitors, platinum-based agents, selective estrogen receptor modulators (SERM), or VEGF inhibitors.

[0023] Additionally or alternatively, in some embodiments of the methods disclosed herein, the lung cancer patient is immunotherapy-naive or has received/is receiving immunotherapy. Examples of immunotherapy include, but are not limited to, anti-PD-1 antibody, anti-PD-Ll antibody, anti-PD-L2 antibody, anti-CTLA-4 antibody, anti-TIM3 antibody, anti-4-lBB antibody, anti-CD73 antibody, anti-GITR antibody, and anti-LAG-3 antibody. [0024] Additionally or alternatively, in certain embodiments of the methods disclosed herein, the lung cancer patient is radiotherapy -naive or has received/is receiving radiotherapy. The radiotherapy may comprise external radiotherapy, radiotherapy implants (brachytherapy), pre-targeted radioimmunotherapy, radiotherapy injections, radioisotope therapy, or intrabeam radiotherapy.

[0025] In any and all embodiments of the methods disclosed herein, the CAT is pulmonary embolism or lower extremity deep vein thrombosis (DVT). In some embodiments, lower extremity DVT includes thrombi involving a common iliac vein, an external iliac vein, a common femoral vein, a superficial femoral vein, a deep femoral vein, a popliteal vein, a peroneal vein, an anterior tibial vein, a posterior tibial vein, or a deep calf vein.

[0026] Additionally or alternatively, in certain embodiments of the methods disclosed herein, the at least one alteration comprises a SNV and/or an indel in one or more of AKT1, ALK, B2M, BRAF, EGFR, ERBB2 (HER2), FGFR2, FGFR3, KEAP1, KRAS, MAP2K1 (MEK1), MET, NRAS, PIK3CA, RET, ROS1, STK11 and TP53. In some embodiments of the methods disclosed herein, the at least one alteration comprises a gene fusion in one or more of ALK, EGFR, FGFR2, FGFR3, NTRK1, RET, and ROS1. Additionally or alternatively, in some embodiments, the at least one alteration comprises a CNV in one or more of B2M, EGFR, ERBB2 (HER2), FGFR1, KRAS, MET, MYC, NTRK1, PIK3CA, PTEN, RICTOR, STK11, and TP53.

[0027] In one aspect, the present disclosure provides a method of training a machine learning classifier for estimating risk of cancer-associated venous thromboembolism (VTE) in cancer patients comprising: (a) receiving data on a cohort of subjects, the subjects in the cohort having a plurality of cancer types; (b) generating a training dataset based on the received data, wherein the training dataset comprises a plurality of features for each subject in the cohort, wherein the plurality of features comprises (i) cell free DNA concentration, (ii) maximum ctDNA VAF, (iii) ctDNA alterations in at least one cancer associated gene, and (iv) cancer type; and (c) applying a machine learning method to the training dataset to develop the machine learning classifier for estimating risk of cancer-associated VTE in cancer patients, wherein applying the machine learning method comprises: applying a machine learning technique to the training dataset; performing hyperparameter optimization to identify one or more machine learning models with an accuracy that exceeds an accuracy threshold for the classifier; and determining an optimal operating-point threshold based on optimization of sensitivity and specificity of the receiver operating characteristic (ROC) curves for the training dataset; wherein the classifier is configured to receive the plurality of features for cancer patients and generate predictors for risk of cancer-associated VTE in cancer patients. The subjects in the cohort may be chemotherapy -naive or may have received systemic chemotherapy. Additionally or alternatively, in certain embodiments, the plurality of cancer types are selected from the group consisting of non-small cell lung cancer, breast cancer, pancreatic cancer, melanoma, retinoblastoma, prostate cancer, esophagogastric cancer, histiocytosis, germ cell tumor, endometrial cancer, small cell lung cancer, soft tissue sarcoma, Gastrointestinal Stromal Tumor, ovarian cancer, mature B-Cell neoplasms, small bowel cancer, renal cell carcinoma, thyroid cancer, ampullary cancer, appendiceal cancer, sellar tumor, uterine sarcoma, bone cancer, non-melanoma skin cancer, cervical cancer, mesothelioma, glioma, thymic tumor, gastrointestinal neuroendocrine tumor, salivary gland cancer, sex cord stromal tumor, anal cancer, mature T and NK neoplasms, peritoneal cancer, Head and neck cancer, choroid plexus tumor, leukemia, primary CNS melanocytic tumors, Myelodysplastic Syndromes, Peripheral Nervous System, mastocytosis, Wilms tumor, lymphatic cancer, vaginal cancer, Hodgkin lymphoma, adrenocortical carcinoma, brain tumors, embryonal tumors and Non-Hodgkin lymphoma.

[0028] The machine learning technique may model survival outcomes with competing risks. In some embodiments, the machine learning technique is a random forest technique, and the one or more machine learning models are random forest models. Additionally or alternatively, in certain embodiments, the machine learning classifier is an ensemble learning random forest classifier. Additionally or alternatively, in some embodiments, performing the hyperparameter optimization comprises performing an exhaustive grid search technique.

[0029] Additionally or alternatively, in some embodiments of the methods disclosed herein, the at least one cancer associated gene is selected from the group consisting of AKT1, ALK, APC, AR, ARAF, ARID1 A, ARID2, ATM, B2M, BCL2, BCOR, BRAF, BRCA1, BRCA2, CARD11, CBFB, CCND1, CDH1, CDK4, CDKN2A, CIC, CREBBP, CTCF, CTNNB1, DICER1, DIS3, DNMT3A, EGFR, EIF1AX, EP300, ERBB2, ERBB3, ERCC2, ESRI, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, FOXA1, FOXL2, FOXO1, FUBP1, GATA3, GNA11, GNAQ, GNAS, H3F3A, HIST1H3B, HRAS, IDH1, IDH2, IKZF1, INPPL1, JAK1, KDM6A, KEAP1, KIT, KNSTRN, KRAS, MAP2K1, MAPK1, MAX, MED12, MET, MLH1, MSH2, MSH3, MSH6, MTOR, MYC, MYCN, MYD88, MYODI, NF1, NFE2L2, NOTCH1, NRAS, NTRK1, NTRK2, NTRK3, NUP93, PAK7, PDGFRA, PIK3CA, PIK3CB, PIK3R1, PIK3R2, PMS2, POLE, PPP2R1A, PPP6C, PRKCI, PTCHI, PTEN, PTPN11, RAC1, RAFI, RBI, RET, RHOA, RIT1, ROS1, RRAS2, RXRA, SETD2, SF3B1, SMAD3, SMAD4, SMARCA4, SMARCB1, S0S1, SPOP, STAT3, STK11, STK19, TCF7L2, TGFBR1, TGFBR2, TP53, TP63, TSC1, TSC2, U2AF1, VHL, XPO1, and TERT.

[0030] Additionally or alternatively, in some embodiments of the methods disclosed herein, the plurality of features further comprises platelet count, hemoglobin levels, leukocyte counts, body mass index (BMI), administration of chemotherapy, age, time from cancer diagnosis, race, and metastatic sites of disease. In certain embodiments, the metastatic sites of disease comprise one or more of adrenal gland, bone, brain, liver, lung, lymph, and pleura.

[0031] In any of the preceding embodiments, the method further comprises applying the classifier to data on a cancer patient to generate a predictor, and determining whether the cancer patient is at risk for cancer-associated VTE based on the predictor and the operatingpoint threshold. In some embodiments, the predictor comprises a cumulative incidence function (CIF) for cancer-associated VTE.

[0032] In any of the foregoing embodiments, the method further comprises administering an effective amount of anticoagulant therapy to the cancer patient predicted to be at risk for cancer-associated VTE based on the predictor and the operating-point threshold. Examples of anticoagulant therapy include, but are not limited to, apixaban, betrixaban, dabigatran, edoxaban, fondaparinux, heparin, rivaroxaban, warfarin, Xa inhibitors, statins, and enoxaparin. Examples of statins include, but are not limited to atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0033] In some embodiments, the cancer patient is chemotherapy-naive or has received/is receiving systemic chemotherapy.

[0034] In one aspect, the present disclosure provides a method of estimating risk of cancer-associated venous thromboembolism (VTE) in a cancer patient using a machine learning classifier, the method comprising: receiving patient data corresponding to a plurality of features for the cancer patient; applying the machine learning classifier to the patient data to generate a predictor; and determining whether the cancer patient is at risk for cancer-associated VTE based on the predictor and an operating-point threshold, wherein the machine learning classifier is trained by: (a) receiving cohort data on a cohort of subjects, the subjects in the cohort having a plurality of cancer types; (b) generating a training dataset based on the received cohort data, wherein the training dataset comprises the plurality of features for each subject in the cohort, wherein the plurality of features comprises (i) cell free DNA concentration, (ii) maximum ctDNA VAF, (iii) ctDNA alterations in at least one cancer associated gene, and (iv) cancer type; and (c) applying a machine learning method to the training dataset to develop the machine learning classifier for estimating risk of cancer- associated VTE, wherein applying the machine learning method comprises: applying a machine learning technique to the training dataset; performing hyperparameter optimization to identify one or more machine learning models with an accuracy that exceeds an accuracy threshold for the machine learning classifier; and determining the optimal operating-point threshold based on optimization of sensitivity and specificity of the receiver operating characteristic (ROC) curves for the training dataset; wherein the machine learning classifier is configured to receive the plurality of features for cancer patients and generate predictors for risk of cancer-associated VTE in cancer patients. In some embodiments, the method further comprises administering an effective amount of anticoagulant therapy to the cancer patient predicted to be at risk for cancer-associated VTE based on the predictor and the operating-point threshold. Examples of anticoagulant therapy include, but are not limited to, apixaban, betrixaban, dabigatran, edoxaban, fondaparinux, heparin, rivaroxaban, warfarin, Xa inhibitors, statins, and enoxaparin. Examples of statins include, but are not limited to atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. Additionally or alternatively, in some embodiments, the predictor comprises a cumulative incidence function (CIF) for cancer-associated VTE. The subjects in the cohort may be chemotherapy-naive or may have received systemic chemotherapy. In any of the preceding embodiments of the methods disclosed herein, one or more of the plurality of features for the cancer patient are determined by assaying blood and/or sequencing tumor DNA.

[0035] Additionally or alternatively, in certain embodiments, the plurality of cancer types are selected from the group consisting of non-small cell lung cancer, breast cancer, pancreatic cancer, melanoma, retinoblastoma, prostate cancer, esophagogastric cancer, histiocytosis, germ cell tumor, endometrial cancer, small cell lung cancer, soft tissue sarcoma, Gastrointestinal Stromal Tumor, ovarian cancer, mature B-Cell neoplasms, small bowel cancer, renal cell carcinoma, thyroid cancer, ampullary cancer, appendiceal cancer, sellar tumor, uterine sarcoma, bone cancer, non-melanoma skin cancer, cervical cancer, mesothelioma, glioma, thymic tumor, gastrointestinal neuroendocrine tumor, salivary gland cancer, sex cord stromal tumor, anal cancer, mature T and NK neoplasms, peritoneal cancer, Head and neck cancer, choroid plexus tumor, leukemia, primary CNS melanocytic tumors, Myelodysplastic Syndromes, Peripheral Nervous System, mastocytosis, Wilms tumor, lymphatic cancer, vaginal cancer, Hodgkin lymphoma, adrenocortical carcinoma, brain tumors, embryonal tumors and Non-Hodgkin lymphoma.

[0036] The machine learning technique may model survival outcomes with competing risks. In some embodiments, the machine learning technique is a random forest technique, and the one or more machine learning models are random forest models. Additionally or alternatively, in certain embodiments, the machine learning classifier is an ensemble learning random forest classifier. Additionally or alternatively, in some embodiments, performing the hyperparameter optimization comprises performing an exhaustive grid search technique.

[0037] Additionally or alternatively, in some embodiments of the methods disclosed herein, the plurality of features further comprises platelet count, hemoglobin levels, leukocyte counts, body mass index (BMI), administration of chemotherapy, age, time from cancer diagnosis, race, and metastatic sites of disease.

[0038] Additionally or alternatively, in some embodiments of the methods disclosed herein, the at least one cancer associated gene is selected from the group consisting of AKT1, ALK, APC, AR, ARAF, ARID 1 A, AR.ID2, ATM, B2M, BCL2, BCOR, BRAF, BRCA1, BRCA2, CARD11, CBFB, CCND1, CDH1, CDK4, CDKN2A, CIC, CREBBP, CTCF, CTNNB1, DICER1, DIS3, DNMT3A, EGFR, EIF1AX, EP300, ERBB2, ERBB3, ERCC2, ESRI, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, FOXA1, FOXL2, FOXO1, FUBP1, GATA3, GNA11, GNAQ, GNAS, H3F3A, HIST1H3B, HRAS, IDH1, IDH2, IKZF1, INPPL1, JAK1, KDM6A, KEAP1, KIT, KNSTRN, KRAS,

MAP2K1, MAPK1, MAX, MED12, MET, MLH1, MSH2, MSH3, MSH6, MTOR, MYC,

MYCN, MYD88, MYODI, NF1, NFE2L2, NOTCH1, NRAS, NTRK1, NTRK2, NTRK3, NUP93, PAK7, PDGFRA, PIK3CA, PIK3CB, PIK3R1, PIK3R2, PMS2, POLE, PPP2R1A, PPP6C, PRKCI, PTCHI, PTEN, PTPN11, RAC1, RAFI, RBI, RET, RHOA, RIT1, ROS1, RRAS2, RXRA, SETD2, SF3B1, SMAD3, SMAD4, SMARCA4, SMARCB1, SOS1, SPOP, STAT3, STK11, STK19, TCF7L2, TGFBR1, TGFBR2, TP53, TP63, TSC1, TSC2, U2AF1, VHL, XP01, and TERT.

[0039] In some embodiments, the cancer patient is chemotherapy -naive or has received/is receiving systemic chemotherapy.

[0040] In any and all embodiments of the methods disclosed herein, one or more of the plurality of features for each subject in the cohort are determined by assaying blood and/or sequencing tumor DNA.

[0041] In any and all embodiments of the methods disclosed herein, the cancer- associated VTE is pulmonary embolism or lower extremity deep vein thrombosis (DVT), optionally wherein lower extremity DVT includes thrombi involving a common iliac vein, an external iliac vein, a common femoral vein, a superficial femoral vein, a deep femoral vein, a popliteal vein, a peroneal vein, an anterior tibial vein, a posterior tibial vein, or a deep calf vein.

[0042] In another aspect, the present disclosure provides a machine learning system for training a machine learning classifier for estimating risk of cancer-associated venous thromboembolism (VTE) in cancer patients, the system comprising a processor and a memory with instructions which, when executed by the processor, cause the processor to: (a) receive data on a cohort of subjects, the subjects in the cohort having a plurality of cancer types; (b) generate a training dataset based on the received data, wherein the training dataset comprises a plurality of features for each subject in the cohort, wherein the plurality of features comprises (i) cell free DNA concentration, (ii) maximum ctDNA VAF, (iii) ctDNA alterations in at least one cancer associated gene, and (iv) cancer type; and (c) apply a machine learning method to the training dataset to develop the machine learning classifier for estimating risk of cancer-associated VTE in cancer patients; wherein applying the machine learning method comprises: applying a machine learning technique to the training dataset; performing hyperparameter optimization to identify one or more machine learning models with an accuracy that exceeds an accuracy threshold for the machine learning classifier; and determining an optimal operating-point threshold based on optimization of sensitivity and specificity of the receiver operating characteristic (ROC) curves for the training dataset; wherein the machine learning classifier is configured to receive the plurality of features for cancer patients and generate predictors for risk of cancer-associated VTE in cancer patients. The subjects in the cohort may be chemotherapy-naive or may have received systemic chemotherapy.

[0043] The machine learning technique may model survival outcomes with competing risks. In some embodiments, the machine learning technique is a random forest technique, and the one or more machine learning models are random forest models. Additionally or alternatively, in certain embodiments, the machine learning classifier is an ensemble learning random forest classifier.

[0044] Additionally or alternatively, in some embodiments, performing the hyperparameter optimization comprises performing an exhaustive grid search technique.

[0045] Additionally or alternatively, in some embodiments of the systems disclosed herein, the at least one cancer associated gene is selected from the group consisting of AKT1, ALK, APC, AR, ARAF, ARID! A, ARID2, ATM, B2M, BCL2, BCOR, BRAF, BRCA1, BRCA2, CARD11, CBFB, CCND1, CDH1, CDK4, CDKN2A, CIC, CREBBP, CTCF, CTNNB1, DICER1, DIS3, DNMT3A, EGFR, EIF1AX, EP300, ERBB2, ERBB3, ERCC2, ESRI, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, FOXA1, FOXL2, FOXO1, FUBP1, GATA3, GNA11, GNAQ, GNAS, H3F3A, HIST1H3B, HRAS, IDH1, IDH2, IKZF1, INPPL1, JAK1, KDM6A, KEAP1, KIT, KNSTRN, KRAS, MAP2K1, MAPK1, MAX, MED12, MET, MLH1, MSH2, MSH3, MSH6, MTOR, MYC, MYCN, MYD88, MYODI, NF1, NFE2L2, NOTCH1, NRAS, NTRK1, NTRK2, NTRK3, NUP93, PAK7, PDGFRA, PIK3CA, PIK3CB, PIK3R1, PIK3R2, PMS2, POLE, PPP2R1A, PPP6C, PRKCI, PTCHI, PTEN, PTPN11, RAC1, RAFI, RBI, RET, RHOA, RIT1, ROS1, RRAS2, RXRA, SETD2, SF3B1, SMAD3, SMAD4, SMARCA4, SMARCB1, S0S1, SPOP, STAT3, STK11, STK19, TCF7L2, TGFBR1, TGFBR2, TP53, TP63, TSC1, TSC2, U2AF1, VHL, XPO1, and TERT.

[0046] Additionally or alternatively, in some embodiments of the systems disclosed herein, the plurality of features further comprises platelet count, hemoglobin levels, leukocyte counts, body mass index (BMI), administration of chemotherapy, age, time from cancer diagnosis, race, and metastatic sites of disease. Metastatic sites of disease may comprise one or more of adrenal gland, bone, brain, liver, lung, lymph, and pleura.

[0047] Additionally or alternatively, in certain embodiments of the systems disclosed herein, the plurality of cancer types are selected from the group consisting of non-small cell lung cancer, breast cancer, pancreatic cancer, melanoma, retinoblastoma, prostate cancer, esophagogastric cancer, histiocytosis, germ cell tumor, endometrial cancer, small cell lung cancer, soft tissue sarcoma, Gastrointestinal Stromal Tumor, ovarian cancer, mature B-Cell neoplasms, small bowel cancer, renal cell carcinoma, thyroid cancer, ampullary cancer, appendiceal cancer, sellar tumor, uterine sarcoma, bone cancer, non-melanoma skin cancer, cervical cancer, mesothelioma, glioma, thymic tumor, gastrointestinal neuroendocrine tumor, salivary gland cancer, sex cord stromal tumor, anal cancer, mature T and NK neoplasms, peritoneal cancer, Head and neck cancer, choroid plexus tumor, leukemia, primary CNS melanocytic tumors, Myelodysplastic Syndromes, Peripheral Nervous System, mastocytosis, Wilms tumor, lymphatic cancer, vaginal cancer, Hodgkin lymphoma, adrenocortical carcinoma, brain tumors, embryonal tumors and Non-Hodgkin lymphoma.

[0048] In any of the preceding embodiments of the systems described herein, the instructions further cause the processor to apply the machine learning classifier to data on a cancer patient to generate a predictor, and determine whether the cancer patient is at risk for cancer-associated VTE based on the predictor and the operating-point threshold. In some embodiments, the predictor comprises a cumulative incidence function (CIF) for cancer- associated VTE.

[0049] In any of the foregoing embodiments of the systems described herein, the instructions further cause the processor to recommend an anticoagulant therapy to the cancer patient predicted to be at risk for cancer-associated VTE based on the predictor and the operating-point threshold. Examples of anticoagulant therapy include, but are not limited to, apixaban, betrixaban, dabigatran, edoxaban, fondaparinux, heparin, rivaroxaban, warfarin, Xa inhibitors, statins, and enoxaparin. Examples of statins include, but are not limited to atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0050] In some embodiments, the cancer patient is chemotherapy -naive or has received/is receiving systemic chemotherapy. [0051] In yet another aspect, the present disclosure provides a computing system for estimating risk of cancer-associated venous thromboembolism (VTE) in a cancer patient, the computing system comprising a processor and a memory with instructions which, when executed by the processor, cause the processor to: receive patient data corresponding to a plurality of features for the cancer patient; apply a machine learning classifier to the patient data to generate a predictor; and determine whether the cancer patient is at risk for cancer- associated VTE based on the predictor and an operating-point threshold, wherein the classifier is trained by: (a) receiving cohort data on a cohort of subjects, the subjects in the cohort having a plurality of cancer types; (b) generating a training dataset based on the received cohort data, wherein the training dataset comprises the plurality of features for each subject in the cohort, wherein the plurality of features comprises (i) cell free DNA concentration, (ii) maximum ctDNA VAF, (iii) ctDNA alterations in at least one cancer associated gene, and (iv) cancer type; and (c) applying a machine learning method to the training dataset to develop the machine learning classifier for estimating risk of cancer- associated VTE, wherein applying the machine learning method comprises: applying a machine learning technique to the training dataset; performing hyperparameter optimization to identify one or more machine learning models with an accuracy that exceeds an accuracy threshold for the machine learning classifier; and determining the optimal operating-point threshold based on optimization of sensitivity and specificity of the receiver operating characteristic (ROC) curves for the training dataset; wherein the machine learning classifier is configured to receive the plurality of features for cancer patients and generate predictors for risk of cancer-associated VTE in cancer patients.

[0052] The machine learning technique may model survival outcomes with competing risks. In some embodiments, the machine learning technique is a random forest technique, and the one or more machine learning models are random forest models. Additionally or alternatively, in certain embodiments, the machine learning classifier is an ensemble learning random forest classifier.

[0053] Additionally or alternatively, in some embodiments, performing the hyperparameter optimization comprises performing an exhaustive grid search technique.

[0054] Additionally or alternatively, in some embodiments of the systems disclosed herein, the plurality of features further comprises platelet count, hemoglobin levels, leukocyte counts, body mass index (BMI), administration of chemotherapy, age, time from cancer diagnosis, race, and metastatic sites of disease.

[0055] In certain embodiments, the at least one cancer associated gene is selected from the group consisting of AKT1, ALK, APC, AR, ARAF, ARID1A, ARID2, ATM, B2M, BCL2, BCOR, BRAF, BRCA1, BRCA2, CARD11, CBFB, CCND1, CDH1, CDK4, CDKN2A, CIC, CREBBP, CTCF, CTNNB1, DICER1, DIS3, DNMT3A, EGFR, EIF1AX, EP300, ERBB2, ERBB3, ERCC2, ESRI, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, FOXA1, FOXL2, FOXO1, FUBP1, GATA3, GNA11, GNAQ, GNAS, H3F3A, HIST1H3B, HRAS, IDH1, IDH2, IKZF1, INPPL1, JAK1, KDM6A, KEAP1, KIT, KNSTRN, KRAS, MAP2K1, MAPK1, MAX, MED12, MET, MLH1, MSH2, MSH3, MSH6, MTOR, MYC, MYCN, MYD88, MYODI, NF1, NFE2L2, NOTCH1, NRAS, NTRK1, NTRK2, NTRK3, NUP93, PAK7, PDGFRA, PIK3CA, PIK3CB, PIK3R1, PIK3R2, PMS2, POLE, PPP2R1 A, PPP6C, PRKCI, PTCHI, PTEN, PTPN11, RAC1, RAFI, RBI, RET, RHOA, RIT1, ROS1, RRAS2, RXRA, SETD2, SF3B1, SMAD3, SMAD4, SMARCA4, SMARCB1, S0S1, SPOP, STAT3, STK11, STK19, TCF7L2, TGFBR1, TGFBR2, TP53, TP63, TSC1, TSC2, U2AF1, VHL, XPO1, and TERT

[0056] In any of the preceding embodiments of the systems described herein, the instructions further cause the processor to recommend an anticoagulant therapy to the cancer patient predicted to be at risk for cancer-associated VTE based on the predictor and the operating-point threshold. In some embodiments, the predictor comprises a cumulative incidence function (CIF) for cancer-associated VTE. Examples of anticoagulant therapy include, but are not limited to, apixaban, betrixaban, dabigatran, edoxaban, fondaparinux, heparin, rivaroxaban, warfarin, Xa inhibitors, statins, and enoxaparin. Examples of statins include, but are not limited to atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0057] Additionally or alternatively, in certain embodiments of the systems disclosed herein, the plurality of cancer types are selected from the group consisting of non-small cell lung cancer, breast cancer, pancreatic cancer, melanoma, retinoblastoma, prostate cancer, esophagogastric cancer, histiocytosis, germ cell tumor, endometrial cancer, small cell lung cancer, soft tissue sarcoma, Gastrointestinal Stromal Tumor, ovarian cancer, mature B-Cell neoplasms, small bowel cancer, renal cell carcinoma, thyroid cancer, ampullary cancer, appendiceal cancer, sellar tumor, uterine sarcoma, bone cancer, non-melanoma skin cancer, cervical cancer, mesothelioma, glioma, thymic tumor, gastrointestinal neuroendocrine tumor, salivary gland cancer, sex cord stromal tumor, anal cancer, mature T and NK neoplasms, peritoneal cancer, Head and neck cancer, choroid plexus tumor, leukemia, primary CNS melanocytic tumors, Myelodysplastic Syndromes, Peripheral Nervous System, mastocytosis, Wilms tumor, lymphatic cancer, vaginal cancer, Hodgkin lymphoma, adrenocortical carcinoma, brain tumors, embryonal tumors and Non-Hodgkin lymphoma.

[0058] In some embodiments, the cancer patient is chemotherapy -naive or has received/is receiving systemic chemotherapy.

[0059] In any and all embodiments of the systems disclosed herein, one or more of the plurality of features for each subject in the cohort are determined by assaying blood and/or sequencing tumor DNA.

[0060] In one aspect, the present disclosure provides a non-transitory computer-readable storage medium comprising instructions which, when executed by a processor of a machine learning system, configure the machine learning system to train a machine learning classifier to estimate risk of cancer-associated venous thromboembolism (VTE) in cancer patients, wherein the instructions are configured to cause the processor to: (a) receive data on a cohort of subjects, the subjects in the cohort having a plurality of cancer types; (b) generate a training dataset based on the received data, wherein the training dataset comprises a plurality of features for each subject in the cohort, the plurality of features comprising (i) cell free DNA concentration, (ii) maximum ctDNA VAF, (iii) ctDNA alterations in at least one cancer associated gene, and (iv) cancer type; and (c) apply a machine learning method to the training dataset to develop the machine learning classifier for estimating risk of cancer-associated VTE in cancer patients; wherein applying the machine learning method comprises: applying a machine learning technique to the training dataset; performing hyperparameter optimization to identify one or more machine learning models with an accuracy that exceeds an accuracy threshold for the machine learning classifier; and determining an optimal operating-point threshold based on optimization of sensitivity and specificity of the receiver operating characteristic (ROC) curves for the training dataset; wherein the machine learning classifier is configured to receive the plurality of features for cancer patients and generate predictors for risk of cancer-associated VTE in cancer patients. The subjects in the cohort may be chemotherapy-naive or may have received systemic chemotherapy. [0061] The machine learning technique may model survival outcomes with competing risks. In some embodiments, the machine learning technique is a random forest technique, and the one or more machine learning models are random forest models. Additionally or alternatively, in certain embodiments, the machine learning classifier is an ensemble learning random forest classifier.

[0062] Additionally or alternatively, in some embodiments, performing the hyperparameter optimization comprises performing an exhaustive grid search technique.

[0063] Additionally or alternatively, in some embodiments of the computer-readable storage medium disclosed herein, the at least one cancer associated gene is selected from the group consisting of AKT1, ALK, APC, AR, ARAF, ARID1A, ARID2, ATM, B2M, BCL2, BCOR, BRAF, BRCA1, BRCA2, CARD11, CBFB, CCND1, CDH1, CDK4, CDKN2A, CIC, CREBBP, CTCF, CTNNB1, DICER1, DIS3, DNMT3A, EGFR, EIF1AX, EP300, ERBB2, ERBB3, ERCC2, ESRI, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, FOXA1, FOXL2, FOXO1, FUBP1, GATA3, GNA11, GNAQ, GNAS, H3F3A, HIST1H3B, HRAS, IDH1, IDH2, IKZF1, INPPL1, JAK1, KDM6A, KEAP1, KIT, KNSTRN, KRAS, MAP2K1, MAPK1, MAX, MED12, MET, MLH1, MSH2, MSH3, MSH6, MTOR, MYC, MYCN, MYD88, MYODI, NF1, NFE2L2, NOTCH1, NRAS, NTRK1, NTRK2, NTRK3, NUP93, PAK7, PDGFRA, PIK3CA, PIK3CB, PIK3R1, PIK3R2, PMS2, POLE, PPP2R1 A, PPP6C, PRKCI, PTCHI, PTEN, PTPN11, RAC1, RAFI, RBI, RET, RHOA, RIT1, ROS1, RRAS2, RXRA, SETD2, SF3B1, SMAD3, SMAD4, SMARCA4, SMARCB1, S0S1, SPOP, STAT3, STK11, STK19, TCF7L2, TGFBR1, TGFBR2, TP53, TP63, TSC1, TSC2, U2AF1, VHL, XPO1, and TERT.

[0064] Additionally or alternatively, in some embodiments of the computer-readable storage medium disclosed herein, the plurality of features further comprises platelet count, hemoglobin levels, leukocyte counts, body mass index (BMI), administration of chemotherapy, age, time from cancer diagnosis, race, and metastatic sites of disease. Metastatic sites of disease may comprise one or more of adrenal gland, bone, brain, liver, lung, lymph, and pleura.

[0065] In any of the preceding embodiments of the computer-readable storage medium described herein, the instructions further cause the processor to apply the machine learning classifier to data on a cancer patient to generate a predictor, and determine whether the cancer patient is at risk for cancer-associated VTE based on the predictor and the operatingpoint threshold. In some embodiments, the predictor comprises a cumulative incidence function (CIF) for cancer-associated VTE.

[0066] Additionally or alternatively, in certain embodiments of the computer-readable storage medium disclosed herein, the plurality of cancer types are selected from the group consisting of non-small cell lung cancer, breast cancer, pancreatic cancer, melanoma, retinoblastoma, prostate cancer, esophagogastric cancer, histiocytosis, germ cell tumor, endometrial cancer, small cell lung cancer, soft tissue sarcoma, Gastrointestinal Stromal Tumor, ovarian cancer, mature B-Cell neoplasms, small bowel cancer, renal cell carcinoma, thyroid cancer, ampullary cancer, appendiceal cancer, sellar tumor, uterine sarcoma, bone cancer, non-melanoma skin cancer, cervical cancer, mesothelioma, glioma, thymic tumor, gastrointestinal neuroendocrine tumor, salivary gland cancer, sex cord stromal tumor, anal cancer, mature T and NK neoplasms, peritoneal cancer, Head and neck cancer, choroid plexus tumor, leukemia, primary CNS melanocytic tumors, Myelodysplastic Syndromes, Peripheral Nervous System, mastocytosis, Wilms tumor, lymphatic cancer, vaginal cancer, Hodgkin lymphoma, adrenocortical carcinoma, brain tumors, embryonal tumors and NonHodgkin lymphoma.

[0067] In any of the preceding embodiments of the computer-readable storage medium described herein, the instructions further cause the processor to recommend an anticoagulant therapy to the cancer patient predicted to be at risk for cancer-associated VTE based on the predictor and the operating-point threshold. Examples of anticoagulant therapy include, but are not limited to, apixaban, betrixaban, dabigatran, edoxaban, fondaparinux, heparin, rivaroxaban, warfarin, Xa inhibitors, statins, and enoxaparin. Examples of statins include, but are not limited to atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0068] In some embodiments, the cancer patient is chemotherapy-naive or has received/is receiving systemic chemotherapy.

[0069] In another aspect, the present disclosure provides a non-transitory computer- readable storage medium comprising instructions which, when executed by a processor of a computing system, configure the computing system to estimate risk of cancer-associated venous thromboembolism (VTE) in a cancer patient, wherein the instructions are configured to cause the processor to: receive patient data corresponding to a plurality of features for the cancer patient; apply a machine learning classifier to the patient data to generate a predictor; and determine whether the cancer patient is at risk for cancer-associated VTE based on the predictor and an operating-point threshold, wherein the classifier is trained by: (a) receiving cohort data on a cohort of subjects, the subjects in the cohort having a plurality of cancer types; (b) generating a training dataset based on the received cohort data, wherein the training dataset comprises the plurality of features for each subject in the cohort, wherein the plurality of features comprises (i) cell free DNA concentration, (ii) maximum ctDNA VAF, (iii) ctDNA alterations in at least one cancer associated gene, and (iv) cancer type; and (c) applying a machine learning method to the training dataset to develop the machine learning classifier for estimating risk of cancer-associated VTE, wherein applying the machine learning method comprises: applying a machine learning technique to the training dataset; performing hyperparameter optimization to identify one or more machine learning models with an accuracy that exceeds an accuracy threshold for the machine learning classifier; and determining the optimal operating-point threshold based on optimization of sensitivity and specificity of the receiver operating characteristic (ROC) curves for the training dataset; wherein the machine learning classifier is configured to receive the plurality of features for cancer patients and generate predictors for risk of cancer-associated VTE in cancer patients.

[0070] The machine learning technique may model survival outcomes with competing risks. In some embodiments, the machine learning technique is a random forest technique, and the one or more machine learning models are random forest models. Additionally or alternatively, in certain embodiments, the machine learning classifier is an ensemble learning random forest classifier.

[0071] Additionally or alternatively, in some embodiments, performing the hyperparameter optimization comprises performing an exhaustive grid search technique.

[0072] Additionally or alternatively, in some embodiments of the computer-readable storage medium disclosed herein, the at least one cancer associated gene is selected from the group consisting of AKT1, ALK, APC, AR, ARAF, ARID1A, ARID2, ATM, B2M, BCL2, BCOR, BRAF, BRCA1, BRCA2, CARD11, CBFB, CCND1, CDH1, CDK4, CDKN2A, CIC, CREBBP, CTCF, CTNNB1, DICER1, DIS3, DNMT3A, EGFR, EIF1AX, EP300, ERBB2, ERBB3, ERCC2, ESRI, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, F0XA1, FOXL2, FOXO1, FUBP1, GATA3, GNA11, GNAQ, GNAS, H3F3A, HIST1H3B, HRAS, IDH1, IDH2, IKZF1, INPPL1, JAK1, KDM6A, KEAP1, KIT, KNSTRN, KRAS, MAP2K1, MAPK1, MAX, MED12, MET, MLH1, MSH2, MSH3, MSH6, MTOR, MYC, MYCN, MYD88, MYODI, NF1, NFE2L2, NOTCH1, NRAS, NTRK1, NTRK2, NTRK3, NUP93, PAK7, PDGFRA, PIK3CA, PIK3CB, PIK3R1, PIK3R2, PMS2, POLE, PPP2R1 A, PPP6C, PRKCI, PTCHI, PTEN, PTPN11, RAC1, RAFI, RBI, RET, RHOA, RIT1, ROS1, RRAS2, RXRA, SETD2, SF3B1, SMAD3, SMAD4, SMARCA4, SMARCB1, SOS1, SPOP, STAT3, STK11, STK19, TCF7L2, TGFBR1, TGFBR2, TP53, TP63, TSC1, TSC2, U2AF1, VHL, XPO1, and TERT.

[0073] Additionally or alternatively, in some embodiments of the computer-readable storage medium disclosed herein, the plurality of features further comprises platelet count, hemoglobin levels, leukocyte counts, body mass index (BMI), administration of chemotherapy, age, time from cancer diagnosis, race, and metastatic sites of disease.

[0074] In any of the preceding embodiments of the computer-readable storage medium described herein, the instructions further cause the processor to recommend an anticoagulant therapy to the cancer patient predicted to be at risk for cancer-associated VTE based on the predictor and the operating-point threshold. In some embodiments, the predictor comprises a cumulative incidence function (CIF) for cancer-associated VTE. Examples of anticoagulant therapy include, but are not limited to, apixaban, betrixaban, dabigatran, edoxaban, fondaparinux, heparin, rivaroxaban, warfarin, Xa inhibitors, statins, and enoxaparin. Examples of statins include, but are not limited to atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0075] Additionally or alternatively, in certain embodiments of the computer-readable storage medium disclosed herein, the plurality of cancer types are selected from the group consisting of non-small cell lung cancer, breast cancer, pancreatic cancer, melanoma, retinoblastoma, prostate cancer, esophagogastric cancer, histiocytosis, germ cell tumor, endometrial cancer, small cell lung cancer, soft tissue sarcoma, Gastrointestinal Stromal Tumor, ovarian cancer, mature B-Cell neoplasms, small bowel cancer, renal cell carcinoma, thyroid cancer, ampullary cancer, appendiceal cancer, sellar tumor, uterine sarcoma, bone cancer, non-melanoma skin cancer, cervical cancer, mesothelioma, glioma, thymic tumor, gastrointestinal neuroendocrine tumor, salivary gland cancer, sex cord stromal tumor, anal cancer, mature T and NK neoplasms, peritoneal cancer, Head and neck cancer, choroid plexus tumor, leukemia, primary CNS melanocytic tumors, Myelodysplastic Syndromes, Peripheral Nervous System, mastocytosis, Wilms tumor, lymphatic cancer, vaginal cancer, Hodgkin lymphoma, adrenocortical carcinoma, brain tumors, embryonal tumors and NonHodgkin lymphoma.

[0076] In some embodiments, the cancer patient is chemotherapy -naive or has received/is receiving systemic chemotherapy.

[0077] In any of the preceding embodiments of the computer-readable storage medium disclosed herein, one or more of the plurality of features for the cancer patient are determined by assaying blood and/or sequencing tumor DNA.

BRIEF DESCRIPTION OF THE DRAWINGS

[0078] FIG. 1 shows the number of ctDNA alterations within the patient cohort (n=480).

[0079] FIG. 2 shows the correlation between patients with ctDNA alteration and risk for CAT.

[0080] FIG. 3 shows the relationship between alterations in specific individual cancer genes and risk for CAT.

[0081] FIG. 4 shows the correlation between CAT risk and ctDNA variant allele fraction (VAF).

[0082] FIG. 5 demonstrates that ctDNA levels are not correlated with Khorana Score or its individual components.

[0083] FIG. 6 demonstrates that ctDNA predicts CAT risk in a manner that is orthogonal to the Khorana Score.

[0084] FIGs. 7A-7D demonstrate that ctDNA is associated with CAT risk. FIG. 7A: Aalen-Johansen survival curves for CAT from time of plasma draw with death as a competing risk in the MSK-ACCESS cohort. FIG. 7B: Survival curves with ctDNA+ cohort stratified by VAF quartile. FIG. 7C: Cox proportional hazard for CAT if ctDNA+ by cancer type. Number of patients per cancer type shown in FIG. 11. FIG. 7D: Cox proportional hazard for CAT if ctDNA+ for the listed genes adjusted (in a multivariate Cox proportional hazards model) for the cancer types in FIG. 7C. [0085] FIG. 8A: Multivariate Cox proportional hazards model with the listed variables. +ctDNA = any ctDNA mutation or copy number change. FIG. 8B: Random survival forest trained on only listed subset of variables (KS=Khorana Score. MSK-ACCESS=circulating tumor (ct)DNA variant allele fraction, cell-free (cf)DNA concentration, detection of genelevel alterations, Demographics+ = Sex, self-reported race (White, Asian, Black or Other), and closest albumin level to ctDNA draw, All=all variables in separate categories combined. C-index reported to time of CAT from time of ctDNA draw in 5-fold cross- validation experiments. Error bars are 95% confidence intervals. FIG. 8C: Permutation variable importances (for all variables with >0.001 importance) in the “All” RSF in FIG. 8B. FIG. 8D: Aalen-Johansen survival curves for CAT from time of plasma draw with death as a competing risk stratified by the risk decile from the ’’All” RSF in FIG. 8B.

[0086] FIGs. 9A-9B: Assessing the potential benefit of previous anti coagulation therapy for preventing CAT stratified by ctDNA presence in a real-world dataset. Aalen- Johansen survival curves for CAT from time of plasma draw with death as a competing risk with or without previous Xa inhibition in ctDNA+ (FIG. 9A) and ctDNA- (FIG. 9B) patients.

[0087] FIGs. 10A-10B: Assessing the potential benefit of previous statin use for preventing CAT stratified by ctDNA presence in a real-world dataset. Aalen-Johansen survival curves for CAT from time of plasma draw with death as a competing risk with or without previous statin use in ctDNA+ (FIG. 10A) and ctDNA- (FIG. 10B) patients.

[0088] FIG. 11 shows the number of patients with each cancer type included in the pancancer study described herein.

[0089] FIG. 12A is a block diagram depicting an embodiment of a network environment comprising a client device in communication with server device.

[0090] FIG. 12B is a block diagram depicting a cloud computing environment comprising client device in communication with cloud service providers.

[0091] FIGs. 12C and 12D are block diagrams depicting embodiments of computing devices useful in connection with the methods and systems described herein.

[0092] FIG. 13 depicts a system that includes a computing device and a sample processing system according to various potential embodiments. [0093] FIG. 14 shows the AUC metrics for the Khorana Score, Liquid biopsy and combined models.

DETAILED DESCRIPTION

[0094] It is to be appreciated that certain aspects, modes, embodiments, variations and features of the present methods are described below in various levels of detail in order to provide a substantial understanding of the present technology. It is to be understood that the present disclosure is not limited to particular uses, methods, reagents, compounds, compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0095] CAT is an important complication of cancer for which effective pharmacological prophylaxis methods exist. However, currently available prediction rules have limited accuracy in stratifying patients for CAT risk. Accordingly, approaches to enhance the overall benefit of CAT prophylaxis in cancer patients will be contingent on improved methods for predicting risk. The present disclosure demonstrates that ctDNA is a useful biomarker for accurately predicting the risk of cancer-associated thromboembolism in lung cancer patients. These results were unexpected because the methods of the present technology do not correlate with/are not dependent on conventional clinical prediction scores (e.g., Khorana Score) for predicting CAT risk. Indeed, ctDNA predicts CAT risk in a way that is orthogonal/statistically independent to the Khorana Score.

Definitions

[0096] Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this technology belongs. As used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise. For example, reference to “a cell” includes a combination of two or more cells, and the like. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, analytical chemistry and nucleic acid chemistry and hybridization described below are those well-known and commonly employed in the art. [0097] As used herein, the term “about” in reference to a number is generally taken to include numbers that fall within a range of 1%, 5%, or 10% in either direction (greater than or less than) of the number unless otherwise stated or otherwise evident from the context (except where such number would be less than 0% or exceed 100% of a possible value).

[0098] The term “adapter” refers to a short, chemically synthesized, nucleic acid sequence which can be used to ligate to the end of a nucleic acid sequence in order to facilitate attachment to another molecule. The adapter can be single-stranded or doublestranded. An adapter can incorporate a short (typically less than 50 base pairs) sequence useful for PCR amplification or sequencing.

[0099] As used herein, the “administration” of an agent or drug to a subject includes any route of introducing or delivering to a subject a compound to perform its intended function. Administration can be carried out by any suitable route, including but not limited to, orally, intranasally, parenterally (intravenously, intramuscularly, intraperitoneally, or subcutaneously), rectally, intrathecally, intratumorally or topically. Administration includes self-administration and the administration by another.

[0100] As used herein, an “alteration” of a gene or gene product (e.g., a marker gene or gene product) refers to the presence of a mutation or mutations within the gene or gene product, e.g., a mutation, which affects the quantity or activity of the gene or gene product, as compared to the normal or wild-type gene. The genetic alteration can result in changes in the quantity, structure, and/or activity of the gene or gene product in a cancer tissue or cancer cell, as compared to its quantity, structure, and/or activity, in a normal or healthy tissue or cell (e.g., a control). For example, an alteration which is predictive of CAT can have an altered nucleotide sequence (e.g., a mutation), amino acid sequence, chromosomal translocation, intra-chromosomal inversion, copy number, expression level, protein level, protein activity, in a cancer tissue or cancer cell, as compared to a normal, healthy tissue or cell. Exemplary mutations include, but are not limited to, point mutations (e.g., silent, missense, or nonsense), deletions, insertions, inversions, linking mutations, duplications, translocations, inter- and intra-chromosomal rearrangements. Mutations can be present in the coding or non-coding region of the gene.

[0101] As used herein, “C-index” refers to the proportion of all pairs of patients with usable data in whom the predicted and observed outcomes are ranked appropriately. A higher c-index indicates a better-performing model in that it more correctly ranks relative patient risk (in this case for CAT). See, e.g., Harrell et al JAMA 247( 18):2543-2546 (1982).

[0102] The terms “cancer” or “tumor” are used interchangeably and refer to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features. Cancer cells are often in the form of a tumor, but such cells can exist alone within an animal, or can be a non-tumorigenic cancer cell. As used herein, the term “cancer” includes premalignant, as well as malignant cancers. In some embodiments, the cancer is bladder cancer, breast cancer, colorectal cancer, esophagogastric cancer, gynecological cancer (e.g., uterine cancer, cervical cancer, ovarian cancer), head and neck cancer, hepatobiliary cancer, high-grade glioma, low-grade glioma, lung cancer, melanoma, pancreatic cancer, prostate cancer, renal cancer, or soft tissue sarcoma.

[0103] As used herein, a "control" is an alternative sample used in an experiment for comparison purpose. A control can be "positive" or "negative." For example, where the purpose of the experiment is to determine a correlation of the efficacy of a therapeutic agent for the treatment for a particular type of disease, a positive control (a compound or composition known to exhibit the desired therapeutic effect) and a negative control (a subject or a sample that does not receive the therapy or receives a placebo) are typically employed.

[0104] As used herein, a “deletion” refers to a mutation (or a genetic alteration) in which part of a DNA sequence at a chromosome location is absent or lost compared to that observed in a reference genome. A deletion may occur within a gene or may encompass one or more genes. A “homozygous deletion” refers to the loss of both alleles of a gene within a genome. A homozygous deletion may comprise a partial or complete loss of each copy (maternal and paternal) of the gene sequence.

[0105] “Detecting” as used herein refers to determining the presence of a mutation or alteration in a nucleic acid of interest in a sample. Detection does not require the method to provide 100% sensitivity. Analysis of nucleic acid markers can be performed using techniques known in the art including, but not limited to, sequence analysis, and electrophoretic analysis. Non-limiting examples of sequence analysis include Maxam- Gilbert sequencing, Sanger sequencing, capillary array DNA sequencing, thermal cycle sequencing (Sears et al., Biotechniques, 13:626-633 (1992)), solid-phase sequencing (Zimmerman et al., Methods Mol. CellBiol, 3:39-42 (1992)), sequencing with mass spectrometry such as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS; Fu et al, Nat. Biotechnol, 16:381-384 (1998)), and sequencing by hybridization. Chee et al., Science, 274:610-614 (1996); Drmanac et al., Science, 260: 1649-1652 (1993); Drmanac et al., Nat. Biotechnol, 16:54-58 (1998). Nonlimiting examples of electrophoretic analysis include slab gel electrophoresis such as agarose or polyacrylamide gel electrophoresis, capillary electrophoresis, and denaturing gradient gel electrophoresis. Additionally, next generation sequencing methods can be performed using commercially available kits and instruments from companies such as the Life Technologies/Ion Torrent PGM or Proton, the Illumina HiSEQ or MiSEQ, and the Roche/454 next generation sequencing system.

[0106] As used herein, the term “effective amount” refers to a quantity sufficient to achieve a desired therapeutic and/or prophylactic effect, e.g., an amount which results in the prevention of, or a decrease in a disease or condition described herein or one or more signs or symptoms associated with a disease or condition described herein. In the context of therapeutic or prophylactic applications, the amount of a composition administered to the subject will vary depending on the composition, the degree, type, and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. The compositions can also be administered in combination with one or more additional therapeutic compounds. In the methods described herein, the therapeutic compositions may be administered to a subject having one or more signs or symptoms of a disease or condition described herein. As used herein, a "therapeutically effective amount" of a composition refers to composition levels in which the physiological effects of a disease or condition are ameliorated or eliminated. A therapeutically effective amount can be given in one or more administrations.

[0107] As used herein, “expression” includes one or more of the following: transcription of the gene into precursor mRNA; splicing and other processing of the precursor mRNA to produce mature mRNA; mRNA stability; translation of the mature mRNA into protein (including codon usage and tRNA availability); and glycosylation and/or other modifications of the translation product, if required for proper expression and function.

[0108] Gene” as used herein refers to a DNA sequence that comprises regulatory and coding sequences necessary for the production of an RNA, which may have a non-coding function (e.g., a ribosomal or transfer RNA) or which may include a polypeptide or a polypeptide precursor. The RNA or polypeptide may be encoded by a full length coding sequence or by any portion of the coding sequence so long as the desired activity or function is retained. Although a sequence of the nucleic acids may be shown in the form of DNA, a person of ordinary skill in the art recognizes that the corresponding RNA sequence will have a similar sequence with the thymine being replaced by uracil, i.e., "T" is replaced with "U."

[0109] “Next-generation sequencing or NGS” as used herein, refers to any sequencing method that determines the nucleotide sequence of either individual nucleic acid molecules (e.g., in single molecule sequencing) or clonally expanded proxies for individual nucleic acid molecules in a high throughput parallel fashion (e.g., greater than 10 ³ , 10 ⁴ , 10 ⁵ or more molecules are sequenced simultaneously). In one embodiment, the relative abundance of the nucleic acid species in the library can be estimated by counting the relative number of occurrences of their cognate sequences in the data generated by the sequencing experiment. Next generation sequencing methods are known in the art, and are described, e.g., in Metzker, M. Nature Biotechnology Reviews 11 :31-46 (2010).

[0110] As used herein, a “sample” refers to a substance that is being assayed for the presence of a mutation in a nucleic acid of interest. Processing methods to release or otherwise make available a nucleic acid for detection are well known in the art and may include steps of nucleic acid manipulation. A biological sample may be a body fluid or a tissue sample. In some cases, a biological sample may consist of or comprise blood, plasma, sera, urine, feces, epidermal sample, vaginal sample, skin sample, cheek swab, sperm, amniotic fluid, cultured cells, bone marrow sample, tumor biopsies, aspirate and/or chorionic villi, cultured cells, and the like. Fresh, fixed or frozen tissues may also be used. In one embodiment, the sample is preserved as a frozen sample or as formaldehyde- or paraformaldehyde-fixed paraffin-embedded (FFPE) tissue preparation. For example, the sample can be embedded in a matrix, e.g., an FFPE block or a frozen sample. Whole blood samples of about 0.5 to 5 ml collected with EDTA, ACD or heparin as anti -coagulant are suitable.

[0111] As used herein, the terms “subject”, “patient”, or “individual” can be an individual organism, a vertebrate, a mammal, or a human. In some embodiments, the subject, patient or individual is a human.

[0112] As used herein, the term “therapeutic agent” is intended to mean a compound that, when present in an effective amount, produces a desired therapeutic effect on a subject in need thereof.

[0113] “Treating” or “treatment” as used herein covers the treatment of a disease or disorder described herein, in a subject, such as a human, and includes: (i) inhibiting a disease or disorder, z.e., arresting its development; (ii) relieving a disease or disorder, z.e., causing regression of the disorder; (iii) slowing progression of the disorder; and/or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the disease or disorder. In some embodiments, treatment means that the symptoms associated with the disease are, e.g., alleviated, reduced, cured, or placed in a state of remission.

[0114] The terms “variant allele fraction,” “VAF,” “mutant allele fraction” or “MAF” refer to fractions of a mutant allele over the total number of mutant (alternate allele) plus wild-type alleles (reference allele). ctDNA VAF represents %ctDNA alteration reported as percentage and computed as the number of mutated DNA molecules divided by the total number (mutated plus wild-type) of DNA fragments at that allele. Most of the cell-free DNA is wild-type (germline); therefore, the median VAF of somatic alterations is <0.5%.

[0115] It is also to be appreciated that the various modes of treatment of disorders as described herein are intended to mean “substantial,” which includes total but also less than total treatment, and wherein some biologically or medically relevant result is achieved. The treatment may be a continuous prolonged treatment for a chronic disease or a single, or few time administrations for the treatment of an acute condition.

Methods for Detecting Polynucleotides Associated with Elevated VTE Risk

[0116] Polynucleotides associated with elevated VTE risk may be detected by a variety of methods known in the art. Non-limiting examples of detection methods are described below. The detection assays in the methods of the present technology may include purified or isolated DNA (genomic or cDNA), RNA or protein or the detection step may be performed directly from a biological sample without the need for further DNA, RNA or protein purification/isolation.

Nucleic Acid Ampli fication and/or Detection

[0117] Polynucleotides associated with elevated VTE risk can be detected by the use of nucleic acid amplification techniques that are well known in the art. The starting material may be genomic DNA, cDNA, RNA, ctDNA, cfDNA, or mRNA. Nucleic acid amplification can be linear or exponential. Specific variants or mutations may be detected by the use of amplification methods with the aid of oligonucleotide primers or probes designed to interact with or hybridize to a particular target sequence in a specific manner, thus amplifying only the target variant.

[0118] Non-limiting examples of nucleic acid amplification techniques include polymerase chain reaction (PCR), real-time quantitative PCR (qPCR), digital PCR (dPCR), reverse transcriptase polymerase chain reaction (RT-PCR), nested PCR, ligase chain reaction (see Abravaya, K. et al., Nucleic Acids Res. (1995), 23:675-682), branched DNA signal amplification (see Urdea, M. S. et al., AIDS (1993), 7(suppl 2):S11- S14), amplifiable RNA reporters, Q-beta replication, transcription-based amplification, boomerang DNA amplification, strand displacement activation, cycling probe technology, isothermal nucleic acid sequence based amplification (NASBA) (see Kievits, T. et al., J Virological Methods (1991), 35:273-286), Invader Technology, next-generation sequencing technology or other sequence replication assays or signal amplification assays.

[0119] Primers'. Oligonucleotide primers for use in amplification methods can be designed according to general guidance well known in the art as described herein, as well as with specific requirements as described herein for each step of the particular methods described. In some embodiments, oligonucleotide primers for cDNA synthesis and PCR are 10 to 100 nucleotides in length, preferably between about 15 and about 60 nucleotides in length, more preferably 25 and about 50 nucleotides in length, and most preferably between about 25 and about 40 nucleotides in length.

[0120] T _m of a polynucleotide affects its hybridization to another polynucleotide (e.g., the annealing of an oligonucleotide primer to a template polynucleotide). In certain embodiments of the disclosed methods, the oligonucleotide primer used in various steps selectively hybridizes to a target template or polynucleotides derived from the target template (z.e., first and second strand cDNAs and amplified products). Typically, selective hybridization occurs when two polynucleotide sequences are substantially complementary (at least about 65% complementary over a stretch of at least 14 to 25 nucleotides, preferably at least about 75%, more preferably at least about 90% complementary). See Kanehisa, M., Polynucleotides Res. (1984), 12:203, incorporated herein by reference. As a result, it is expected that a certain degree of mismatch at the priming site is tolerated. Such mismatch may be small, such as a mono-, di- or tri -nucleotide. In certain embodiments, 100% complementarity exists.

[0121] Probes'. Probes are capable of hybridizing to at least a portion of the nucleic acid of interest or a reference nucleic acid (z.e., wild-type sequence). Probes may be an oligonucleotide, artificial chromosome, fragmented artificial chromosome, genomic nucleic acid, fragmented genomic nucleic acid, RNA, recombinant nucleic acid, fragmented recombinant nucleic acid, peptide nucleic acid (PNA), locked nucleic acid, oligomer of cyclic heterocycles, or conjugates of nucleic acid. Probes may be used for detecting and/or capturing/purifying a nucleic acid of interest.

[0122] Typically, probes can be about 10 nucleotides, about 20 nucleotides, about 25 nucleotides, about 30 nucleotides, about 35 nucleotides, about 40 nucleotides, about 50 nucleotides, about 60 nucleotides, about 75 nucleotides, or about 100 nucleotides long. However, longer probes are possible. Longer probes can be about 200 nucleotides, about 300 nucleotides, about 400 nucleotides, about 500 nucleotides, about 750 nucleotides, about 1,000 nucleotides, about 1,500 nucleotides, about 2,000 nucleotides, about 2,500 nucleotides, about 3,000 nucleotides, about 3,500 nucleotides, about 4,000 nucleotides, about 5,000 nucleotides, about 7,500 nucleotides, or about 10,000 nucleotides long.

[0123] Probes may also include a detectable label or a plurality of detectable labels. The detectable label associated with the probe can generate a detectable signal directly. Additionally, the detectable label associated with the probe can be detected indirectly using a reagent, wherein the reagent includes a detectable label, and binds to the label associated with the probe.

[0124] In some embodiments, detectably labeled probes can be used in hybridization assays including, but not limited to Northern blots, Southern blots, microarray, dot or slot blots, and in situ hybridization assays such as fluorescent in situ hybridization (FISH) to detect a target nucleic acid sequence within a biological sample. Certain embodiments may employ hybridization methods for measuring expression of a polynucleotide gene product, such as mRNA. Methods for conducting polynucleotide hybridization assays have been well developed in the art. Hybridization assay procedures and conditions will vary depending on the application and are selected in accordance with the general binding methods known including those referred to in: Maniatis et al. Molecular Cloning: A Laboratory Manual (2nd Ed. Cold Spring Harbor, N.Y., 1989); Berger and Kimmel Methods in Enzymology, Vol. 152, Guide to Molecular Cloning Techniques (Academic Press, Inc., San Diego, Calif, 1987); Young and Davis, PNAS. 80: 1194 (1983).

[0125] Detectably labeled probes can also be used to monitor the amplification of a target nucleic acid sequence. In some embodiments, detectably labeled probes present in an amplification reaction are suitable for monitoring the amount of amplicon(s) produced as a function of time. Examples of such probes include, but are not limited to, the 5'- exonuclease assay (TAQMAN® probes described herein (see also U.S. Pat. No. 5,538,848) various stem-loop molecular beacons (see for example, U.S. Pat. Nos. 6,103,476 and 5,925,517 and Tyagi and Kramer, 1996, Nature Biotechnology 14:303- 308), stemless or linear beacons (see, e.g., WO 99/21881), PNA Molecular Beacons™ (see, e.g., U.S. Pat. Nos. 6,355,421 and 6,593,091), linear PNA beacons (see, for example, Kubista et al., 2001, SPIE 4264:53-58), non-FRET probes (see, for example, U.S. Pat. No. 6,150,097), Sunrise®/ Amplifluor™ probes (U.S. Pat. No. 6,548,250), stem-loop and duplex Scorpion probes (Solinas et al., 2001, Nucleic Acids Research 29:E96 and U.S. Pat. No. 6,589,743), bulge loop probes (U.S. Pat. No. 6,590,091), pseudo knot probes (U.S. Pat. No. 6,589,250), cyclicons (U.S. Pat. No. 6,383,752), MGB Eclipse™ probe (Epoch Biosciences), hairpin probes (U.S. Pat. No. 6,596,490), peptide nucleic acid (PNA) light-up probes, selfassembled nanoparticle probes, and ferrocene-modified probes described, for example, in U.S. Pat. No. 6,485,901 ; Mhlanga et al., 2001, Methods 25:463-471 ; Whitcombe et al., 1999, Nature Biotechnology. 17:804-807; Isacsson et al., 2000, Molecular Cell Probes.

14:321-328; Svanvik et al., 2000, Anal Biochem. 281 :26-35; Wolffs et al., 2001, Biotechniques 766: 769-771 ; Tsourkas et al., 2002, Nucleic Acids Research. 30:4208-4215; Riccelli et al., 2002, Nucleic Acids Research 30:4088-4093; Zhang et al., 2002 Shanghai. 34:329-332; Maxwell et al., 2002, J. Am. Chem. Soc. 124:9606-9612; Broude et al., 2002, Trends Biotechnol . 20:249-56; Huang et al., 2002, Chem. Res. Toxicol. 15: 118- 126; and Yu et al., 2001, J. Am. Chem. Soc 14: 11155-11161.

[0126] In some embodiments, the detectable label is a fluorophore. Suitable fluorescent moieties include but are not limited to the following fluorophores working individually or in combination: 4-acetamido-4'-isothiocyanatostilbene- 2,2'disulfonic acid; acridine and derivatives: acridine, acridine isothiocyanate; Alexa Fluors: Alexa Fluor® 350, Alexa Fluor® 488, Alexa Fluor® 546, Alexa Fluor® 555, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 647 (Molecular Probes); 5-(2- aminoethyl)aminonaphthalene-l -sulfonic acid (EDANS); 4-amino-N-[3- vinylsulfonyl)phenyl]naphthalimide-3,5 disulfonate (Lucifer Yellow VS); N-(4-anilino-l- naphthyl)maleimide; anthranilamide; Black Hole Quencher™ (BHQ™) dyes (biosearch Technologies); BODIPY dyes: BODIPY® R-6G, BOPIPY® 530/550, BODIPY® FL; Brilliant Yellow; coumarin and derivatives: coumarin, 7-amino-4- methylcoumarin (AMC, Coumarin 120),7-amino-4-trifluoromethylcouluarin (Coumarin 151); Cy2®, Cy3®, Cy3.5®, Cy5®, Cy5.5®; cyanosine; 4',6-diaminidino-2-phenylindole (DAP I); 5', 5"-dibromopyrogallol- sulfonephthalein (Bromopyrogallol Red); 7- diethylamino-3-(4'-isothiocyanatophenyl)-4- methylcoumarin; di ethylenetriamine pentaacetate; 4,4'-diisothiocyanatodihydro-stilbene-2,2'- disulfonic acid; 4,4'- diisothiocyanatostilbene-2,2'-disulfonic acid; 5- [dimethylamino]naphthalene-l -sulfonyl chloride (DNS, dansyl chloride); 4-(4'- dimethylaminophenylazo)benzoic acid (DABCYL);

4-dimethylaminophenylazophenyl-4'- isothiocyanate (DABITC); Eclipse™ (Epoch Biosciences Inc.); eosin and derivatives: eosin, eosin isothiocyanate; erythrosin and derivatives: erythrosin B, erythrosin isothiocyanate; ethidium; fluorescein and derivatives:

5-carboxyfluorescein (FAM), 5-(4,6-dichlorotriazin-2- yl)amino fluorescein (DTAF), 2', 7'- dimethoxy-4'5'-dichloro-6-carboxyfluorescein (JOE), fluorescein, fluorescein isothiocyanate (FITC), hexachloro-6-carboxyfluorescein (HEX), QFITC (XRITC), tetrachlorofluorescem (TET); fiuorescamine; IR144; IR1446; lanthamide phosphors;

Malachite Green isothiocyanate; 4-methylumbelliferone; ortho cresolphthalein; nitrotyrosine; pararosaniline; Phenol Red; B-phycoerythrin, R-phycoerythrin; allophycocyanin; o-phthaldialdehyde; Oregon Green®; propidium iodide; pyrene and derivatives: pyrene, pyrene butyrate, succinimidyl 1 -pyrene butyrate; QSY® 7; QSY® 9; QSY® 21; QSY® 35 (Molecular Probes); Reactive Red 4 (Cibacron®Brilliant Red 3B-A); rhodamine and derivatives: 6-carboxy-X-rhodamine (ROX), 6-carboxyrhodamine (R6G), lissamine rhodamine B sulfonyl chloride, rhodamine (Rhod), rhodamine B, rhodamine 123, rhodamine green, rhodamine X isothiocyanate, riboflavin, rosolic acid, sulforhodamine B, sulforhodamine 101, sulfonyl chloride derivative of sulforhodamine 101 (Texas Red); terbium chelate derivatives; N,N,N',N'-tetramethyl-6-carboxyrhodamine (TAMRA); tetramethyl rhodamine; tetramethyl rhodamine isothiocyanate (TRITC); and VIC®.

Detector probes can also comprise sulfonate derivatives of fluorescenin dyes with S03 instead of the carboxylate group, phosphoramidite forms of fluorescein, phosphoramidite forms of CY 5 (commercially available for example from Amersham).

[0127] Detectably labeled probes can also include quenchers, including without limitation black hole quenchers (Biosearch), Iowa Black (IDT), QSY quencher (Molecular Probes), and Dabsyl and Dabcel sulfonate/carboxylate Quenchers (Epoch).

[0128] Detectably labeled probes can also include two probes, wherein for example a fluorophore is on one probe, and a quencher is on the other probe, wherein hybridization of the two probes together on a target quenches the signal, or wherein hybridization on the target alters the signal signature via a change in fluorescence.

[0129] In some embodiments, interchelating labels such as ethidium bromide, SYBR® Green I (Molecular Probes), and PicoGreen® (Molecular Probes) are used, thereby allowing visualization in real-time, or at the end point, of an amplification product in the absence of a detector probe. In some embodiments, real-time visualization may involve the use of both an intercalating detector probe and a sequence-based detector probe. In some embodiments, the detector probe is at least partially quenched when not hybridized to a complementary sequence in the amplification reaction, and is at least partially unquenched when hybridized to a complementary sequence in the amplification reaction.

[0130] In some embodiments, the amount of probe that gives a fluorescent signal in response to an excited light typically relates to the amount of nucleic acid produced in the amplification reaction. Thus, in some embodiments, the amount of fluorescent signal is related to the amount of product created in the amplification reaction. In such embodiments, one can therefore measure the amount of amplification product by measuring the intensity of the fluorescent signal from the fluorescent indicator.

[0131] Primers or probes may be designed to selectively hybridize to any portion of a nucleic acid sequence encoding a polypeptide selected from among AKT1, ALK, B2M, BRAF, EGFR, ERBB2 (HER2), FGFR2, FGFR3, KEAP1, KRAS, MAP2K1 (MEK1), MET, NRAS, PIK3CA, RET, R0S1, STK11, TP53, NTRK1, FGFR1, MYC, PTEN, and RICTOR. Exemplary nucleic acid sequences of the human orthologs of these genes are provided below:

[0132] NM_005163.2 Homo sapiens AKT serine/threonine kinase 1 (AKT1), transcript variant 1, mRNA (SEQ ID NO: 1)

TAATTATGGGTCTGTAACCACCCTGGACTGGGTGCTCCTCACTGACGGACTTGTCTG AACCTCTCTTTGT CTCCAGCGCCCAGCACTGGGCCTGGCAAAACCTGAGACGCCCGGTACATGTTGGCCAAAT GAATGAACCA GATTCAGACCGGCAGGGGCGCTGTGGTTTAGGAGGGGCCTGGGGTTTCTCCCAGGAGGTT TTTGGGCTTG CGCTGGAGGGCTCTGGACTCCCGTTTGCGCCAGTGGCCTGCATCCTGGTCCTGTCTTCCT CATGTTTGAA TTTCTTTGCTTTCCTAGTCTGGGGAGCAGGGAGGAGCCCTGTGCCCTGTCCCAGGATCCA TGGGTAGGAA CACCATGGACAGGGAGAGCAAACGGGGCCATCTGTCACCAGGGGCTTAGGGAAGGCCGAG CCAGCCTGGG TCAAAGAAGTCAAAGGGGCTGCCTGGAGGAGGCAGCCTGTCAGCTGGTGCATCAGAGGCT GTGGCCAGGC CAGCTGGGCTCGGGGAGCGCCAGCCTGAGAGGAGCGCGTGAGCGTCGCGGGAGCCTCGGG CACCATGAGC GACGTGGCTATTGTGAAGGAGGGTTGGCTGCACAAACGAGGGGAGTACATCAAGACCTGG CGGCCACGCT ACTTCCTCCTCAAGAATGATGGCACCTTCATTGGCTACAAGGAGCGGCCGCAGGATGTGG ACCAACGTGA GGCTCCCCTCAACAACTTCTCTGTGGCGCAGTGCCAGCTGATGAAGACGGAGCGGCCCCG GCCCAACACC TTCATCATCCGCTGCCTGCAGTGGACCACTGTCATCGAACGCACCTTCCATGTGGAGACT CCTGAGGAGC GGGAGGAGTGGACAACCGCCATCCAGACTGTGGCTGACGGCCTCAAGAAGCAGGAGGAGG AGGAGATGGA CTTCCGGTCGGGCTCACCCAGTGACAACTCAGGGGCTGAAGAGATGGAGGTGTCCCTGGC CAAGCCCAAG CACCGCGTGACCATGAACGAGTTTGAGTACCTGAAGCTGCTGGGCAAGGGCACTTTCGGC AAGGTGATCC TGGTGAAGGAGAAGGCCACAGGCCGCTACTACGCCATGAAGATCCTCAAGAAGGAAGTCA TCGTGGCCAA GGACGAGGTGGCCCACACACTCACCGAGAACCGCGTCCTGCAGAACTCCAGGCACCCCTT CCTCACAGCC CTGAAGTACTCTTTCCAGACCCACGACCGCCTCTGCTTTGTCATGGAGTACGCCAACGGG GGCGAGCTGT TCTTCCACCTGTCCCGGGAGCGTGTGTTCTCCGAGGACCGGGCCCGCTTCTATGGCGCTG AGATTGTGTC AGCCCTGGACTACCTGCACTCGGAGAAGAACGTGGTGTACCGGGACCTCAAGCTGGAGAA CCTCATGCTG GACAAGGACGGGCACATTAAGATCACAGACTTCGGGCTGTGCAAGGAGGGGATCAAGGAC GGTGCCACCA TGAAGACCTTTTGCGGCACACCTGAGTACCTGGCCCCCGAGGTGCTGGAGGACAATGACT ACGGCCGTGC AGTGGACTGGTGGGGGCTGGGCGTGGTCATGTACGAGATGATGTGCGGTCGCCTGCCCTT CTACAACCAG GACCATGAGAAGCTTTTTGAGCTCATCCTCATGGAGGAGATCCGCTTCCCGCGCACGCTT GGTCCCGAGG CCAAGTCCTTGCTTTCAGGGCTGCTCAAGAAGGACCCCAAGCAGAGGCTTGGCGGGGGCT CCGAGGACGC CAAGGAGATCATGCAGCATCGCTTCTTTGCCGGTATCGTGTGGCAGCACGTGTACGAGAA GAAGCTCAGC CCACCCTTCAAGCCCCAGGTCACGTCGGAGACTGACACCAGGTATTTTGATGAGGAGTTC ACGGCCCAGA TGATCACCATCACACCACCTGACCAAGATGACAGCATGGAGTGTGTGGACAGCGAGCGCA GGCCCCACTT CCCCCAGTTCTCCTACTCGGCCAGCGGCACGGCCTGAGGCGGCGGTGGACTGCGCTGGAC GATAGCTTGG AGGGATGGAGAGGCGGCCTCGTGCCATGATCTGTATTTAATGGTTTTTATTTCTCGGGTG CATTTGAGAG AAGCCACGCTGTCCTCTCGAGCCCAGATGGAAAGACGTTTTTGTGCTGTGGGCAGCACCC TCCCCCGCAG CGGGGTAGGGAAGAAAACTATCCTGCGGGTTTTAATTTATTTCATCCAGTTTGTTCTCCG GGTGTGGCCT CAGCCCTCAGAACAATCCGATTCACGTAGGGAAATGTTAAGGACTTCTGCAGCTATGCGC AATGTGGCAT TGGGGGGCCGGGCAGGTCCTGCCCATGTGTCCCCTCACTCTGTCAGCCAGCCGCCCTGGG CTGTCTGTCA CCAGCTATCTGTCATCTCTCTGGGGCCCTGGGCCTCAGTTCAACCTGGTGGCACCAGATG CAACCTCACT ATGGTATGCTGGCCAGCACCCTCTCCTGGGGGTGGCAGGCACACAGCAGCCCCCCAGCAC TAAGGCCGTG TCTCTGAGGACGTCATCGGAGGCTGGGCCCCTGGGATGGGACCAGGGATGGGGGATGGGC CAGGGTTTAC CCAGTGGGACAGAGGAGCAAGGTTTAAATTTGTTATTGTGTATTATGTTGTTCAAATGCA TTTTGGGGGT TTTTAATCTTTGTGACAGGAAAGCCCTCCCCCTTCCCCTTCTGTGTCACAGTTCTTGGTG ACTGTCCCAC CGGGAGCCTCCCCCTCAGATGATCTCTCCACGGTAGCACTTGACCTTTTCGACGCTTAAC CTTTCCGCTG TCGCCCCAGGCCCTCCCTGACTCCCTGTGGGGGTGGCCATCCCTGGGCCCCTCCACGCCT CCTGGCCAGA CGCTGCCGCTGCCGCTGCACCACGGCGTTTTTTTACAACATTCAACTTTAGTATTTTTAC TATTATAATA TAATATGGAACCTTCCCTCCAAATTCTTCAATAAAAGTTGCTTTTCAAAAAAAAAAAAAA AAAAAAAA

[0133] NM_004304.5 Homo sapiens ALK receptor tyrosine kinase (ALK), transcript variant 1, mRNA (SEQ ID NO: 2) AGATGCGATCCAGCGGCTCTGGGGGCGGCAGCGGTGGTAGCAGCTGGTACCTCCCGCCGC CTCTGTTCGG AGGGTCGCGGGGCACCGAGGTGCTTTCCGGCCGCCCTCTGGTCGGCCACCCAAAGCCGCG GGCGCTGATG ATGGGTGAGGAGGGGGCGGCAAGATTTCGGGCGCCCCTGCCCTGAACGCCCTCAGCTGCT GCCGCCGGGG CCGCTCCAGTGCCTGCGAACTCTGAGGAGCCGAGGCGCCGGTGAGAGCAAGGACGCTGCA AACTTGCGCA GCGCGGGGGCTGGGATTCACGCCCAGAAGTTCAGCAGGCAGACAGTCCGAAGCCTTCCCG CAGCGGAGAG ATAGCTTGAGGGTGCGCAAGACGGCAGCCTCCGCCCTCGGTTCCCGCCCAGACCGGGCAG AAGAGCTTGG AGGAGCCAAAAGGAACGCAAAAGGCGGCCAGGACAGCGTGCAGCAGCTGGGAGCCGCCGT TCTCAGCCTT AAAAGTTGCAGAGATTGGAGGCTGCCCCGAGAGGGGACAGACCCCAGCTCCGACTGCGGG GGGCAGGAGA GGACGGTACCCAACTGCCACCTCCCTTCAACCATAGTAGTTCCTCTGTACCGAGCGCAGC GAGCTACAGA CGGGGGCGCGGCACTCGGCGCGGAGAGCGGGAGGCTCAAGGTCCCAGCCAGTGAGCCCAG TGTGCTTGAG TGTCTCTGGACTCGCCCCTGAGCTTCCAGGTCTGTTTCATTTAGACTCCTGCTCGCCTCC GTGCAGTTGG GGGAAAGCAAGAGACTTGCGCGCACGCACAGTCCTCTGGAGATCAGGTGGAAGGAGCCGC TGGGTACCAA GGACTGTTCAGAGCCTCTTCCCATCTCGGGGAGAGCGAAGGGTGAGGCTGGGCCCGGAGA GCAGTGTAAA CGGCCTCCTCCGGCGGGATGGGAGCCATCGGGCTCCTGTGGCTCCTGCCGCTGCTGCTTT CCACGGCAGC TGTGGGCTCCGGGATGGGGACCGGCCAGCGCGCGGGCTCCCCAGCTGCGGGGCCGCCGCT GCAGCCCCGG GAGCCACTCAGCTACTCGCGCCTGCAGAGGAAGAGTCTGGCAGTTGACTTCGTGGTGCCC TCGCTCTTCC GTGTCTACGCCCGGGACCTACTGCTGCCACCATCCTCCTCGGAGCTGAAGGCTGGCAGGC CCGAGGCCCG CGGCTCGCTAGCTCTGGACTGCGCCCCGCTGCTCAGGTTGCTGGGGCCGGCGCCGGGGGT CTCCTGGACC GCCGGTTCACCAGCCCCGGCAGAGGCCCGGACGCTGTCCAGGGTGCTGAAGGGCGGCTCC GTGCGCAAGC TCCGGCGTGCCAAGCAGTTGGTGCTGGAGCTGGGCGAGGAGGCGATCTTGGAGGGTTGCG TCGGGCCCCC CGGGGAGGCGGCTGTGGGGCTGCTCCAGTTCAATCTCAGCGAGCTGTTCAGTTGGTGGAT TCGCCAAGGC GAAGGGCGACTGAGGATCCGCCTGATGCCCGAGAAGAAGGCGTCGGAAGTGGGCAGAGAG GGAAGGCTGT CCGCGGCAATTCGCGCCTCCCAGCCCCGCCTTCTCTTCCAGATCTTCGGGACTGGTCATA GCTCCTTGGA ATCACCAACAAACATGCCTTCTCCTTCTCCTGATTATTTTACATGGAATCTCACCTGGAT AATGAAAGAC TCCTTCCCTTTCCTGTCTCATCGCAGCCGATATGGTCTGGAGTGCAGCTTTGACTTCCCC TGTGAGCTGG AGTATTCCCCTCCACTGCATGACCTCAGGAACCAGAGCTGGTCCTGGCGCCGCATCCCCT CCGAGGAGGC CTCCCAGATGGACTTGCTGGATGGGCCTGGGGCAGAGCGTTCTAAGGAGATGCCCAGAGG CTCCTTTCTC CTTCTCAACACCTCAGCTGACTCCAAGCACACCATCCTGAGTCCGTGGATGAGGAGCAGC AGTGAGCACT GCACACTGGCCGTCTCGGTGCACAGGCACCTGCAGCCCTCTGGAAGGTACATTGCCCAGC TGCTGCCCCA CAACGAGGCTGCAAGAGAGATCCTCCTGATGCCCACTCCAGGGAAGCATGGTTGGACAGT GCTCCAGGGA AGAATCGGGCGTCCAGACAACCCATTTCGAGTGGCCCTGGAATACATCTCCAGTGGAAAC CGCAGCTTGT CTGCAGTGGACTTCTTTGCCCTGAAGAACTGCAGTGAAGGAACATCCCCAGGCTCCAAGA TGGCCCTGCA GAGCTCCTTCACTTGTTGGAATGGGACAGTCCTCCAGCTTGGGCAGGCCTGTGACTTCCA CCAGGACTGT GCCCAGGGAGAAGATGAGAGCCAGATGTGCCGGAAACTGCCTGTGGGTTTTTACTGCAAC TTTGAAGATG GCTTCTGTGGCTGGACCCAAGGCACACTGTCACCCCACACTCCTCAATGGCAGGTCAGGA CCCTAAAGGA TGCCCGGTTCCAGGACCACCAAGACCATGCTCTATTGCTCAGTACCACTGATGTCCCCGC TTCTGAAAGT GCTACAGTGACCAGTGCTACGTTTCCTGCACCGATCAAGAGCTCTCCATGTGAGCTCCGA ATGTCCTGGC TCATTCGTGGAGTCTTGAGGGGAAACGTGTCCTTGGTGCTAGTGGAGAACAAAACCGGGA AGGAGCAAGG CAGGATGGTCTGGCATGTCGCCGCCTATGAAGGCTTGAGCCTGTGGCAGTGGATGGTGTT GCCTCTCCTC GATGTGTCTGACAGGTTCTGGCTGCAGATGGTCGCATGGTGGGGACAAGGATCCAGAGCC ATCGTGGCTT TTGACAATATCTCCATCAGCCTGGACTGCTACCTCACCATTAGCGGAGAGGACAAGATCC TGCAGAATAC AGCACCCAAATCAAGAAACCTGTTTGAGAGAAACCCAAACAAGGAGCTGAAACCCGGGGA AAATTCACCA AGACAGACCCCCATCTTTGACCCTACAGTTCATTGGCTGTTCACCACATGTGGGGCCAGC GGGCCCCATG GCCCCACCCAGGCACAGTGCAACAACGCCTACCAGAACTCCAACCTGAGCGTGGAGGTGG GGAGCGAGGG CCCCCTGAAAGGCATCCAGATCTGGAAGGTGCCAGCCACCGACACCTACAGCATCTCGGG CTACGGAGCT GCTGGCGGGAAAGGCGGGAAGAACACCATGATGCGGTCCCACGGCGTGTCTGTGCTGGGC ATCTTCAACC TGGAGAAGGATGACATGCTGTACATCCTGGTTGGGCAGCAGGGAGAGGACGCCTGCCCCA GTACAAACCA GT T AAT C CAGAAAGT CT GCAT T GGAGAGAACAAT GT GAT AGAAGAAGAAAT C C GT GT GAACAGAAGC GT G CATGAGTGGGCAGGAGGCGGAGGAGGAGGGGGTGGAGCCACCTACGTATTTAAGATGAAG GATGGAGTGC CGGTGCCCCTGATCATTGCAGCCGGAGGTGGTGGCAGGGCCTACGGGGCCAAGACAGACA CGTTCCACCC AGAGAGACTGGAGAATAACTCCTCGGTTCTAGGGCTAAACGGCAATTCCGGAGCCGCAGG TGGTGGAGGT GGCTGGAATGATAACACTTCCTTGCTCTGGGCCGGAAAATCTTTGCAGGAGGGTGCCACC GGAGGACATT CCTGCCCCCAGGCCATGAAGAAGTGGGGGTGGGAGACAAGAGGGGGTTTCGGAGGGGGTG GAGGGGGGTG CTCCTCAGGTGGAGGAGGCGGAGGATATATAGGCGGCAATGCAGCCTCAAACAATGACCC CGAAATGGAT GGGGAAGATGGGGTTTCCTTCATCAGTCCACTGGGCATCCTGTACACCCCAGCTTTAAAA GTGATGGAAG GCCACGGGGAAGT GAATATTAAGCATTAT CTAAACT GCAGT CACT GT GAGGTAGACGAAT GT CACAT GGA CCCTGAAAGCCACAAGGTCATCTGCTTCTGTGACCACGGGACGGTGCTGGCTGAGGATGG CGTCTCCTGC ATTGTGTCACCCACCCCGGAGCCACACCTGCCACTCTCGCTGATCCTCTCTGTGGTGACC TCTGCCCTCG TGGCCGCCCTGGTCCTGGCTTTCTCCGGCATCATGATTGTGTACCGCCGGAAGCACCAGG AGCTGCAAGC CATGCAGATGGAGCTGCAGAGCCCTGAGTACAAGCTGAGCAAGCTCCGCACCTCGACCAT CATGACCGAC

TACAACCCCAACTACTGCTTTGCTGGCAAGACCTCCTCCATCAGTGACCTGAAGGAG GTGCCGCGGAAAA

ACATCACCCTCATTCGGGGTCTGGGCCATGGCGCCTTTGGGGAGGTGTATGAAGGCC AGGTGTCCGGAAT

GCCCAACGACCCAAGCCCCCTGCAAGTGGCTGTGAAGACGCTGCCTGAAGTGTGCTC TGAACAGGACGAA

CTGGATTTCCTCATGGAAGCCCTGATCATCAGCAAATTCAACCACCAGAACATTGTT CGCTGCATTGGGG

TGAGCCTGCAATCCCTGCCCCGGTTCATCCTGCTGGAGCTCATGGCGGGGGGAGACC TCAAGTCCTTCCT

CCGAGAGACCCGCCCTCGCCCGAGCCAGCCCTCCTCCCTGGCCATGCTGGACCTTCT GCACGTGGCTCGG

GACATTGCCTGTGGCTGTCAGTATTTGGAGGAAAACCACTTCATCCACCGAGACATT GCTGCCAGAAACT

GCCTCTTGACCTGTCCAGGCCCTGGAAGAGTGGCCAAGATTGGAGACTTCGGGATGG CCCGAGACATCTA

CAGGGCGAGCTACTATAGAAAGGGAGGCTGTGCCATGCTGCCAGTTAAGTGGATGCC CCCAGAGGCCTTC

ATGGAAGGAATATTCACTTCTAAAACAGACACATGGTCCTTTGGAGTGCTGCTATGG GAAATCTTTTCTC

TTGGATATATGCCATACCCCAGCAAAAGCAACCAGGAAGTTCTGGAGTTTGTCACCA GTGGAGGCCGGAT

GGACCCACCCAAGAACTGCCCTGGGCCTGTATACCGGATAATGACTCAGTGCTGGCA ACATCAGCCTGAA

GACAGGCCCAACTTTGCCATCATTTTGGAGAGGATTGAATACTGCACCCAGGACCCG GATGTAATCAACA

CCGCTTTGCCGATAGAATATGGTCCACTTGTGGAAGAGGAAGAGAAAGTGCCTGTGA GGCCCAAGGACCC

TGAGGGGGTTCCTCCTCTCCTGGTCTCTCAACAGGCAAAACGGGAGGAGGAGCGCAG CCCAGCTGCCCCA

CCACCTCTGCCTACCACCTCCTCTGGCAAGGCTGCAAAGAAACCCACAGCTGCAGAG ATCTCTGTTCGAG

TCCCTAGAGGGCCGGCCGTGGAAGGGGGACACGTGAATATGGCATTCTCTCAGTCCA ACCCTCCTTCGGA

GTTGCACAAGGTCCACGGATCCAGAAACAAGCCCACCAGCTTGTGGAACCCAACGTA CGGCTCCTGGTTT

ACAGAGAAACCCACCAAAAAGAATAATCCTATAGCAAAGAAGGAGCCACACGACAGG GGTAACCTGGGGC

TGGAGGGAAGCTGTACTGTCCCACCTAACGTTGCAACTGGGAGACTTCCGGGGGCCT CACTGCTCCTAGA

GCCCTCTTCGCTGACTGCCAATATGAAGGAGGTACCTCTGTTCAGGCTACGTCACTT CCCTTGTGGGAAT

GTCAATTACGGCTACCAGCAACAGGGCTTGCCCTTAGAAGCCGCTACTGCCCCTGGA GCTGGTCATTACG

AGGATACCATTCTGAAAAGCAAGAATAGCATGAACCAGCCTGGGCCCTGAGCTCGGT CGCACACTCACTT

CTCTTCCTTGGGATCCCTAAGACCGTGGAGGAGAGAGAGGCAATGGCTCCTTCACAA ACCAGAGACCAAA

TGTCACGTTTTGTTTTGTGCCAACCTATTTTGAAGTACCACCAAAAAAGCTGTATTT TGAAAATGCTTTA

GAAAGGTTTTGAGCATGGGTTCATCCTATTCTTTCGAAAGAAGAAAATATCATAAAA ATGAGTGATAAAT

ACAAGGCCCAGATGTGGTTGCATAAGGTTTTTATGCATGTTTGTTGTATACTTCCTT ATGCTTCTTTCAA

ATTGTGTGTGCTCTGCTTCAATGTAGTCAGAATTAGCTGCTTCTATGTTTCATAGTT GGGGTCATAGATG TTTCCTTGCCTTGTTGATGTGGACATGAGCCATTTGAGGGGAGAGGGAACGGAAATAAAG GAGTTATTTG TAATGACTAA

[0134] XM_005254549.4: Homo sapiens beta-2 -microglobulin (B2M), transcript variant XI, mRNA (SEQ ID NO: 3)

ATTCCTGAAGCTGACAGCATTCGGGCCGAGATGTCTCGCTCCGTGGCCTTAGCTGTG CTCGCGCTACTCT

CTCTTTCTGGCCTGGAGGCTATCCAGCGTACTCCAAAGATTCAGGTTTACTCACGTC ATCCAGCAGAGAA

TGGAAAGTCAAATTTCCTGAATTGCTATGTGTCTGGGTTTCATCCATCCGACATTGA AGTTGACTTACTG

AAGAATGGAGAGAGAATTGAAAAAGTGGAGCATTCAGACTTGTCTTTCAGCAAGGAC TGGTCTTTCTATC

TCTTGTACTACACTGAATTCACCCCCACTGAAAAAGATGAGTATGCCTGCCGTGTGA ACCATGTGACTTT

GTCACAGCCCAAGATAGTTAAGTGGGGTAAGTCTTACATTCTTTTGTAAGCTGCTGA AAGTTGTGTATGA

GTAGTCATATCATAAAGCTGCTTTGATATAAAAAAGGTCTATGGCCATACTACCCTG AATGAGTCCCATC

CCATCTGATATAAACAATCTGCATATTGGGATTGTCAGGGAATGTTCTTAAAGATCA GATTAGTGGCACC

TGCTGAGATACTGATGCACAGCATGGTTTCTGAACCAGTAGTTTCCCTGCAGTTGAG CAGGGAGCAGCAG

CAGCACTTGCACAAATACATATACACTCTTAACACTTCTTACCTACTGGCTTCCTCT AGCTTTTGTGGCA

GCTTCAGGTATATTTAGCACTGAACGAACATCTCAAGAAGGTATAGGCCTTTGTTTG TAAGTCCTGCTGT

CCTAGCATCCTATAATCCTGGACTTCTCCAGTACTTTCTGGCTGGATTGGTATCTGA GGCTAGTAGGAAG GGCTTGTTCCTGCTGGGTAGCTCTAAACAATGTATTCATGGGTAGGAACAGCAGCCTATT CTGCCAGCCT TATTTCTAACCATTTTAGACATTTGTTAGTACATGGTATTTTAAAAGTAAAACTTAATGT CTTCCTT

[0135] NM 001354609.2 Homo sapiens B-Raf proto-oncogene, serine/threonine kinase

(BRAF), transcript variant 2, mRNA (SEQ ID NO: 4)

CTTCCCCCAATCCCCTCAGGCTCGGCTGCGCCCGGGGCCGCGGGCCGGTACCTGAGG TGGCCCAGGCGCC

CTCCGCCCGCGGCGCCGCCCGGGCCGCTCCTCCCCGCGCCCCCCGCGCCCCCCGCTC CTCCGCCTCCGCC TCCGCCTCCGCCTCCCCCAGCTCTCCGCCTCCCTTCCCCCTCCCCGCCCGACAGCGGCCG CTCGGGCCCC GGCTCTCGGTTATAAGATGGCGGCGCTGAGCGGTGGCGGTGGTGGCGGCGCGGAGCCGGG CCAGGCTCTG TTCAACGGGGACATGGAGCCCGAGGCCGGCGCCGGCGCCGGCGCCGCGGCCTCTTCGGCT GCGGACCCTG CCATTCCGGAGGAGGTGTGGAATATCAAACAAATGATTAAGTTGACACAGGAACATATAG AGGCCCTATT GGACAAATTTGGTGGGGAGCATAATCCACCATCAATATATCTGGAGGCCTATGAAGAATA CACCAGCAAG CTAGATGCACTCCAACAAAGAGAACAACAGTTATTGGAATCTCTGGGGAACGGAACTGAT TTTTCTGTTT CTAGCTCTGCATCAATGGATACCGTTACATCTTCTTCCTCTTCTAGCCTTTCAGTGCTAC CTTCATCTCT TTCAGTTTTTCAAAATCCCACAGATGTGGCACGGAGCAACCCCAAGTCACCACAAAAACC TATCGTTAGA GTCTTCCTGCCCAACAAACAGAGGACAGTGGTACCTGCAAGGTGTGGAGTTACAGTCCGA GACAGTCTAA AGAAAGCACTGATGATGAGAGGTCTAATCCCAGAGTGCTGTGCTGTTTACAGAATTCAGG ATGGAGAGAA GAAACCAATTGGTTGGGACACTGATATTTCCTGGCTTACTGGAGAAGAATTGCATGTGGA AGTGTTGGAG AATGTTCCACTTACAACACACAACTTTGTACGAAAAACGTTTTTCACCTTAGCATTTTGT GACTTTTGTC GAAAGCTGCTTTTCCAGGGTTTCCGCTGTCAAACATGTGGTTATAAATTTCACCAGCGTT GTAGTACAGA AGTTCCACTGATGTGTGTTAATTATGACCAACTTGATTTGCTGTTTGTCTCCAAGTTCTT TGAACACCAC CCAATACCACAGGAAGAGGCGTCCTTAGCAGAGACTGCCCTAACATCTGGATCATCCCCT TCCGCACCCG CCTCGGACTCTATTGGGCCCCAAATTCTCACCAGTCCGTCTCCTTCAAAATCCATTCCAA TTCCACAGCC CTTCCGACCAGCAGATGAAGATCATCGAAATCAATTTGGGCAACGAGACCGATCCTCATC AGCTCCCAAT GTGCATATAAACACAATAGAACCTGTCAATATTGATGACTTGATTAGAGACCAAGGATTT CGTGGTGATG GAGGATCAACCACAGGTTTGTCTGCTACCCCCCCTGCCTCATTACCTGGCTCACTAACTA ACGTGAAAGC CTTACAGAAATCTCCAGGACCTCAGCGAGAAAGGAAGTCATCTTCATCCTCAGAAGACAG GAATCGAATG AAAACACTTGGTAGACGGGACTCGAGTGATGATTGGGAGATTCCTGATGGGCAGATTACA GTGGGACAAA GAATT GGAT CT GGAT CATTT GGAACAGT CTACAAGGGAAAGT GGCAT GGT GAT GT GGCAGT GAAAAT GTT GAATGTGACAGCACCTACACCTCAGCAGTTACAAGCCTTCAAAAATGAAGTAGGAGTACT CAGGAAAACA CGACATGTGAATATCCTACTCTTCATGGGCTATTCCACAAAGCCACAACTGGCTATTGTT ACCCAGTGGT GTGAGGGCTCCAGCTTGTATCACCATCTCCATATCATTGAGACCAAATTTGAGATGATCA AACTTATAGA TATTGCACGACAGACTGCACAGGGCATGGATTACTTACACGCCAAGTCAATCATCCACAG AGACCTCAAG AGTAATAATATATTTCTTCATGAAGACCTCACAGTAAAAATAGGTGATTTTGGTCTAGCT ACAGTGAAAT CTCGATGGAGTGGGTCCCATCAGTTTGAACAGTTGTCTGGATCCATTTTGTGGATGGCAC CAGAAGTCAT CAGAATGCAAGATAAAAATCCATACAGCTTTCAGTCAGATGTATATGCATTTGGAATTGT TCTGTATGAA TTGATGACTGGACAGTTACCTTATTCAAACATCAACAACAGGGACCAGATAATTTTTATG GTGGGACGAG GATACCTGTCTCCAGATCTCAGTAAGGTACGGAGTAACTGTCCAAAAGCCATGAAGAGAT TAATGGCAGA GTGCCTCAAAAAGAAAAGAGATGAGAGACCACTCTTTCCCCAAATTCTCGCCTCTATTGA GCTGCTGGCC CGCTCATTGCCAAAAATTCACCGCAGTGCATCAGAACCCTCCTTGAATCGGGCTGGTTTC CAAACAGAGG ATTTTAGTCTATATGCTTGTGCTTCTCCAAAAACACCCATCCAGGCAGGGGGATATGGAG AATTTGCAGC CTTCAAGTAGCCACCATCATGGCAGCATCTGCTCTTATTTCTTAAGTCTTGTGTTCGTAC AATTTGTTAA CATCAAAACACAGTTCTGTTCCTCAAATCTTTTTTTAAAGATACAAAATTTCCAATGCAT AAGCTGATGT GGAACAGAATGGAATTTCCCATCCAACAAAAGAGGAAAGAATGTTTTAGGAACCAGAATT CTCTGCTGCC AGTGTTTCTTCAACAAAAATACCACGAGCATACAAGTCTGCCCAGTCCCAGGAAGAAAGA GGAGAGACCC TGAATTCTGACCTTTTGATGGTCAGGCATGATGGAAAGAAACTGCTGCTACAGCTTGGGA GATTTGCTAT GGAAAGTCTGCCAGTCAACTTTGCCCTTCTAACCACCAGATCAATTTGTGGCTGATCATC TGATGGGGCA GTTTCAATCACCAAGCATCGTTCTCTTTCCTGTTCTGGAATTTTGTTTTGGAGCTCTTTC CCCTAGTGAC CACCAGTTAGTTTCTGAGGGATGGAACAAAAATGCAGCTTGCCCTTTCTATGTGGTGCGT GTTCAGGCCT TGACAGATTTTATCAAAAGGAAACTATTTTATTTAAATGGAGGCTGAGTGGTGAGTAGAT GTGTCTTGGT ATGGAGGAAAAGGGCATGCTGCATCTTCTTCCTGACCTCCGGGGTCTCTGGCCTTTTGTT TCCTTGCTCA CTGAGGGGTCTGTCTAACCAAGCAGGCTAGATAGTGCTGGCACACATTGCCTTCTTTCTC ATTGGGTCCA GCAATGAAGATAAGTGTTTGGGTTTTTTTTTTTTCCTCCACAATGTAGCAAATTCTCAGG AAATACAGTT TATATCTTCCTCCTATGCTCTTCCAGTCACCAACTACTTATGCGGCTACTTTGTCCAGGG CACAAAATGC CGTGGCAGTATCTAACTAAACCCCCACAAAACTGCTTAATAACAGTTTTGAATGTGAGAA ATTTAGATAA TTTAAATATAAGGTACAGGTTTTAATTTCTGAGTTTCTTCTTTTCTATTTTTATTAAAAA GAAAATAATT T T C AGAT T T AAT T GAAT T G GAAAAAAAC AAT AC T T C C C AC C AGAAT T AT AT AT C C T GAAAAT T GT AT T T T TGTTATATAAACAACTTTTAAGAAAGATCATTATCCTTTTCTCTACCTAAATATGAGGAG TCTTAGCATA ATGACAAATATTTATAATTTTTCAATTAATGGTACTTGCTGGATCCACACTAACATCTTT GCTAATAATC TCATTGTTTCTTCCAACTGATTCCTAACACTATATCCCACATCTTCTTTCTAGTCTTTTA TCTAGAATAT GCAACCTAAAATAAAAATGGTGGCGTCTCCATTCATTCTCCTTCTTCCTTTTTTCCCAAG CCTGGTCTTC AAAAGGTTGGGCAATTTGGCAGCTGAATTCCCAGACAGAGAATAGAGCAATTTTAGGGAT ATTAGGACTG AGGGAGGGTGTGGGAAAGCTGTCATCAGTTGTTTTTATAGAAAGAACTGGCATTCATTAA GAACCTAAAT CTTATCTTTGCACAAATGGAAAATATAACCTAGTTATAGCTTCCTTTGGCCTTTATTAAA GGGTAATATC AATCACAGTCATAGCAAAGAAAGCGGATGTATTAATGGCAAATTAATGGAAAACCTCCCT TATCAGGAAT CTAGACTCAGAATTTAGGAACACAAATCAAATCAGACCAACCAAGCTATAGCCAAGGACT TGAAAGAAAT T AAAC AAGAC C C AGAAT AAAT C AAG GAAT T AGAAAT T GT T AT T T AAAAAT T T C AGAT TGTAACTCCAGGC CCTGCTGTCTATATTGCAGCCACTAAAAGCTCACTACCATTAGATTTTTGCTAACATACA TGTATTCAGA AGAAAGCCTATTGAAATTTTCATTGTCTTGTAAAAGGTTGTCCTAGTAAAATGGAAAAGA TCCTTAAGTT ATTAATCAGTTTGAAAAGCAAATTTGTTTTTAAGTTTTACATCAGCAGGGCAGTGTCTTA CAAAATTCAG AAATTGCAAAGGTGGAAATAATTCACGCTGATTTGAAGAACATCTTCTGTGCAATAATAC TGCCTCTCTT GAAAAGCATTGGCTGTTTTTTCTTTTTAAATATATCTCTAGATGCTTTTAAATGTGGCTG TGTTCCCTTT ACCAAGATTGGCTTCAAGTTTCCGCAGGTAGAGAGACCTGGGCTTGAACAAGAGGATGTG TTTCATGTCC TGCTGAGGAGGTAGAACATGTGCAGCCTGGGTCCGGGACTGCCTCCGTGGGGCAGGGGCA GGGGCGGTAC CATTAGGGAGGAAGCTTAGCATTTCAGTTTCTTAAACAATATTCAGGGTGATACACTTTT TCTTCCCTTG CATTTTAGAATAGGCTGGTATCTCATTTGAACGGGGGAGCAGACTTGATCTCAAATGAAG CTGTGCCCAG GAGCCAGGCTTAGCATATTGAGATTTTTATAGATACCTTAAAAAATAAAATATTTAAACC TCTCTTTTCT TCCTTTTTCTATGAAATAGGTTTTTTCTCTAGTTTACAAATGACATGAAAATAGGTTTTA TTTGTGTTTT ATCTGCTTTATTTTTTGATGCTTAGACAACAGTTAGACTTACTGAGCTCCTAAAAAAACG AGGAAGAAGT CCTTATTTGTGAAAAGCACTTTATGAGTAATTGTATAGACAGTATGTGGCTGCGTCACTG ATCATCTTGT AAGGGTGTAACAGTCTTGTCTGTAAAGTGGCTGCAGTGCCTTCTGTAGTGTGTTTTATTT TTGGTAGGGA GAGGTGAAGCCTTCTGAAAAATTTGAGAGCAACTACAGAGGATTGTTTGTAACTGTGTAG TATTCCTGAT GGACTTTTTTCATCGTTAGAGTCAAGGACCTAGACTTTTGCCACTGAAATAATATTGACC AAAAAAATAG T T T AT AAAAGGGAT T T GT GAAT AGAAAAT T CAGT GT GAT CAT T T GT T GT T AAT GT GCAC CT T AAAAGAAG ATTCTGTCTAGCTGTCAAATTCTGGTTCCCGAATATCTCACCCCTGATTGTATTTGAGAT CTAGTAGGGC ATACTGGGGCATTTTAGAAGATAAAATCCCATACAAATGATATATGCTATATTTATGTTG GTGTTGGAGA AGAAAGAGCAGTATATAAAGAAATAATTCAAGACTGCAGCACTGTCAACCTGAAACTTTG TAAATATTTC CTAGCTTCTGGTTTGGTGCGGTGACAGCACTTTCATCACAGGATGTTACCTTGTATTCAC CAGGCGGAGT GCGAGCTGCTGCACATCCTCCTCAGATCTCACCTGTCCCCACTGTACATCCACCCGCCAG CTGCTTGCAA ACCTCATCTCTAGCTTTAGTTCGAAACCACATTGCAGGGTTCAGGTGACCTCTACAAAAA ACTACCTCTT CAGAATGAGGTAATGAATAGTTATTTATTTTAAAATATGAAAAGTCAGGAGCTCTAGAAC ATGACGATGA TTTAAGATTTTAACTTTTTTGTGTACTTGTATTTGAGCACTCTCATTTTGTCCTAAAGGG CATTATACAT TTAAGCAGTAATACTGTAAAAAAATGTGTTGCTCGGAATATCTGAATGTTGTTGAAAGTG GTGCCAGAAC CGGTTTAGGGGTACGTTTCAGAATCTTAACCTTGAGTCAATTGCATGAAATTAAATAGCT GTGGTATCAC TTCACTAACAGTGATGTAATTTTAATTTTCAGTAGGCTTGGCATGACAGTACATCCTCAT AATGAGTTTG CTGCAGCTTTGTCACATGCACAGGCATTCATAGAAAGACCACCCAGCTAAGAGGGTAGAA TGATTACTCT TTTTGCAAGATTCTCTTCTTTGTCCAAGTTGGCATTGTTAGTGCTAGGAATACCAGCACC TTGAGACGAG CAGATTCCAACCATTAGGCTATAAACACCATAGCCAGAGATGGAAGGTTTACTGTGAGTA TGAACAGCAA ATAGCTTACAGGTCATGAGTTGAAATGGTGTAGGTGAGGCTCTAGAAAAATACCTTGACA ATTTGCCAAA TGATCTTACTGTGCCTTCATGATGCAATAAAAAAGCTAACATTTTAGCAGAAATCAGTGA TTTGTGAAGA GAGCAGCCACTCTGGTTTAACTCAGCTGTGTTAATAATTTTTAGAGTGCAATTTAGACTG CATAGGTAAA T G C AC T AAAGAGT T T AT AG C C AAAAT C AC AT T T AAC AAT GAGAAAAC AC AC AG GT AAAT T T T C AGT GAAC AAAATTATTTTTTTAAAGCACATAATCCCTAGTATAGTCAGATATATTTATCACATAGAG CAACTAGGTT GCAAATATAGTTCAGTGACATTTCTAGAGAAACTTTTTCTACTCCCATAGGCTCTTCAAA GCATGGAACT TTTATACAACAGAAATGTTGACAGAAATTGCTGTAGTTTAGGGTTGAAGTACTGTATGAT GGGCAGCAAT CATGTATTAACTTAGAAGGGGAAATTGAAATATAGGACCGAATTTGGTTTTATCAGTTTC CAGAGTACTG CTGCCAACCTAGACACTGATTTTTCAGAGTTTGAAATGTAAATTTCTTCCCGGGACTTGA TTGCACATGA AGCTGGACTGCGTTAGTCATCCTGTCCCAAAGCGCTGTGGGGGCCAGGGTGGAGGTCTCA AGGCATCCTT TATGACCTGGCCATTGGATGTAAAAGAAAACATATTCCATGCTGTGGTTCTTGTATCTTG TTTCATTCCT CACCATTGAAAGAGAAAGTCCATGTATTGTCTCCAGCACATCCTTGAAATGTTATACTGG GATGGATTAC TGATGCCCATCGGTAGTTGAGCCCCAGAAGAGGGTAGTAGCATCTCTGCCTCAGGTGATG ATTTGTAGCT TGGCCAGAGGAGAGCGGAGTCACCAGTATATCTGTGGTCCATGTTGCTAGCTCTGGTAAA ATTAAAAATA CTGGTAAGATGTTTGTTTTATTAGTACACTAGACAGTAAGCTCTGTTTTGTTGTTTTCAA ATAACCTATT TTCACTTTTGTTTGGGCAAAGACATTTAAATTGAAATTCAATTCTAATTTTTGTTAATTG TGGAAAGGGT AATTAACAGTTCCTATCAGGTATTTTTAATGTGGAAAAGGACAGAAACCCAACTCCTAAA ATCTTAAATT AAGGTAACAGT GCTTTAAAAAAAAAAAAT GCAT GGGGCAATTAGT CGGCAACT CAAT GAGT GACTAAAGT ACTTTTATTTAACATCCACAACTTCAACTGTTAAGTTTTATTAATTACTAAATCAGCTTT ATTAAAATGT TGACATTTATTTAGCTATTTTGAATAATTATAGTGACTTGACGAGTGTGTATGAGGACAC AGCCAATGTA AGCCAGTGTATCCATTTTTTAGAGGTGCATTTTTTTTTAAAGAATTCTGTAGATAGAAGT GCTCTGAAAA CAACTAAAATATGTTTATTCATGGTAGTATCAAAAAATGTTTGTACAAACCATCTGCTTC TCCCGGCCAG CCGAGTTCATTCTCCAGCACCGTGACCGCTGGTTCTCATGTACAGCACATATGCGGGAGA GTTGGCAGAA AATTTGTGAAGAGATGCCGCAAAGGAAGGGTCTGTTGACGGGTGGGATTGGGGGTTTTGA TGAAGTTGCT TAGTCCTGGTTTTGTTTTGAAAATTACTGCGTTGCATTTTTGTGTTAAGTTTTTGAACCC ACGTGTGTTT T GGT GGAGTAT GAGTT GGAAGT CACTGCAAACTAGCATAAACAACAAAGCT CACAGAGTAGGCACAGAT G TAGAGAACAGAGACCAAAAT GGGGT GAGGT GGCAGTAAAT CTAGGATAGGGAAAAATTAAT GT GAGGGT G GGAAATAAACTGTAATTACCTGAAATCAAATGTAAGAGTGCAATAAGTATGCTTTTTATT CTAAGCTGTG AACGGTTTTTTTAAGAATCATTCCTTCCTAATACATTTGTGTATGTTCCATAGCTGATTA AAACCAGCTA TATCAACATATAATGCCTTTTTATTCATGTTAATGACCAACGTAAGTGGCTAGCCTTTAT GTCTTATTTA TCTTCATGTTATGTTAGTTTACATACAGGGGTGTATGTCTCTGTGCTGTCCCCTTCTCCT GCCTTCATTT TAAAATGCATCCATGGGTCCTCCGTGTTTCCTTTGGCCATGCCACATATATAGACTCAGT TTGGCCTTCA TGATATCGCCTGATTTTTGAGGACTGTATCACAGTGATATGTATTTGTGGTAATCTCATT TGTTGGTTGT ACATCTGATCCTTTCCTCAACATGGCAATTGCTGCCTTTCCTAAGATAGGATCATACAAC TGATCAGGGG ATTGAATTTGATCATTCATCAACATGTGTCTCTGAATTTTATTCAGTAGTTGTCATTGCT CTTTGGTTTA GACCAAGAAAAAGGAAATCCCCCCTTTTCATGTATTCCTTGGTTTGAGGACATGACTCCT GTAAGGGAGA GGAAAGGGAGATGCTTCCTGTTTGAACTGCAGTGAATTCACGGTTCCTGTTTCACCACTC CAAACCTTAT GGCGACTCACACACACATTCCTCTTTTCTGTTACTGCCAAAGGTTCGGGTTTAGTACACT TCAGTTCCAC TCAAGCATTGAAAAGGTTCTCGTGGAGTCTGGGGCGTGCCCAGTGAAAAGATGGGGACTT TTTAATTGTC CACAGACCTCTCTATACCTGCTTTGCAAAAATTACAATGGAGTAACTATTTTTAAAGCTT ATTTTTCAAT TCATAAAAAAGACATTTATTTTCAGTCAAATGGATGATGTCTCCCTCTTTTCCCCTATTC TCAATGTTTG CTTGAATCTTTTATTATTTTTTTTAATTCTCCCCCATACCCACTTCCTGATACTTTGGTT CTCTTTCCTG CTCAGGTCCCTTCATTTGTACTTTGGAGTTTTTCTCATGTAAATTTGTATAACAGAAAAT ATTGTTCAGT TTGGATAGAAAGCATGGAGAATAAAAAAAGATAGCTGAAATTCAGATTGAAGAAATTTAT TTCTGTGTAA AGTTATTTAAAAACTGTATTATATAAAAGGCAAAAAAAGTTCTATGTACTTGATGTGAAT ATGCGAATAC T GCTATAATAAAGATT GACT GCAT GGA

[0136] XM 047419953.1 : Homo sapiens epidermal growth factor receptor (EGFR), transcript variant X2, mRNA (SEQ ID NO: 5)

ACTCCTTCATGGAATCTAAAAAATTGTATTCAGAGAAGCAGAGAGTGGAATGGTGGT TACCAGGGGCTGG GAAGGTGTGAGCTTGGGGAGATTTGGTGAAAGGACATAGAATCTCAGTTAGACAGGAGGA ATAAGTTAAA GAGATCTATTGCACATCATGGTAACTGTAGTTAGTGACAATGTATTGTATACATGAAAAT TGCTAAGAGA GTAGATTTTAAGTGTTCTCACCACACCAAAAAAAGGTATGTGCAGTAATACAGTCATTAA TTAGCTTGAT GTAGCCATTCCACAATGGATACATATATCAAAACATCATGTTGTATACCATAAATATATA CTGTCTCTTT ATGTAAATTTAAAAATAAGATAAAATAAATGTTATTCACTTGTCGTGGATGTGGTGGGGA CAGGTGTGGG ATAGCCCTCCCTGTACAACTAGGACCCAGGGGTGATCTAGTGACACTAGCCATTTATCAG GACGTATGGG TGCCAGTCAGGATGATAAAGCTTCCTTTTGGCCACTATACTACTTAGAAATGCCCTGCAA AAGGTGCACA TCAAAGATTGAAAGCTCAATCCTGGATTTTAAGTGCTTCAAAAGTGCACTTAATTGCCAC ATTTTTGTCA AACAT T T T C C CAGGT AGT AT T T T T C CT CAT GT AAAACAACAGCAAT T T AAT T T GAACAGAAAGCAT T T T G AAACATACTTTTGGCAGGGTTCCTTGCAGATCAGAATGGAAATGATTAACAGGGCAATTA TCAATCATGG ACTTTTGGCGGCAGAAGGAACTGTATTGTTTGGTACAGTCTGGGCCAGGGCCACACACCG TAACGGAGAT ACTCTATTCTGTGGACGGTTGGAGGGGGCTGTGCTGAGCAGGGTAACTGCATCTTTTCCT AGACTGTTCA CACTGCTGCCACGAAGGAGTCTTGTTTAGACTGGACCTGGCTTTCTTCTTCGCAATGAGT GTTGCAGACT CCCGACAAAGGCCAGGTGGTAAAGTGTGGTGTCTGTGAGCGAGAGCCTGAGATGCCTGAG CTGACCTGTC CTCAGCCACCTGCCATCGTGCAGAGTTTGCCAAGGCACGAGTAACAAGCTCACGCAGTTG GGCACTTTTG AAGATCATTTTCTCAGCCTCCAGAGGATGTTCAATAACTGTGAGGTGGTCCTTGGGAATT TGGAAATTAC CTATGTGCAGAGGAATTATGATCTTTCCTTCTTAAAGACCATCCAGGAGGTGGCTGGTTA TGTCCTCATT GCCCTCAACACAGTGGAGCGAATTCCTTTGGAAAACCTGCAGATCATCAGAGGAAATATG TACTACGAAA ATTCCTATGCCTTAGCAGTCTTATCTAACTATGATGCAAATAAAACCGGACTGAAGGAGC TGCCCATGAG AAATTTACAGGAAATCCTGCATGGCGCCGTGCGGTTCAGCAACAACCCTGCCCTGTGCAA CGTGGAGAGC ATCCAGTGGCGGGACATAGTCAGCAGTGACTTTCTCAGCAACATGTCGATGGACTTCCAG AACCACCTGG GCAGCTGCCAAAAGTGTGATCCAAGCTGTCCCAATGGGAGCTGCTGGGGTGCAGGAGAGG AGAACTGCCA GAAACTGACCAAAATCATCTGTGCCCAGCAGTGCTCCGGGCGCTGCCGTGGCAAGTCCCC CAGTGACTGC TGCCACAACCAGTGTGCTGCAGGCTGCACAGGCCCCCGGGAGAGCGACTGCCTGGTCTGC CGCAAATTCC GAGACGAAGCCACGTGCAAGGACACCTGCCCCCCACTCATGCTCTACAACCCCACCACGT ACCAGATGGA TGTGAACCCCGAGGGCAAATACAGCTTTGGTGCCACCTGCGTGAAGAAGTGTCCCCGTAA TTATGTGGTG ACAGATCACGGCTCGTGCGTCCGAGCCTGTGGGGCCGACAGCTATGAGATGGAGGAAGAC GGCGTCCGCA AGTGTAAGAAGTGCGAAGGGCCTTGCCGCAAAGTGTGTAACGGAATAGGTATTGGTGAAT TTAAAGACTC ACTCTCCATAAATGCTACGAATATTAAACACTTCAAAAACTGCACCTCCATCAGTGGCGA TCTCCACATC CTGCCGGTGGCATTTAGGGGTGACTCCTTCACACATACTCCTCCTCTGGATCCACAGGAA CTGGATATTC TGAAAACCGTAAAGGAAATCACAGGGTTTTTGCTGATTCAGGCTTGGCCTGAAAACAGGA CGGACCTCCA TGCCTTTGAGAACCTAGAAATCATACGCGGCAGGACCAAGCAACATGGTCAGTTTTCTCT TGCAGTCGTC AGCCTGAACATAACATCCTTGGGATTACGCTCCCTCAAGGAGATAAGTGATGGAGATGTG ATAATTTCAG GAAACAAAAATTTGTGCTATGCAAATACAATAAACTGGAAAAAACTGTTTGGGACCTCCG GTCAGAAAAC CAAAATTATAAGCAACAGAGGTGAAAACAGCTGCAAGGCCACAGGCCAGGTCTGCCATGC CTTGTGCTCC CCCGAGGGCTGCTGGGGCCCGGAGCCCAGGGACTGCGTCTCTTGCCGGAATGTCAGCCGA GGCAGGGAAT GCGTGGACAAGTGCAACCTTCTGGAGGGTGAGCCAAGGGAGTTTGTGGAGAACTCTGAGT GCATACAGTG CCACCCAGAGTGCCTGCCTCAGGCCATGAACATCACCTGCACAGGACGGGGACCAGACAA CTGTATCCAG TGTGCCCACTACATTGACGGCCCCCACTGCGTCAAGACCTGCCCGGCAGGAGTCATGGGA GAAAACAACA CCCTGGTCTGGAAGTACGCAGACGCCGGCCATGTGTGCCACCTGTGCCATCCAAACTGCA CCTACGGATG CACTGGGCCAGGTCTTGAAGGCTGTCCAACGAATGGGCCTAAGATCCCGTCCATCGCCAC TGGGATGGTG GGGGCCCTCCTCTTGCTGCTGGTGGTGGCCCTGGGGATCGGCCTCTTCATGCGAAGGCGC CACATCGTTC GGAAGCGCACGCTGCGGAGGCTGCTGCAGGAGAGGGAGCTTGTGGAGCCTCTTACACCCA GTGGAGAAGC TCCCAACCAAGCTCTCTTGAGGATCTTGAAGGAAACTGAATTCAAAAAGATCAAAGTGCT GGGCTCCGGT GCGTTCGGCACGGTGTATAAGGGACTCTGGATCCCAGAAGGTGAGAAAGTTAAAATTCCC GTCGCTATCA AGGAATTAAGAGAAGCAACATCTCCGAAAGCCAACAAGGAAATCCTCGATGAAGCCTACG TGATGGCCAG CGTGGACAACCCCCACGTGTGCCGCCTGCTGGGCATCTGCCTCACCTCCACCGTGCAGCT CATCACGCAG CTCATGCCCTTCGGCTGCCTCCTGGACTATGTCCGGGAACACAAAGACAATATTGGCTCC CAGTACCTGC TCAACTGGTGTGTGCAGATCGCAAAGGGCATGAACTACTTGGAGGACCGTCGCTTGGTGC ACCGCGACCT GGCAGCCAGGAACGTACTGGTGAAAACACCGCAGCATGTCAAGATCACAGATTTTGGGCT GGCCAAACTG CT GGGT GCGGAAGAGAAAGAATACCAT GCAGAAGGAGGCAAAGT GCCTAT CAAGT GGAT GGCATT GGAAT CAATTTTACACAGAATCTATACCCACCAGAGTGATGTCTGGAGCTACGGGGTGACTGTTT GGGAGTTGAT GACCTTTGGATCCAAGCCATATGACGGAATCCCTGCCAGCGAGATCTCCTCCATCCTGGA GAAAGGAGAA CGCCTCCCTCAGCCACCCATATGTACCATCGATGTCTACATGATCATGGTCAAGTGCTGG ATGATAGACG CAGATAGTCGCCCAAAGTTCCGTGAGTTGATCATCGAATTCTCCAAAATGGCCCGAGACC CCCAGCGCTA CCTTGTCATTCAGGGGGATGAAAGAATGCATTTGCCAAGTCCTACAGACTCCAACTTCTA CCGTGCCCTG ATGGATGAAGAAGACATGGACGACGTGGTGGATGCCGACGAGTACCTCATCCCACAGCAG GGCTTCTTCA GCAGCCCCTCCACGTCACGGACTCCCCTCCTGAGCTCTCTGAGTGCAACCAGCAACAATT CCACCGTGGC TTGCATTGATAGAAATGGGCTGCAAAGCTGTCCCATCAAGGAAGACAGCTTCTTGCAGCG ATACAGCTCA GACCCCACAGGCGCCTTGACTGAGGACAGCATAGACGACACCTTCCTCCCAGTGCCTGAA TACATAAACC AGTCCGTTCCCAAAAGGCCCGCTGGCTCTGTGCAGAATCCTGTCTATCACAATCAGCCTC TGAACCCCGC GCCCAGCAGAGACCCACACTACCAGGACCCCCACAGCACTGCAGTGGGCAACCCCGAGTA TCTCAACACT GTCCAGCCCACCTGTGTCAACAGCACATTCGACAGCCCTGCCCACTGGGCCCAGAAAGGC AGCCACCAAA TTAGCCTGGACAACCCTGACTACCAGCAGGACTTCTTTCCCAAGGAAGCCAAGCCAAATG GCATCTTTAA GGGCTCCACAGCTGAAAATGCAGAATACCTAAGGGTCGCGCCACAAAGCAGTGAATTTAT TGGAGCATGA CCACGGAGGATAGTATGAGCCCTAAAAATCCAGACTCTTTCGATACCCAGGACCAAGCCA CAGCAGGTCC TCCATCCCAACAGCCATGCCCGCATTAGCTCTTAGACCCACAGACTGGTTTTGCAACGTT TACACCGACT AGCCAGGAAGTACTTCCACCTCGGGCACATTTTGGGAAGTTGCATTCCTTTGTCTTCAAA CTGTGAAGCA TTTACAGAAACGCATCCAGCAAGAATATTGTCCCTTTGAGCAGAAATTTATCTTTCAAAG AGGTATATTT GAAAAAAAAAAAAAGTATATGTGAGGATTTTTATTGATTGGGGATCTTGGAGTTTTTCAT TGTCGCTATT GATTTTTACTTCAATGGGCTCTTCCAACAAGGAAGAAGCTTGCTGGTAGCACTTGCTACC CTGAGTTCAT CCAGGCCCAACTGTGAGCAAGGAGCACAAGCCACAAGTCTTCCAGAGGATGCTTGATTCC AGTGGTTCTG CTTCAAGGCTTCCACTGCAAAACACTAAAGATCCAAGAAGGCCTTCATGGCCCCAGCAGG CCGGATCGGT ACTGTATCAAGTCATGGCAGGTACAGTAGGATAAGCCACTCTGTCCCTTCCTGGGCAAAG AAGAAACGGA GGGGATGGAATTCTTCCTTAGACTTACTTTTGTAAAAATGTCCCCACGGTACTTACTCCC CACTGATGGA CCAGTGGTTTCCAGTCATGAGCGTTAGACTGACTTGTTTGTCTTCCATTCCATTGTTTTG AAACTCAGTA TGCTGCCCCTGTCTTGCTGTCATGAAATCAGCAAGAGAGGATGACACATCAAATAATAAC TCGGATTCCA GCCCACATTGGATTCATCAGCATTTGGACCAATAGCCCACAGCTGAGAATGTGGAATACC TAAGGATAGC ACCGCTTTTGTTCTCGCAAAAACGTATCTCCTAATTTGAGGCTCAGATGAAATGCATCAG GTCCTTTGGG GCATAGATCAGAAGACTACAAAAATGAAGCTGCTCTGAAATCTCCTTTAGCCATCACCCC AACCCCCCAA AATTAGTTTGTGTTACTTATGGAAGATAGTTTTCTCCTTTTACTTCACTTCAAAAGCTTT TTACTCAAAG AGTATATGTTCCCTCCAGGTCAGCTGCCCCCAAACCCCCTCCTTACGCTTTGTCACACAA AAAGTGTCTC TGCCTTGAGTCATCTATTCAAGCACTTACAGCTCTGGCCACAACAGGGCATTTTACAGGT GCGAATGACA GTAGCATTATGAGTAGTGTGGAATTCAGGTAGTAAATATGAAACTAGGGTTTGAAATTGA TAATGCTTTC ACAACATTTGCAGATGTTTTAGAAGGAAAAAAGTTCCTTCCTAAAATAATTTCTCTACAA TTGGAAGATT GGAAGATTCAGCTAGTTAGGAGCCCACCTTTTTTCCTAATCTGTGTGTGCCCTGTAACCT GACTGGTTAA CAGCAGTCCTTTGTAAACAGTGTTTTAAACTCTCCTAGTCAATATCCACCCCATCCAATT TATCAAGGAA GAAATGGTTCAGAAAATATTTTCAGCCTACAGTTATGTTCAGTCACACACACATACAAAA TGTTCCTTTT GCTTTTAAAGTAATTTTTGACTCCCAGATCAGTCAGAGCCCCTACAGCATTGTTAAGAAA GTATTTGATT TTTGTCTCAATGAAAATAAAACTATATTCATTTCCACTCTATTATGCTCTCAAATACCCC TAAGCATCTA TACTAGCCTGGTATGGGTATGAAAGATACAAAGATAAATAAAACATAGTCCCTGATTCTA AGAAATTCAC AATTTAGCAAAGGAAATGGACTCATAGATGCTAACCTTAAAACAACGTGACAAATGCCAG ACAGGACCCA TCAGCCAGGCACTGTGAGAGCACAGAGCAGGGAGGTTGGGTCCTGCCTGAGGAGACCTGG AAGGGAGGCC TCACAGGAGGATGACCAGGTCTCAGTCAGCGGGGAGGTGGAAAGTGCAGGTGCATCAGGG GCACCCTGAC CGAGGAAACAGCTGCCAGAGGCCTCCACTGCTAAAGTCCACATAAGGCTGAGGTCAGTCA CCCTAAACAA CCTGCTCCCTCTAAGCCAGGGGATGAGCTTGGAGCATCCCACAAGTTCCCTAAAAGTTGC AGCCCCCAGG GGGATTTTGAGCTATCATCTCTGCACATGCTTAGTGAGAAGACTACACAACATTTCTAAG AATCTGAGAT TTTATATTGTCAGTTAACCACTTT CAT T AT T CAT T C AC C T C AG GAC AT G C AGAAAT AT T T C AGT C AGAAC T GGGAAACAGAAGGACCTACATT CT GCT GT CACTTAT GT GT CAAGAAGCAGAT GAT CGAT GAGGCAGGT C AGT T GT AAGT GAGT CACAT T GT AGCAT T AAAT T CT AGT AT T T T T GT AGT T T GAAACAGT AACT T AAT AAA AGAGCAAAAGCTATTCTAGCTTTCTTCTTCATATTTTAATTTTCCACCATAAAGTTTAGT TGCTAAATTC TATTAATTTTAAGATTGTGCTTCCCAAAATAGTTCTCACTTCATCTGTCCAGGGAGGCAC AGTTCTGTCT GGTAGAAGCCGCAAAGCCCTTAGCCTCTTCACGGATCTGGCGACTGTGATGGGCAGGTCA GGAGAGGAGC TGCCCAAAGTCCCATGATTTTCACCTAACAGCCCTGATCAGTCAGTACTCAAAGCTTGGA CTCCATCCCT GAAGGTCTTCCTGATTGATAGCCTGGCCTTAATACCCTACAGAAAGCCTGTCCATTGGCT GTTTCTTCCT CAGTCAGTTCCTGGAAGACCTTACCCCATGACCCCAGCTTCAGATGTGGTCTTTGGAAAC AGAGGTCGAA GGAAAGTAAGGAGCTGAGAGCTCACATTCATAGGTGCCGCCAGCCTTCGTGCATCTTCTT GCATCATCTC TAAGGAGCTCCTCTAATTACACCATGCCCGTCACCCCATGAGGGATCAGAGAAGGGATGA GTCTTCTAAA CTCTATATTCGCTGTGAGTCCAGGTTGTAAGGGGGAGCACTGTGGATGCATCCTATTGCA CTCCAGCTGA TGACACCAAAGCTTAGGTGTTTGCTGAAAGTTCTTGATGTTGTGACTTACCACCCCTGCC TCACAACTGC AGACATAAGGGGACTATGGATTGCTTAGCAGGAAAGGCACTGGTTCTCAAGGGCGGCTGC CCTTGGGAAT CTTCTGGTCCCAACCAGAAAGACTGTGGCTTGATTTTCTCAGGTGCAGCCCAGCCGTAGG GCCTTTTCAG AGCACCCCCTGGTTATTGCAACATTCATCAAAGTTTCTAGAACCTCTGGCCTAAAGGAAG GGCCTGGTGG GATCTACTTGGCACTCGCTGGGGGGCCACCCCCCAGTGCCACTCTCACTAGGCCTCTGAT TGCACTTGTG TAGGATGAAGCTGGTGGGTGATGGGAACTCAGCACCTCCCCTCAGGCAGAAAAGAATCAT CTGTGGAGCT TCAAAAGAAGGGGCCTGGAGTCTCTGCAGACCAATTCAACCCAAATCTCGGGGGCTCTTT CATGATTCTA ATGGGCAACCAGGGTTGAAACCCTTATTTCTAGGGTCTTCAGTTGTACAAGACTGTGGGT CTGTACCAGA GCCCCCGTCAGAGTAGAATAAAAGGCTGGGTAGGGTAGAGATTCCCATGTGCAGTGGAGA GAACAATCTG CAGTCACTGATAAGCCTGAGACTTGGCTCATTTCAAAAGCGTTCAATTCATCCTCACCAG CAGTTCAGCT GGAAAGGGGCAAATACCCCCACCTGAGCTTTGAAAACGCCCTGGGACCCTCTGCATTCTC TAAGTAAGTT ATAGAAACCAGTCTCTTCCCTCCTTTGTGAGTGAGCTGCTATTCCACGTAGGCAACACCT GTTGAAATTG CCCTCAATGTCTACTCTGCATTTCTTTCTTGTGATAAGCACACACTTTTATTGCAACATA ATGATCTGCT CACATTTCCTTGCCTGGGGGCTGTAAAACCTTACAGAACAGAAATCCTTGCCTCTTTCAC CAGCCACACC TGCCATACCAGGGGTACAGCTTTGTACTATTGAAGACACAGACAGGATTTTTAAATGTAA ATCTATTTTT GTAACTTTGTTGCGGGATATAGTTCTCTTTATGTAGCACTGAACTTTGTACAATATATTT TTAGAAACTC ATTTTTCTACTAAAACAAACACAGTTTACTTTAGAGAGACTGCAATAGAATCAAAATTTG AAACTGAAAT CTTTGTTTAAAAGGGTTAAGTTGAGGCAAGAGGAAAGCCCTTTCTCTCTCTTATAAAAAG GCACAACCTC ATTGGGGAGCTAAGCTAGGTCATTGTCATGGTGAAGAAGAGAAGCATCGTTTTTATATTT AGGAAATTTT AAAAGATGATGGAAAGCACATTTAGCTTGGTCTGAGGCAGGTTCTGTTGGGGCAGTGTTA ATGGAAAGGG CTCACTGTTGTTACTACTAGAAAAATCCAGTTGCATGCCATACTCTCATCATCTGCCAGT GTAACCCTGT ACATGTAAGAAAAGCAATAACATAGCACTTTGTTGGTTTATATATATAATGTGACTTCAA TGCAAATTTT ATTTTTATATTTACAATTGATATGCATTTACCAGTATAAACTAGACATGTCTGGAGAGCC TAATAATGTT CAGCACACTTTGGTTAGTTCACCAACAGTCTTACCAAGCCTGGGCCCAGCCACCCTAGAG AAGTTATTCA GCCCTGGCTGCAGTGACATCACCTGAGGAGCTTTTAAAAGCTTGAAGCCCAGCTACACCT CAGACCGATT AAACGCAAATCTCTGGGGCTGAAACCCAAGCATTCGTAGTTTTTAAAGCTCCTGAGGTCA TTCCAATGTG CGGCCAAAGTTGAGAACTACTGGCCTAGGGATTAGCCACAAGGACATGGACTTGGAGGCA AATTCTGCAG GTGTATGTGATTCTCAGGCCTAGAGAGCTAAGACACAAAGACCTCCACATCTGTCGCTGA GAGTCAAGAA CCTGAACAGAGTTTCCATGAAGGTTCTCCAAGCACTAGAAGGGAGAGTGTCTAAACAATG GTTGAAAAGC AAAGGAAATATAAAACAGACACCTCTTTCCATTTCCTAAGGTTTCTCTCTTTATTAAGGG TGGACTAGTA ATAAAATATAATATTCTTGCTGCTTATGCAGCTGACATTGTTGCCCTCCCTAAAGCAACC AAGTAGCCTT TATTTCCCACAGTGAAAGAAAACGCTGGCCTATCAGTTACATTACAAAAGGCAGATTTCA AGAGGATTGA GTAAGTAGTTGGATGGCTTTCATAAAAACAAGAATTCAAGAAGAGGATTCATGCTTTAAG AAACATTTGT TATACATTCCTCACAAATTATACCTGGGATAAAAACTATGTAGCAGGCAGTGTGTTTTCC TTCCATGTCT CTCTGCACTACCTGCAGTGTGTCCTCTGAGGCTGCAAGTCTGTCCTATCTGAATTCCCAG CAGAAGCACT AAGAAGCTCCACCCTATCACCTAGCAGATAAAACTATGGGGAAAACTTAAATCTGTGCAT ACATTTCTGG ATGCATTTACTTATCTTTAAAAAAAAAGGAATCCTATGACCTGATTTGGCCACAAAAATA ATCTTGCTGT ACAATACAATCTCTTGGAAATTAAGAGATCCTATGGATTTGATGACTGGTATTAGAGGTG ACAATGTAAC CGATTAACAACAGACAGCAATAACTTCGTTTTAGAAACATTCAAGCAATAGCTTTATAGC TTCAACATAT GGTACGTTTTAACCTTGAAAGTTTTGCAATGATGAAAGCAGTATTTGTACAAATGAAAAG CAGAATTCTC T T T T AT AT GGT T TAT ACT GT T GAT CAGAAAT GT T GAT T GT GCAT T GAGT AT T AAAAAAT T AGAT GT AT AT TATTCATTGTTCTTTACTCCTGAGTACCTTATAATAATAATAATGTATTCTTTGTTAACA A [0137] NM_001005862.3 Homo sapiens erb-b2 receptor tyrosine kinase 2 (ERBB2), transcript variant 2, mRNA (SEQ ID NO: 6)

GTTCTTTATTCTACTCTCCGCTGAAGTCCACACAGTTTAAATTAAAGTTCCCGGATT TTTGTGGGCGCCT GCCCCGCCCCTCGTCCCCCTGCTGTGTCCATATATCGAGGCGATAGGGTTAAGGGAAGGC GGACGCCTGA

TGGGTTAATGAGCAAACTGAAGTGTTTTCCATGATCTTTTTTGAGTCGCAATTGAAG TACCACCTCCCGA GGGTGATTGCTTCCCCATGCGGGGTAGAACCTTTGCTGTCCTGTTCACCACTCTACCTCC AGCACAGAAT

TTGGCTTATGCCTACTCAATGTGAAGATGATGAGGATGAAAACCTTTGTGATGATCC ACTTCCACTTAAT GAATGGTGGCAAAGCAAAGCTATATTCAAGACCACATGCAAAGCTACTCCCTGAGCAAAG AGTCACAGAT

AAAACGGGGGCACCAGTAGAATGGCCAGGACAAACGCAGTGCAGCACAGAGACTCAG ACCCTGGCAGCCA TGCCTGCGCAGGCAGTGATGAGAGTGACATGTACTGTTGTGGACATGCACAAAAGTGAGT GTGCACCGGC

ACAGACATGAAGCTGCGGCTCCCTGCCAGTCCCGAGACCCACCTGGACATGCTCCGC CACCTCTACCAGG GCTGCCAGGTGGTGCAGGGAAACCTGGAACTCACCTACCTGCCCACCAATGCCAGCCTGT CCTTCCTGCA GGATATCCAGGAGGTGCAGGGCTACGTGCTCATCGCTCACAACCAAGTGAGGCAGGTCCC ACTGCAGAGG CTGCGGATTGTGCGAGGCACCCAGCTCTTTGAGGACAACTATGCCCTGGCCGTGCTAGAC AATGGAGACC CGCTGAACAATACCACCCCTGTCACAGGGGCCTCCCCAGGAGGCCTGCGGGAGCTGCAGC TTCGAAGCCT CACAGAGATCTTGAAAGGAGGGGTCTTGATCCAGCGGAACCCCCAGCTCTGCTACCAGGA CACGATTTTG TGGAAGGACATCTTCCACAAGAACAACCAGCTGGCTCTCACACTGATAGACACCAACCGC TCTCGGGCCT GCCACCCCTGTTCTCCGATGTGTAAGGGCTCCCGCTGCTGGGGAGAGAGTTCTGAGGATT GTCAGAGCCT GACGCGCACTGTCTGTGCCGGTGGCTGTGCCCGCTGCAAGGGGCCACTGCCCACTGACTG CTGCCATGAG CAGTGTGCTGCCGGCTGCACGGGCCCCAAGCACTCTGACTGCCTGGCCTGCCTCCACTTC AACCACAGTG GCATCTGTGAGCTGCACTGCCCAGCCCTGGTCACCTACAACACAGACACGTTTGAGTCCA TGCCCAATCC CGAGGGCCGGTATACATTCGGCGCCAGCTGTGTGACTGCCTGTCCCTACAACTACCTTTC TACGGACGTG GGATCCTGCACCCTCGTCTGCCCCCTGCACAACCAAGAGGTGACAGCAGAGGATGGAACA CAGCGGTGTG AGAAGTGCAGCAAGCCCTGTGCCCGAGTGTGCTATGGTCTGGGCATGGAGCACTTGCGAG AGGTGAGGGC AGTTACCAGTGCCAATATCCAGGAGTTTGCTGGCTGCAAGAAGATCTTTGGGAGCCTGGC ATTTCTGCCG GAGAGCTTTGATGGGGACCCAGCCTCCAACACTGCCCCGCTCCAGCCAGAGCAGCTCCAA GTGTTTGAGA CTCTGGAAGAGATCACAGGTTACCTATACATCTCAGCATGGCCGGACAGCCTGCCTGACC TCAGCGTCTT CCAGAACCTGCAAGTAATCCGGGGACGAATTCTGCACAATGGCGCCTACTCGCTGACCCT GCAAGGGCTG GGCATCAGCTGGCTGGGGCTGCGCTCACTGAGGGAACTGGGCAGTGGACTGGCCCTCATC CACCATAACA CCCACCTCTGCTTCGTGCACACGGTGCCCTGGGACCAGCTCTTTCGGAACCCGCACCAAG CTCTGCTCCA CACTGCCAACCGGCCAGAGGACGAGTGTGTGGGCGAGGGCCTGGCCTGCCACCAGCTGTG CGCCCGAGGG CACTGCTGGGGTCCAGGGCCCACCCAGTGTGTCAACTGCAGCCAGTTCCTTCGGGGCCAG GAGTGCGTGG

AGGAATGCCGAGTACTGCAGGGGCTCCCCAGGGAGTATGTGAATGCCAGGCACTGTT TGCCGTGCCACCC TGAGTGTCAGCCCCAGAATGGCTCAGTGACCTGTTTTGGACCGGAGGCTGACCAGTGTGT GGCCTGTGCC

CACTATAAGGACCCTCCCTTCTGCGTGGCCCGCTGCCCCAGCGGTGTGAAACCTGAC CTCTCCTACATGC CCATCTGGAAGTTTCCAGATGAGGAGGGCGCATGCCAGCCTTGCCCCATCAACTGCACCC ACTCCTGTGT

GGACCTGGATGACAAGGGCTGCCCCGCCGAGCAGAGAGCCAGCCCTCTGACGTCCAT CATCTCTGCGGTG GTTGGCATTCTGCTGGTCGTGGTCTTGGGGGTGGTCTTTGGGATCCTCATCAAGCGACGG CAGCAGAAGA

TCCGGAAGTACACGATGCGGAGACTGCTGCAGGAAACGGAGCTGGTGGAGCCGCTGA CACCTAGCGGAGC GATGCCCAACCAGGCGCAGATGCGGATCCTGAAAGAGACGGAGCTGAGGAAGGTGAAGGT GCTTGGATCT GGCGCTTTTGGCACAGTCTACAAGGGCATCTGGATCCCTGATGGGGAGAATGTGAAAATT CCAGTGGCCA

TCAAAGTGTTGAGGGAAAACACATCCCCCAAAGCCAACAAAGAAATCTTAGACGAAG CATACGTGATGGC TGGTGTGGGCTCCCCATATGTCTCCCGCCTTCTGGGCATCTGCCTGACATCCACGGTGCA GCTGGTGACA

CAGCTTATGCCCTATGGCTGCCTCTTAGACCATGTCCGGGAAAACCGCGGACGCCTG GGCTCCCAGGACC TGCTGAACTGGTGTATGCAGATTGCCAAGGGGATGAGCTACCTGGAGGATGTGCGGCTCG TACACAGGGA

CTTGGCCGCTCGGAACGTGCTGGTCAAGAGTCCCAACCATGTCAAAATTACAGACTT CGGGCTGGCTCGG CTGCTGGACATTGACGAGACAGAGTACCATGCAGATGGGGGCAAGGTGCCCATCAAGTGG ATGGCGCTGG

AGTCCATTCTCCGCCGGCGGTTCACCCACCAGAGTGATGTGTGGAGTTATGGTGTGA CTGTGTGGGAGCT GATGACTTTTGGGGCCAAACCTTACGATGGGATCCCAGCCCGGGAGATCCCTGACCTGCT GGAAAAGGGG GAGCGGCTGCCCCAGCCCCCCATCTGCACCATTGATGTCTACATGATCATGGTCAAATGT TGGATGATTG

ACTCTGAATGTCGGCCAAGATTCCGGGAGTTGGTGTCTGAATTCTCCCGCATGGCCA GGGACCCCCAGCG CTTTGTGGTCATCCAGAATGAGGACTTGGGCCCAGCCAGTCCCTTGGACAGCACCTTCTA CCGCTCACTG CTGGAGGACGATGACATGGGGGACCTGGTGGATGCTGAGGAGTATCTGGTACCCCAGCAG GGCTTCTTCT GTCCAGACCCTGCCCCGGGCGCTGGGGGCATGGTCCACCACAGGCACCGCAGCTCATCTA CCAGGAGTGG CGGTGGGGACCTGACACTAGGGCTGGAGCCCTCTGAAGAGGAGGCCCCCAGGTCTCCACT GGCACCCTCC GAAGGGGCTGGCTCCGATGTATTTGATGGTGACCTGGGAATGGGGGCAGCCAAGGGGCTG CAAAGCCTCC CCACACATGACCCCAGCCCTCTACAGCGGTACAGTGAGGACCCCACAGTACCCCTGCCCT CTGAGACTGA TGGCTACGTTGCCCCCCTGACCTGCAGCCCCCAGCCTGAATATGTGAACCAGCCAGATGT TCGGCCCCAG CCCCCTTCGCCCCGAGAGGGCCCTCTGCCTGCTGCCCGACCTGCTGGTGCCACTCTGGAA AGGCCCAAGA CTCTCTCCCCAGGGAAGAATGGGGTCGTCAAAGACGTTTTTGCCTTTGGGGGTGCCGTGG AGAACCCCGA GTACTTGACACCCCAGGGAGGAGCTGCCCCTCAGCCCCACCCTCCTCCTGCCTTCAGCCC AGCCTTCGAC AACCTCTATTACTGGGACCAGGACCCACCAGAGCGGGGGGCTCCACCCAGCACCTTCAAA GGGACACCTA CGGCAGAGAACCCAGAGTACCTGGGTCTGGACGTGCCAGTGTGAACCAGAAGGCCAAGTC CGCAGAAGCC CTGATGTGTCCTCAGGGAGCAGGGAAGGCCTGACTTCTGCTGGCATCAAGAGGTGGGAGG GCCCTCCGAC CACTTCCAGGGGAACCTGCCATGCCAGGAACCTGTCCTAAGGAACCTTCCTTCCTGCTTG AGTTCCCAGA TGGCTGGAAGGGGTCCAGCCTCGTTGGAAGAGGAACAGCACTGGGGAGTCTTTGTGGATT CTGAGGCCCT GCCCAATGAGACTCTAGGGTCCAGTGGATGCCACAGCCCAGCTTGGCCCTTTCCTTCCAG ATCCTGGGTA CTGAAAGCCTTAGGGAAGCTGGCCTGAGAGGGGAAGCGGCCCTAAGGGAGTGTCTAAGAA CAAAAGCGAC CCATTCAGAGACTGTCCCTGAAACCTAGTACTGCCCCCCATGAGGAAGGAACAGCAATGG TGTCAGTATC CAGGCTTTGTACAGAGTGCTTTTCTGTTTAGTTTTTACTTTTTTTGTTTTGTTTTTTTAA AGATGAAATA AAGACCCAGGGGGAGAATGGGTGTTGTATGGGGAGGCAAGTGTGGGGGGTCCTTCTCCAC ACCCACTTTG T C CAT T T G C AAAT AT AT T T T G GAAAAC A

[0138] NM 000141.5 Homo sapiens fibroblast growth factor receptor 2 (FGFR2), transcript variant 1, mRNA (SEQ ID NO: 7)

GAGAGCGCGGTGGAGAGCCGAGCGGGCGGGCGGCGGGTGCGGAGCGGGCGAGGGAGC GCGCGCGGCCGCC ACAAAGCTCGGGCGCCGCGGGGCTGCATGCGGCGTACCTGGCCCGGCGCGGCGACTGCTC TCCGGGCTGG CGGGGGCCGGCCGCGAGCCCCGGGGGCCCCGAGGCCGCAGCTTGCCTGCGCGCTCTGAGC CTTCGCAACT CGCGAGCAAAGTTTGGTGGAGGCAACGCCAAGCCTGAGTCCTTTCTTCCTCTCGTTCCCC AAATCCGAGG GCAGCCCGCGGGCGTCATGCCCGCGCTCCTCCGCAGCCTGGGGTACGCGTGAAGCCCGGG AGGCTTGGCG CCGGCGAAGACCCAAGGACCACTCTTCTGCGTTTGGAGTTGCTCCCCGCAACCCCGGGCT CGTCGCTTTC TCCATCCCGACCCACGCGGGGCGCGGGGACAACACAGGTCGCGGAGGAGCGTTGCCATTC AAGTGACTGC AGCAGCAGCGGCAGCGCCTCGGTTCCTGAGCCCACCGCAGGCTGAAGGCATTGCGCGTAG TCCATGCCCG TAGAGGAAGTGTGCAGATGGGATTAACGTCCACATGGAGATATGGAAGAGGACCGGGGAT TGGTACCGTA ACCATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGTCC CTGGCCCGGC CCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGAGCCACCAACCAAATACC AAATCTCTCA ACCAGAAGTGTACGTGGCTGCGCCAGGGGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGA TGCCGCCGTG ATCAGTTGGACTAAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGG GAGTACTTGC AGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCAGTAGGACTG TAGACAGTGA AACTTGGTACTTCATGGTGAATGTCACAGATGCCATCTCATCCGGAGATGATGAGGATGA CACCGATGGT GCGGAAGATTTTGTCAGTGAGAACAGTAACAACAAGAGAGCACCATACTGGACCAACACA GAAAAGATGG AAAAGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGGGG GGAACCCAAT GCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCAGGAGCATCGCATTGGAGG CTACAAGGTA CGAAACCAGCACTGGAGCCTCATTATGGAAAGTGTGGTCCCATCTGACAAGGGAAATTAT ACCTGTGTAG TGGAGAATGAATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGC CTCACCGGCC CATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGAGACGTAGAGTT TGTCTGCAAG GTTTACAGTGATGCCCAGCCCCACATCCAGTGGATCAAGCACGTGGAAAAGAACGGCAGT AAATACGGGC CCGACGGGCTGCCCTACCTCAAGGTTCTCAAGGCCGCCGGTGTTAACACCACGGACAAAG AGATTGAGGT TCTCTATATTCGGAATGTAACTTTTGAGGACGCTGGGGAATATACGTGCTTGGCGGGTAA TTCTATTGGG ATATCCTTTCACTCTGCATGGTTGACAGTTCTGCCAGCGCCTGGAAGAGAAAAGGAGATT ACAGCTTCCC CAGACTACCTGGAGATAGCCATTTACTGCATAGGGGTCTTCTTAATCGCCTGTATGGTGG TAACAGTCAT CCTGTGCCGAATGAAGAACACGACCAAGAAGCCAGACTTCAGCAGCCAGCCGGCTGTGCA CAAGCTGACC AAACGTATCCCCCTGCGGAGACAGGTAACAGTTTCGGCTGAGTCCAGCTCCTCCATGAAC TCCAACACCC CGCTGGTGAGGATAACAACACGCCTCTCTTCAACGGCAGACACCCCCATGCTGGCAGGGG TCTCCGAGTA TGAACTTCCAGAGGACCCAAAATGGGAGTTTCCAAGAGATAAGCTGACACTGGGCAAGCC CCTGGGAGAA GGTTGCTTTGGGCAAGTGGTCATGGCGGAAGCAGTGGGAATTGACAAAGACAAGCCCAAG GAGGCGGTCA CCGTGGCCGTGAAGATGTTGAAAGATGATGCCACAGAGAAAGACCTTTCTGATCTGGTGT CAGAGATGGA GATGATGAAGATGATTGGGAAACACAAGAATATCATAAATCTTCTTGGAGCCTGCACACA GGATGGGCCT CTCTATGTCATAGTTGAGTATGCCTCTAAAGGCAACCTCCGAGAATACCTCCGAGCCCGG AGGCCACCCG GGATGGAGTACTCCTATGACATTAACCGTGTTCCTGAGGAGCAGATGACCTTCAAGGACT TGGTGTCATG CACCTACCAGCTGGCCAGAGGCATGGAGTACTTGGCTTCCCAAAAATGTATTCATCGAGA TTTAGCAGCC AGAAATGTTTTGGTAACAGAAAACAATGTGATGAAAATAGCAGACTTTGGACTCGCCAGA GATATCAACA ATATAGACTATTACAAAAAGACCACCAATGGGCGGCTTCCAGTCAAGTGGATGGCTCCAG AAGCCCTGTT TGATAGAGTATACACTCATCAGAGTGATGTCTGGTCCTTCGGGGTGTTAATGTGGGAGAT CTTCACTTTA GGGGGCTCGCCCTACCCAGGGATTCCCGTGGAGGAACTTTTTAAGCTGCTGAAGGAAGGA CACAGAATGG ATAAGCCAGCCAACTGCACCAACGAACTGTACATGATGATGAGGGACTGTTGGCATGCAG TGCCCTCCCA GAGACCAACGTTCAAGCAGTTGGTAGAAGACTTGGATCGAATTCTCACTCTCACAACCAA TGAGGAATAC TTGGACCTCAGCCAACCTCTCGAACAGTATTCACCTAGTTACCCTGACACAAGAAGTTCT TGTTCTTCAG GAGATGATTCTGTTTTTTCTCCAGACCCCATGCCTTACGAACCATGCCTTCCTCAGTATC CACACATAAA CGGCAGTGTTAAAACATGAATGACTGTGTCTGCCTGTCCCCAAACAGGACAGCACTGGGA ACCTAGCTAC ACTGAGCAGGGAGACCATGCCTCCCAGAGCTTGTTGTCTCCACTTGTATATATGGATCAG AGGAGTAAAT AATTGGAAAAGTAATCAGCATATGTGTAAAGATTTATACAGTTGAAAACTTGTAATCTTC CCCAGGAGGA GAAGAAGGTTTCTGGAGCAGTGGACTGCCACAAGCCACCATGTAACCCCTCTCACCTGCC GTGCGTACTG GCTGTGGACCAGTAGGACTCAAGGTGGACGTGCGTTCTGCCTTCCTTGTTAATTTTGTAA TAATTGGAGA AGATTTAT GT CAGCACACACTTACAGAGCACAAAT GCAGTATATAGGT GCT GGAT GTAT GTAAATATATT CAAAT TAT GT AT AAAT AT AT AT TAT AT AT T T ACAAGGAGT TAT T T T T T GTAT T GAT T T T AAAT GGAT GT C CCAATGCACCTAGAAAATTGGTCTCTCTTTTTTTAATAGCTATTTGCTAAATGCTGTTCT TACACATAAT TTCTTAATTTTCACCGAGCAGAGGTGGAAAAATACTTTTGCTTTCAGGGAAAATGGTATA ACGTTAATTT AT T AAT AAAT T G GT AAT AT AC AAAACAAT T AAT CAT TTATAGTTTTTTTT GT AAT T T AAGT G G CAT T T C T ATGCAGGCAGCACAGCAGACTAGTTAATCTATTGCTTGGACTTAACTAGTTATCAGATCC TTTGAAAAGA GAATATTTACAATATATGACTAATTTGGGGAAAATGAAGTTTTGATTTATTTGTGTTTAA ATGCTGCTGT CAGACGATTGTTCTTAGACCTCCTAAATGCCCCATATTAAAAGAACTCATTCATAGGAAG GTGTTTCATT TTGGTGTGCAACCCTGTCATTACGTCAACGCAACGTCTAACTGGACTTCCCAAGATAAAT GGTACCAGCG TCCTCTTAAAAGATGCCTTAATCCATTCCTTGAGGACAGACCTTAGTTGAAATGATAGCA GAATGTGCTT CTCTCTGGCAGCTGGCCTTCTGCTTCTGAGTTGCACATTAATCAGATTAGCCTGTATTCT CTTCAGTGAA TTTTGATAATGGCTTCCAGACTCTTTGGCGTTGGAGACGCCTGTTAGGATCTTCAAGTCC CATCATAGAA AATTGAAACACAGAGTTGTTCTGCTGATAGTTTTGGGGATACGTCCATCTTTTTAAGGGA TTGCTTTCAT CTAATTCTGGCAGGACCTCACCAAAAGATCCAGCCTCATACCTACATCAGACAAAATATC GCCGTTGTTC CTTCTGTACTAAAGTATTGTGTTTTGCTTTGGAAACACCCACTCACTTTGCAATAGCCGT GCAAGATGAA TGCAGATTACACTGATCTTATGTGTTACAAAATTGGAGAAAGTATTTAATAAAACCTGTT AATTTTTATA C T GAC AAT AAAAAT GT T T C T AC AGAT AT T AAT GT T AAC AAGAC AAAAT AAAT GT C AC G C AAC T T AT T T T T TTAA

[0139] NM 001163213.2 Homo sapiens fibroblast growth factor receptor 3 (FGFR3), transcript variant 3, mRNA (SEQ ID NO: 8)

AGTGCGCGGTGGCGGCGGCGTCGCGGGCAGCTGGCGCCGCGCGGTCCTGCTCTGCCG GTCGCACGGACGC ACCGGCGGGCCGCCGGCCGGAGGGACGGGGCGGGAGCTGGGCCCGCGGACAGCGAGCCGG AGCGGGAGCC GCGCGTAGCGAGCCGGGCTCCGGCGCTCGCCAGTCTCCCGAGCGGCGCCCGCCTCCCGCC GGTGCCCGCG CCGGGCCGTGGGGGGCAGCATGCCCGCGCGCGCTGCCTGAGGACGCCGCGGCCCCCGCCC CCGCCATGGG CGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCCGGCGCCTCCTC GGAGTCCTTG GGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCAGAAGTCCCGGGCCCAGAGCCCGGCCAG CAGGAGCAGT TGGTCTTCGGCAGCGGGGATGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGGTCCCA TGGGGCCCAC TGTCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGCCCCA GCGGCTGCAG GTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCTGCCGGCAGCGGCTCACGCAG CGCGTACTGT GCCACTTCAGTGTGCGGGTGACAGACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGG ACGAGGCTGA GGACACAGGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAA GCTGCTGGCC GTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCAACCCCACTCCCTCC ATCTCCTGGC TGAAGAACGGCAGGGAGTTCCGCGGCGAGCACCGCATTGGAGGCATCAAGCTGCGGCATC AGCAGTGGAG CCTGGTCATGGAAAGCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAA CAAGTTTGGC AGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGCCCATCCTG CAGGCGGGGC TGCCGGCCAACCAGACGGCGGTGCTGGGCAGCGACGTGGAGTTCCACTGCAAGGTGTACA GTGACGCACA GCCCCACATCCAGTGGCTCAAGCACGTGGAGGTGAATGGCAGCAAGGTGGGCCCGGACGG CACACCCTAC GTTACCGTGCTCAAGTCCTGGATCAGTGAGAGTGTGGAGGCCGACGTGCGCCTCCGCCTG GCCAATGTGT CGGAGCGGGACGGGGGCGAGTACCTCTGTCGAGCCACCAATTTCATAGGCGTGGCCGAGA AGGCCTTTTG GCTGAGCGTTCACGGGCCCCGAGCAGCCGAGGAGGAGCTGGTGGAGGCTGACGAGGCGGG CAGTGTGTAT GCAGGCATCCTCAGCTACGGGGTGGGCTTCTTCCTGTTCATCCTGGTGGTGGCGGCTGTG ACGCTCTGCC GCCTGCGCAGCCCCCCCAAGAAAGGCCTGGGCTCCCCCACCGTGCACAAGATCTCCCGCT TCCCGCTCAA GCGACAGGTGTCCCTGGAGTCCAACGCGTCCATGAGCTCCAACACACCACTGGTGCGCAT CGCAAGGCTG TCCTCAGGGGAGGGCCCCACGCTGGCCAATGTCTCCGAGCTCGAGCTGCCTGCCGACCCC AAATGGGAGC TGTCTCGGGCCCGGCTGACCCTGGGCAAGCCCCTTGGGGAGGGCTGCTTCGGCCAGGTGG TCATGGCGGA GGCCATCGGCATTGACAAGGACCGGGCCGCCAAGCCTGTCACCGTAGCCGTGAAGATGCT GAAAGACGAT GCCACTGACAAGGACCTGTCGGACCTGGTGTCTGAGATGGAGATGATGAAGATGATCGGG AAACACAAAA ACATCATCAACCTGCTGGGCGCCTGCACGCAGGGCGGGCCCCTGTACGTGCTGGTGGAGT ACGCGGCCAA GGGTAACCTGCGGGAGTTTCTGCGGGCGCGGCGGCCCCCGGGCCTGGACTACTCCTTCGA CACCTGCAAG CCGCCCGAGGAGCAGCTCACCTTCAAGGACCTGGTGTCCTGTGCCTACCAGGTGGCCCGG GGCATGGAGT ACTTGGCCTCCCAGAAGTGCATCCACAGGGACCTGGCTGCCCGCAATGTGCTGGTGACCG AGGACAACGT GATGAAGATCGCAGACTTCGGGCTGGCCCGGGACGTGCACAACCTCGACTACTACAAGAA GACGACCAAC GGCCGGCTGCCCGTGAAGTGGATGGCGCCTGAGGCCTTGTTTGACCGAGTCTACACTCAC CAGAGTGACG TCTGGTCCTTTGGGGTCCTGCTCTGGGAGATCTTCACGCTGGGGGGCTCCCCGTACCCCG GCATCCCTGT GGAGGAGCTCTTCAAGCTGCTGAAGGAGGGCCACCGCATGGACAAGCCCGCCAACTGCAC ACACGACCTG TACATGATCATGCGGGAGTGCTGGCATGCCGCGCCCTCCCAGAGGCCCACCTTCAAGCAG CTGGTGGAGG ACCTGGACCGTGTCCTTACCGTGACGTCCACCGACGAGTACCTGGACCTGTCGGCGCCTT TCGAGCAGTA CTCCCCGGGTGGCCAGGACACCCCCAGCTCCAGCTCCTCAGGGGACGACTCCGTGTTTGC CCACGACCTG CTGCCCCCGGCCCCACCCAGCAGTGGGGGCTCGCGGACGTGAAGGGCCACTGGTCCCCAA CAATGTGAGG GGTCCCTAGCAGCCCACCCTGCTGCTGGTGCACAGCCACTCCCCGGCATGAGACTCAGTG CAGATGGAGA GACAGCTACACAGAGCTTTGGTCTGTGTGTGTGTGTGTGCGTGTGTGTGTGTGTGTGTGC ACATCCGCGT GTGCCTGTGTGCGTGCGCATCTTGCCTCCAGGTGCAGAGGTACCCTGGGTGTCCCCGCTG CTGTGCAACG GTCTCCTGACTGGTGCTGCAGCACCGAGGGGCCTTTGTTCTGGGGGGACCCAGTGCAGAA TGTAAGTGGG CCCACCCGGTGGGACCCCCGTGGGGCAGGGAGCTGGGCCCGACATGGCTCCGGCCTCTGC CTTTGCACCA CGGGACATCACAGGGTGGGCCTCGGCCCCTCCCACACCCAAAGCTGAGCCTGCAGGGAAG CCCCACATGT CCAGCACCTTGTGCCTGGGGTGTTAGTGGCACCGCCTCCCCACCTCCAGGCTTTCCCACT TCCCACCCTG CCCCTCAGAGACTGAAATTACGGGTACCTGAAGATGGGAGCCTTTACCTTTTATGCAAAA GGTTTATTCC GGAAACTAGT GTACATTT CTATAAATAGAT GCT GT GTATAT GGTATATATACATATATATATATAACATA TATGGAAGAGGAAAAGGCTGGTACAACGGAGGCCTGCGACCCTGGGGGCACAGGAGGCAG GCATGGCCCT GGGCGGGGCGTGGGGGGGCGTGGAGGGAGGCCCCAGGGGGTCTCACCCATGCAAGCAGAG GACCAGGGCC TTTTCTGGCACCGCAGTTTTGTTTTAAAACTGGACCTGTATATTTGTAAAGCTATTTATG GGCCCCTGGC ACTCTTGTTCCCACACCCCAACACTTCCAGCATTTAGCTGGCCACATGGCGGAGAGTTTT AATTTTTAAC TTATTGACAACCGAGAAGGTTTATCCCGCCGATAGAGGGACGGCCAAGAATGTACGTCCA GCCTGCCCCG GAGCTGGAGGATCCCCTCCAAGCCTAAAAGGTTGTTAATAGTTGGAGGTGATTCCAGTGA AGATATTTTA TTTCCTTTGTCCTTTTTCAGGAGAATTAGATTTCTATAGGATTTTTCTTTAGGAGATTTA TTTTTTGGAC TTCAAAGCAAGCTGGTATTTTCATACAAATTCTTCTAATTGCTGTGTGTCCCAGGCAGGG AGACGGTTTC CAGGGAGGGGCCGGCCCTGTGTGCAGGTTCCGATGTTATTAGATGTTACAAGTTTATATA TATCTATATA TATAATTTATTGAGTTTTTACAAGATGTATTTGTTGTAGACTTAACACTTCTTACGCAAT GCTTCTAGAG TTTTATAGCCTGGACTGCTACCTTTCAAAGCTTGGAGGGAAGCCGTGAATTCAGTTGGTT CGTTCTGTAC TGTTACTGGGCCCTGAGTCTGGGCAGCTGTCCCTTGCTTGCCTGCAGGGCCATGGCTCAG GGTGGTCTCT TCTTGGGGCCCAGTGCATGGTGGCCAGAGGTGTCACCCAAACCGGCAGGTGCGATTTTGT TAACCCAGCG ACGAACTTTCCGAAAAATAAAGACACCTGGTTGCTAA

[0140] NM 203500.2 Homo sapiens kelch like ECH associated protein 1 (KEAP1), transcript variant 1, mRNA (SEQ ID NO: 9)

CTTTTCGGGCGTCCCGAGGCCGCTCCCCAACCGACAACCAAGACCCCGCAGGCCACG CAGCCCTGGAGCC GAGGCCCCCCGACGGCGGAGGCGCCCGCGGGTCCCCTACAGCCAAGGTCCCTGAGTGCCA GAGGTGGTGG TGTTGCTTATCTTCTGGAACCCCATGCAGCCAGATCCCAGGCCTAGCGGGGCTGGGGCCT GCTGCCGATT CCTGCCCCTGCAGTCACAGTGCCCTGAGGGGGCAGGGGACGCGGTGATGTACGCCTCCAC TGAGTGCAAG GCGGAGGTGACGCCCTCCCAGCATGGCAACCGCACCTTCAGCTACACCCTGGAGGATCAT ACCAAGCAGG CCTTTGGCATCATGAACGAGCTGCGGCTCAGCCAGCAGCTGTGTGACGTCACACTGCAGG TCAAGTACCA GGATGCACCGGCCGCCCAGTTCATGGCCCACAAGGTGGTGCTGGCCTCATCCAGCCCTGT CTTCAAGGCC ATGTTCACCAACGGGCTGCGGGAGCAGGGCATGGAGGTGGTGTCCATTGAGGGTATCCAC CCCAAGGTCA TGGAGCGCCTCATTGAATTCGCCTACACGGCCTCCATCTCCATGGGCGAGAAGTGTGTCC TCCACGTCAT GAACGGTGCTGTCATGTACCAGATCGACAGCGTTGTCCGTGCCTGCAGTGACTTCCTGGT GCAGCAGCTG GACCCCAGCAATGCCATCGGCATCGCCAACTTCGCTGAGCAGATTGGCTGTGTGGAGTTG CACCAGCGTG CCCGGGAGTACATCTACATGCATTTTGGGGAGGTGGCCAAGCAAGAGGAGTTCTTCAACC TGTCCCACTG CCAACTGGTGACCCTCATCAGCCGGGACGACCTGAACGTGCGCTGCGAGTCCGAGGTCTT CCACGCCTGC ATCAACTGGGTCAAGTACGACTGCGAACAGCGACGGTTCTACGTCCAGGCGCTGCTGCGG GCCGTGCGCT GCCACTCGTTGACGCCGAACTTCCTGCAGATGCAGCTGCAGAAGTGCGAGATCCTGCAGT CCGACTCCCG CTGCAAGGACTACCTGGTCAAGATCTTCGAGGAGCTCACCCTGCACAAGCCCACGCAGGT GATGCCCTGC CGGGCGCCCAAGGTGGGCCGCCTGATCTACACCGCGGGCGGCTACTTCCGACAGTCGCTC AGCTACCTGG AGGCTTACAACCCCAGTGACGGCACCTGGCTCCGGTTGGCGGACCTGCAGGTGCCGCGGA GCGGCCTGGC CGGCTGCGTGGTGGGCGGGCTGTTGTACGCCGTGGGCGGCAGGAACAACTCGCCCGACGG CAACACCGAC TCCAGCGCCCTGGACTGTTACAACCCCATGACCAATCAGTGGTCGCCCTGCGCCCCCATG AGCGTGCCCC GTAACCGCATCGGGGTGGGGGTCATCGATGGCCACATCTATGCCGTCGGCGGCTCCCACG GCTGCATCCA CCACAACAGTGTGGAGAGGTATGAGCCAGAGCGGGATGAGTGGCACTTGGTGGCCCCAAT GCTGACACGA AGGATCGGGGTGGGCGTGGCTGTCCTCAATCGTCTCCTTTATGCCGTGGGGGGCTTTGAC GGGACAAACC GCCTTAATTCAGCTGAGTGTTACTACCCAGAGAGGAACGAGTGGCGAATGATCACAGCAA TGAACACCAT CCGAAGCGGGGCAGGCGTCTGCGTCCTGCACAACTGTATCTATGCTGCTGGGGGCTATGA TGGTCAGGAC CAGCTGAACAGCGTGGAGCGCTACGATGTGGAAACAGAGACGTGGACTTTCGTAGCCCCC ATGAAGCACC GGCGAAGTGCCCTGGGGATCACTGTCCACCAGGGGAGAATCTACGTCCTTGGAGGCTATG ATGGTCACAC GTTCCTGGACAGTGTGGAGTGTTACGACCCAGATACAGACACCTGGAGCGAGGTGACCCG AATGACATCG GGCCGGAGTGGGGTGGGCGTGGCTGTCACCATGGAGCCCTGCCGGAAGCAGATTGACCAG CAGAACTGTA CCTGTTGAGGCACTTTTGTTTCTTGGGCAAAAATACAGTCCAATGGGGAGTATCATTGTT TTTGTACAAA AACCGGGACTAAAAGAAAAGACAGCACTGCAAATAACCCATCTTCCGGGAAGGGAGGCCA GGATGCCTCA GTGTTAAAATGACATCTCAAAAGAAGTCCAAAGCGGGAATCATGTGCCCCTCAGCGGAGC CCCGGGAGTG TCCAAGACAGCCTGGCTGGGAAAGGGGGTGTGGAAAGAGCAGGCTTCCAGGAGAGAGGCC CCCAAACCCT CTGGCCGGGTAATAGGCCTGGGTCCCACTCACCCATGCCGGCAGCTGTCACCATGTGATT TATTCTTGGA TACCTGGGAGGGGGCCAATGGGGGCCTCAGGGGGAGGCCCCCTCTGGAAATGTGGTTCCC AGGGATGGGC CTGTACATAGAAGCCACCGGATGGCACTTCCCCACCGGATGGACAGTTATTTTGTTGATA AGTAACCCTG T AAT T T T C C AAG GAAAAT AAAGAAC AGAC TAACTAGTGTCTTTCA

[0141] NM 033360.4 Homo sapiens KRAS proto-oncogene, GTPase (KRAS), transcript variant a, mRNA (SEQ ID NO: 10)

CTAGGCGGCGGCCGCGGCGGCGGAGGCAGCAGCGGCGGCGGCAGTGGCGGCGGCGAA GGTGGCGGCGGCT CGGCCAGTACTCCCGGCCCCCGCCATTTCGGACTGGGAGCGAGCGCGGCGCAGGCACTGA AGGCGGCGGC GGGGCCAGAGGCTCAGCGGCTCCCAGGTGCGGGAGAGAGGCCTGCTGAAAATGACTGAAT ATAAACTTGT GGTAGTTGGAGCTGGTGGCGTAGGCAAGAGTGCCTTGACGATACAGCTAATTCAGAATCA TTTTGTGGAC GAATATGATCCAACAATAGAGGATTCCTACAGGAAGCAAGTAGTAATTGATGGAGAAACC TGTCTCTTGG ATATT CT CGACACAGCAGGT CAAGAGGAGTACAGT GCAAT GAGGGACCAGTACAT GAGGACT GGGGAGGG CTTTCTTTGTGTATTTGC C AT AAAT AAT AC T AAAT CAT T T GAAGAT AT T C AC CAT T AT AGAGAAC AAAT T AAAAGAGTTAAGGACTCTGAAGATGTACCTATGGTCCTAGTAGGAAATAAATGTGATTTG CCTTCTAGAA CAGTAGACACAAAACAGGCTCAGGACTTAGCAAGAAGTTATGGAATTCCTTTTATTGAAA CATCAGCAAA GACAAGACAGAGAGTGGAGGATGCTTTTTATACATTGGTGAGAGAGATCCGACAATACAG ATTGAAAAAA AT CAGCAAAGAAGAAAAGACT CCT GGCT GT GT GAAAAT TAAAAAAT G CAT TAT AAT GTAAT CT GGGT GTT GATGATGCCTTCTATACATTAGTTCGAGAAATTCGAAAACATAAAGAAAAGATGAGCAAA GATGGTAAAA AGAAGAAAAAGAAGT CAAAGACAAAGT GT GTAAT TAT GT AAAT ACAAT T T GT ACT T T T T T CT T AAGGCAT ACTAGTACAAGTGGTAATTTTTGTACATTACACTAAATTATTAGCATTTGTTTTAGCATT ACCTAATTTT TTTCCTGCTCCATGCAGACTGTTAGCTTTTACCTTAAATGCTTATTTTAAAATGACAGTG GAAGTTTTTT TTTCCTCTAAGTGCCAGTATTCCCAGAGTTTTGGTTTTTGAACTAGCAATGCCTGTGAAA AAGAAACTGA ATACCTAAGATTTCTGTCTTGGGGCTTTTGGTGCATGCAGTTGATTACTTCTTATTTTTC TTACCAATTG TGAATGTTGGTGTGAAACAAATTAATGAAGCTTTTGAATCATCCCTATTCTGTGTTTTAT CTAGTCACAT AAATGGATTAATTACTAATTTCAGTTGAGACCTTCTAATTGGTTTTTACTGAAACATTGA GGGAACACAA ATTTATGGGCTTCCTGATGATGATTCTTCTAGGCATCATGTCCTATAGTTTGTCATCCCT GATGAATGTA AAGTTACACTGTTCACAAAGGTTTTGTCTCCTTTCCACTGCTATTAGTCATGGTCACTCT CCCCAAAATA TTATATTTTTTCTATAAAAAGAAAAAAATGGAAAAAAATTACAAGGCAATGGAAACTATT ATAAGGCCAT TTCCTTTTCACATTAGATAAATTACTATAAAGACTCCTAATAGCTTTTCCTGTTAAGGCA GACCCAGTAT GAAATGGGGATTATTATAGCAACCATTTTGGGGCTATATTTACATGCTACTAAATTTTTA TAATAATTGA AAAGATTTTAACAAGTATAAAAAATTCTCATAGGAATTAAATGTAGTCTCCCTGTGTCAG ACTGCTCTTT CATAGTATAACTTTAAATCTTTTCTTCAACTTGAGTCTTTGAAGATAGTTTTAATTCTGC TTGTGACATT AAAAGATTATTTGGGCCAGTTATAGCTTATTAGGTGTTGAAGAGACCAAGGTTGCAAGGC CAGGCCCTGT GTGAACCTTTGAGCTTTCATAGAGAGTTTCACAGCATGGACTGTGTCCCCACGGTCATCC AGTGTTGTCA TGCATTGGTTAGTCAAAATGGGGAGGGACTAGGGCAGTTTGGATAGCTCAACAAGATACA ATCTCACTCT GTGGTGGTCCTGCTGACAAATCAAGAGCATTGCTTTTGTTTCTTAAGAAAACAAACTCTT TTTTAAAAAT TACTTTTAAATATTAACTCAAAAGTTGAGATTTTGGGGTGGTGGTGTGCCAAGACATTAA TTTTTTTTTT AAACAATGAAGTGAAAAAGTTTTACAATCTCTAGGTTTGGCTAGTTCTCTTAACACTGGT TAAATTAACA TTGCATAAACACTTTTCAAGTCTGATCCATATTTAATAATGCTTTAAAATAAAAATAAAA ACAATCCTTT TGATAAATTTAAAATGTTACTTATTTTAAAATAAATGAAGTGAGATGGCATGGTGAGGTG AAAGTATCAC TGGACTAGGAAGAAGGTGACTTAGGTTCTAGATAGGTGTCTTTTAGGACTCTGATTTTGA GGACATCACT TACTATCCATTTCTTCATGTTAAAAGAAGTCATCTCAAACTCTTAGTTTTTTTTTTTTAC AACTATGTAA TTTATATTCCATTTACATAAGGATACACTTATTTGTCAAGCTCAGCACAATCTGTAAATT TTTAACCTAT GTTACACCATCTTCAGTGCCAGTCTTGGGCAAAATTGTGCAAGAGGTGAAGTTTATATTT GAATATCCAT TCTCGTTTTAGGACTCTTCTTCCATATTAGTGTCATCTTGCCTCCCTACCTTCCACATGC CCCATGACTT GATGCAGTTTTAATACTTGTAATTCCCCTAACCATAAGATTTACTGCTGCTGTGGATATC TCCATGAAGT TTTCCCACTGAGTCACATCAGAAATGCCCTACATCTTATTTCCTCAGGGCTCAAGAGAAT CTGACAGATA CCATAAAGGGATTTGACCTAATCACTAATTTTCAGGTGGTGGCTGATGCTTTGAACATCT CTTTGCTGCC CAATCCATTAGCGACAGTAGGATTTTTCAAACCTGGTATGAATAGACAGAACCCTATCCA GTGGAAGGAG AATTTAATAAAGATAGTGCTGAAAGAATTCCTTAGGTAATCTATAACTAGGACTACTCCT GGTAACAGTA ATACATTCCATTGTTTTAGTAACCAGAAATCTTCATGCAATGAAAAATACTTTAATTCAT GAAGCTTACT _{TTTTTTTTTTGGTGTCAGAGTCTCGCTCTTGTCACCCAGGCTGG} ^ _{TGCAGTGGCGCCATCTCAGCTCAC} TGCAACCTCCATCTCCCAGGTTCAAGCGATTCTCGTGCCTCGGCCTCCTGAGTAGCTGGG ATTACAGGCG TGTGCCACTACACTCAACTAATTTTTGTATTTTTAGGAGAGACGGGGTTTCACCCTGTTG GCCAGGCTGG TCTCGAACTCCTGACCTCAAGTGATTCACCCACCTTGGCCTCATAAACCTGTTTTGCAGA ACTCATTTAT TCAGCAAATATTTATTGAGTGCCTACCAGATGCCAGTCACCACACAAGGCACTGGGTATA TGGTATCCCC AAACAAGAGACATAATCCCGGTCCTTAGGTAGTGCTAGTGTGGTCTGTAATATCTTACTA AGGCCTTTGG TATACGACCCAGAGATAACACGATGCGTATTTTAGTTTTGCAAAGAAGGGGTTTGGTCTC TGTGCCAGCT CTATAATTGTTTTGCTACGATTCCACTGAAACTCTTCGATCAAGCTACTTTATGTAAATC ACTTCATTGT TTTAAAGGAATAAACTTGATTATATTGTTTTTTTATTTGGCATAACTGTGATTCTTTTAG GACAATTACT GT ACACAT T AAGGT GT AT GT CAGAT AT T CAT AT T GAC C CAAAT GT GT AAT AT T C CAGT T T T CT CT GCAT A AGTAATTAAAATATACTTAAAAATTAATAGTTTTATCTGGGTACAAATAAACAGGTGCCT GAACTAGTTC ACAGACAAGGAAACTTCTATGTAAAAATCACTATGATTTCTGAATTGCTATGTGAAACTA CAGATCTTTG GAACACTGTTTAGGTAGGGTGTTAAGACTTACACAGTACCTCGTTTCTACACAGAGAAAG AAATGGCCAT ACTTCAGGAACTGCAGTGCTTATGAGGGGATATTTAGGCCTCTTGAATTTTTGATGTAGA TGGGCATTTT TTTAAGGTAGTGGTTAATTACCTTTATGTGAACTTTGAATGGTTTAACAAAAGATTTGTT TTTGTAGAGA TTTTAAAGGGGGAGAATTCTAGAAATAAATGTTACCTAATTATTACAGCCTTAAAGACAA AAATCCTTGT TGAAGTTTTTTTAAAAAAAGCTAAATTACATAGACTTAGGCATTAACATGTTTGTGGAAG AATATAGCAG ACGTATATTGTATCATTTGAGTGAATGTTCCCAAGTAGGCATTCTAGGCTCTATTTAACT GAGTCACACT GCATAGGAATTTAGAACCTAACTTTTATAGGTTATCAAAACTGTTGTCACCATTGCACAA TTTTGTCCTA ATATATACATAGAAACTTTGTGGGGCATGTTAAGTTACAGTTTGCACAAGTTCATCTCAT TTGTATTCCA TTGATTTTTTTTTTCTTCTAAACATTTTTTCTTCAAACAGTATATAACTTTTTTTAGGGG ATTTTTTTTT AGACAGCAAAAACT AT CT GAAGAT T T C CAT T T GT CAAAAAGT AAT GAT T T CT T GAT AAT T GT GT AGT AAT _{GTTTTTTAGAACCCAGCAGTTACCTTAAAGCTGAATTTATATTTAGTAACTTCTG TGTTAATACTGGATA} GCATGAATTCTGCATTGAGAAACTGAATAGCTGTCATAAAATGAAACTTTCTTTCTAAAG AAAGATACTC ACATGAGTTCTTGAAGAATAGTCATAACTAGATTAAGATCTGTGTTTTAGTTTAATAGTT TGAAGTGCCT GTTTGGGATAATGATAGGTAATTTAGATGAATTTAGGGGAAAAAAAAGTTATCTGCAGAT ATGTTGAGGG CCCATCTCTCCCCCCACACCCCCACAGAGCTAACTGGGTTACAGTGTTTTATCCGAAAGT TTCCAATTCC ACTGTCTTGTGTTTTCATGTTGAAAATACTTTTGCATTTTTCCTTTGAGTGCCAATTTCT TACTAGTACT ATTTCTTAATGTAACATGTTTACCTGGAATGTATTTTAACTATTTTTGTATAGTGTAAAC TGAAACATGC ACATTTTGTACATTGTGCTTTCTTTTGTGGGACATATGCAGTGTGATCCAGTTGTTTTCC ATCATTTGGT TGCGCTGACCTAGGAATGTTGGTCATATCAAACATTAAAAATGACCACTCTTTTAATTGA AATTAACTTT TAAATGTTTATAGGAGTATGTGCTGTGAAGTGATCTAAAATTTGTAATATTTTTGTCATG AACTGTACTA CT C CT AAT TAT T GT AAT GT AAT AAAAAT AGT T ACAGT GAC

[0142] NM 001411065.1 Homo sapiens mitogen-activated protein kinase kinase 1 (MAP2K1), transcript variant 2, mRNA (SEQ ID NO: 11)

AGAGAAGCCAGCAAGTAGTTGAGTGTGACGGGTGCATCGGTTCGGGTCGAAGGAAAT GAAGCTGGAGAGG ACCAACTTGGAGGCCTTGCAGAAGAAGCTGGAGGAGCTAGAGCTTGATGAGCAGCAGCGA AAGCGCCTTG AGGCCTTTCTTACCCAGAAGCAGAAGGTGGGAGAACTGAAGGATGACGACTTTGAGAAGA TCAGTGAGCT GGGGGCTGGCAATGGCGGTGTGGTGTTCAAGGTCTCCCACAAGCCTTCTGGCCTGGTCAT GGCCAGAAAG CTAATTCATCTGGAGATCAAACCCGCAATCCGGAACCAGATCATAAGGGAGCTGCAGGTT CTGCATGAGT GCAACTCTCCGTACATCGTGGGCTTCTATGGTGCGTTCTACAGCGATGGCGAGATCAGTA TCTGCATGGA GCACAT GGTAATAAAAGGCCT GACATAT CT GAGGGAGAAGCACAAGAT CAT GCACAGAGAT GT CAAGCCC

TCCAACATCCTAGTCAACTCCCGTGGGGAGATCAAGCTCTGTGACTTTGGGGTCAGC GGGCAGCTCATCG ACTCCATGGCCAACTCCTTCGTGGGCACAAGGTCCTACATGTCGCCAGAAAGACTCCAGG GGACTCATTA CTCTGTGCAGTCAGACATCTGGAGCATGGGACTGTCTCTGGTAGAGATGGCGGTTGGGAG GTATCCCATC CCTCCTCCAGATGCCAAGGAGCTGGAGCTGATGTTTGGGTGCCAGGTGGAAGGAGATGCG GCTGAGACCC CACCCAGGCCAAGGACCCCCGGGAGGCCCCTTAGCTCATACGGAATGGACAGCCGACCTC CCATGGCAAT TTTTGAGTTGTTGGATTACATAGTCAACGAGCCTCCTCCAAAACTGCCCAGTGGAGTGTT CAGTCTGGAA

TTTCAAGATTTTGTGAATAAATGCTTAATAAAAAACCCCGCAGAGAGAGCAGATTTG AAGCAACTCATGG TTCATGCTTTTATCAAGAGATCTGATGCTGAGGAAGTGGATTTTGCAGGTTGGCTCTGCT CCACCATCGG CCTTAACCAGCCCAGCACACCAACCCATGCTGCTGGCGTCTAAGTGTTTGGGAAGCAACA AAGAGCGAGT

CCCCTGCCCGGTGGTTTGCCATGTCGCTTTTGGGCCTCCTTCCCATGCCTGTCTCTG TTCAGATGTGCAT TTCACCTGTGACAAAGGATGAAGAACACAGCATGTGCCAAGATTCTACTCTTGTCATTTT TAATATTACT GTCTTTATTCTTATTACTATTATTGTTCCCCTAAGTGGATTGGCTTTGTGCTTGGGGCTA TTTGTGTGTA

TGCTGATGATCAAAACCTGTGCCAGGCTGAATTACAGTGAAATTTTGGTGAATGTGG GTAGTCATTCTTA CAATTGCACTGCTGTTCCTGCTCCATGACTGGCTGTCTGCCTGTATTTTCGGGATTCTTT GACATTTGGT GGTACTTTATTCTTGCTGGGCATACTTTCTCTCTAGGAGGGAGCCTTGTGAGATCCTTCA CAGGCAGTGC

ATGTGAAGCATGCTTTGCTGCTATGAAAATGAGCATCAGAGAGTGTACATCATGTTA TTTTATTATTATT ATTTGCTTTTCATGTAGAACTCAGCAGTTGACATCCAAATCTAGCCAGAGCCCTTCACTG CCATGATAGC TGGGGCTTCACCAGTCTGTCTACTGTGGTGATCTGTAGACTTCTGGTTGTATTTCTATAT TTATTTTCAG

TATACTGTGTGGGATACTTAGTGGTATGTCTCTTTAAGTTTTGATTAATGTTTCTTA AATGGAATTATTT TGAATGTCACAAATTGATCAAGATATTAAAATGTCGGATTTATCTTTCCCCATATCCAAG TACCAATGCT GT T GT AAACAAC GT GT AT AGT GC CT AAAAT T GT AT GAAAAT C CT T T T AAC CAT T T T AAC CT AGAT GT T T A

ACAAAT CTAAT CT CTTATT CTAATAAATATACTAT GAAATAAAAAAAAAAGGAT GAAAGCTA

[0143] NM_001127500.3 Homo sapiens MET proto-oncogene, receptor tyrosine kinase

(MET), transcript variant 1, mRNA (SEQ ID NO: 12)

AGACACGTGCTGGGGCGGGCAGGCGAGCGCCTCAGTCTGGTCGCCTGGCGGTGCCTC CGGCCCCAACGCG CCCGGGCCGCCGCGGGCCGCGCGCGCCGATGCCCGGCTGAGTCACTGGCAGGGCAGCGCG CGTGTGGGAA GGGGCGGAGGGAGTGCGGCCGGCGGGCGGGCGGGGCGCTGGGCTCAGCCCGGCCGCAGGT GACCCGGAGG

CCCTCGCCGCCCGCGGCGCCCCGAGCGCTTTGTGAGCAGATGCGGAGCCGAGTGGAG GGCGCGAGCCAGA TGCGGGGCGACAGCTGACTTGCTGAGAGGAGGCGGGGAGGCGCGGAGCGCGCGTGTGGTC CTTGCGCCGC TGACTTCTCCACTGGTTCCTGGGCACCGAAAGATAAACCTCTCATAATGAAGGCCCCCGC TGTGCTTGCA

CCTGGCATCCTCGTGCTCCTGTTTACCTTGGTGCAGAGGAGCAATGGGGAGTGTAAA GAGGCACTAGCAA AGTCCGAGATGAATGTGAATATGAAGTATCAGCTTCCCAACTTCACCGCGGAAACACCCA TCCAGAATGT CATTCTACATGAGCATCACATTTTCCTTGGTGCCACTAACTACATTTATGTTTTAAATGA GGAAGACCTT

CAGAAGGTTGCTGAGTACAAGACTGGGCCTGTGCTGGAACACCCAGATTGTTTCCCA TGTCAGGACTGCA GCAGCAAAGCCAATTTATCAGGAGGTGTTTGGAAAGATAACATCAACATGGCTCTAGTTG TCGACACCTA CTATGATGATCAACTCATTAGCTGTGGCAGCGTCAACAGAGGGACCTGCCAGCGACATGT CTTTCCCCAC

AATCATACTGCTGACATACAGTCGGAGGTTCACTGCATATTCTCCCCACAGATAGAA GAGCCCAGCCAGT GTCCTGACTGTGTGGTGAGCGCCCTGGGAGCCAAAGTCCTTTCATCTGTAAAGGACCGGT TCATCAACTT CTTTGTAGGCAATACCATAAATTCTTCTTATTTCCCAGATCATCCATTGCATTCGATATC AGTGAGAAGG

CTAAAGGAAACGAAAGATGGTTTTATGTTTTTGACGGACCAGTCCTACATTGATGTT TTACCTGAGTTCA GAGATTCTTACCCCATTAAGTATGTCCATGCCTTTGAAAGCAACAATTTTATTTACTTCT TGACGGTCCA AAGGGAAACTCTAGATGCTCAGACTTTTCACACAAGAATAATCAGGTTCTGTTCCATAAA CTCTGGATTG

CATTCCTACATGGAAATGCCTCTGGAGTGTATTCTCACAGAAAAGAGAAAAAAGAGA TCCACAAAGAAGG AAGTGTTTAATATACTTCAGGCTGCGTATGTCAGCAAGCCTGGGGCCCAGCTTGCTAGAC AAATAGGAGC CAGCCTGAATGATGACATTCTTTTCGGGGTGTTCGCACAAAGCAAGCCAGATTCTGCCGA ACCAATGGAT

CGATCTGCCATGTGTGCATTCCCTATCAAATATGTCAACGACTTCTTCAACAAGATC GTCAACAAAAACA ATGTGAGATGTCTCCAGCATTTTTACGGACCCAATCATGAGCACTGCTTTAATAGGACAC TTCTGAGAAA

TTCATCAGGCTGTGAAGCGCGCCGTGATGAATATCGAACAGAGTTTACCACAGCTTT GCAGCGCGTTGAC TTATTCATGGGTCAATTCAGCGAAGTCCTCTTAACATCTATATCCACCTTCATTAAAGGA GACCTCACCA TAGCTAATCTTGGGACATCAGAGGGTCGCTTCATGCAGGTTGTGGTTTCTCGATCAGGAC CATCAACCCC

TCATGTGAATTTTCTCCTGGACTCCCATCCAGTGTCTCCAGAAGTGATTGTGGAGCA TACATTAAACCAA AATGGCTACACACTGGTTATCACTGGGAAGAAGATCACGAAGATCCCATTGAATGGCTTG GGCTGCAGAC ATTTCCAGTCCTGCAGTCAATGCCTCTCTGCCCCACCCTTTGTTCAGTGTGGCTGGTGCC ACGACAAATG

TGTGCGATCGGAGGAATGCCTGAGCGGGACATGGACTCAACAGATCTGTCTGCCTGC AATCTACAAGGTT TTCCCAAATAGTGCACCCCTTGAAGGAGGGACAAGGCTGACCATATGTGGCTGGGACTTT GGATTTCGGA GGAATAATAAATTTGATTTAAAGAAAACTAGAGTTCTCCTTGGAAATGAGAGCTGCACCT TGACTTTAAG

TGAGAGCACGATGAATACATTGAAATGCACAGTTGGTCCTGCCATGAATAAGCATTT CAATATGTCCATA ATTATTTCAAATGGCCACGGGACAACACAATACAGTACATTCTCCTATGTGGATCCTGTA ATAACAAGTA TTTCGCCGAAATACGGTCCTATGGCTGGTGGCACTTTACTTACTTTAACTGGAAATTACC TAAACAGTGG GAAT T CT AGACACAT T T CAAT T GGT GGAAAAACAT GT ACT T T AAAAAGT GT GT CAAACAGT AT T CT T GAA TGTTATACCCCAGCCCAAACCATTTCAACTGAGTTTGCTGTTAAATTGAAAATTGACTTA GCCAACCGAG AGAC AAG CAT CTTCAGTTACCGT GAAGAT C C CAT T GT C T AT GAAAT T CAT C C AAC C AAAT CTTTTATTAG TACTTGGTGGAAAGAACCTCTCAACATTGTCAGTTTTCTATTTTGCTTTGCCAGTGGTGG GAGCACAATA ACAGGTGTTGGGAAAAACCTGAATTCAGTTAGTGTCCCGAGAATGGTCATAAATGTGCAT GAAGCAGGAA GGAACTTTACAGTGGCATGTCAACATCGCTCTAATTCAGAGATAATCTGTTGTACCACTC CTTCCCTGCA ACAGCTGAATCTGCAACTCCCCCTGAAAACCAAAGCCTTTTTCATGTTAGATGGGATCCT TTCCAAATAC TTTGATCTCATTTATGTACATAATCCTGTGTTTAAGCCTTTTGAAAAGCCAGTGATGATC TCAATGGGCA ATGAAAATGTACTGGAAATTAAGGGAAATGATATTGACCCTGAAGCAGTTAAAGGTGAAG TGTTAAAAGT TGGAAATAAGAGCTGTGAGAATATACACTTACATTCTGAAGCCGTTTTATGCACGGTCCC CAATGACCTG CTGAAATTGAACAGCGAGCTAAATATAGAGTGGAAGCAAGCAATTTCTTCAACCGTCCTT GGAAAAGTAA TAGTTCAACCAGATCAGAATTTCACAGGATTGATTGCTGGTGTTGTCTCAATATCAACAG CACTGTTATT ACTACTTGGGTTTTTCCTGTGGCTGAAAAAGAGAAAGCAAATTAAAGATCTGGGCAGTGA ATTAGTTCGC TACGATGCAAGAGTACACACTCCTCATTTGGATAGGCTTGTAAGTGCCCGAAGTGTAAGC CCAACTACAG AAATGGTTTCAAATGAATCTGTAGACTACCGAGCTACTTTTCCAGAAGATCAGTTTCCTA ATTCATCTCA GAACGGTTCATGCCGACAAGTGCAGTATCCTCTGACAGACATGTCCCCCATCCTAACTAG TGGGGACTCT GATATATCCAGTCCATTACTGCAAAATACTGTCCACATTGACCTCAGTGCTCTAAATCCA GAGCTGGTCC AGGCAGTGCAGCATGTAGTGATTGGGCCCAGTAGCCTGATTGTGCATTTCAATGAAGTCA TAGGAAGAGG GCATTTTGGTTGTGTATATCATGGGACTTTGTTGGACAATGATGGCAAGAAAATTCACTG TGCTGTGAAA TCCTTGAACAGAATCACTGACATAGGAGAAGTTTCCCAATTTCTGACCGAGGGAATCATC ATGAAAGATT TTAGTCATCCCAATGTCCTCTCGCTCCTGGGAATCTGCCTGCGAAGTGAAGGGTCTCCGC TGGTGGTCCT ACCATACATGAAACATGGAGATCTTCGAAATTTCATTCGAAATGAGACTCATAATCCAAC TGTAAAAGAT CTTATTGGCTTTGGTCTTCAAGTAGCCAAAGGCATGAAATATCTTGCAAGCAAAAAGTTT GTCCACAGAG ACTTGGCTGCAAGAAACTGTATGCTGGATGAAAAATTCACAGTCAAGGTTGCTGATTTTG GTCTTGCCAG AGACAT GTAT GATAAAGAATACTATAGT GTACACAACAAAACAGGT GCAAAGCT GCCAGT GAAGT GGAT G GCTTTGGAAAGTCTGCAAACTCAAAAGTTTACCACCAAGTCAGATGTGTGGTCCTTTGGC GTGCTCCTCT GGGAGCTGATGACAAGAGGAGCCCCACCTTATCCTGACGTAAACACCTTTGATATAACTG TTTACTTGTT GCAAGGGAGAAGACTCCTACAACCCGAATACTGCCCAGACCCCTTATATGAAGTAATGCT AAAATGCTGG CACCCTAAAGCCGAAATGCGCCCATCCTTTTCTGAACTGGTGTCCCGGATATCAGCGATC TTCTCTACTT TCATTGGGGAGCACTATGTCCATGTGAACGCTACTTATGTGAACGTAAAATGTGTCGCTC CGTATCCTTC TCTGTTGTCATCAGAAGATAACGCTGATGATGAGGTGGACACACGACCAGCCTCCTTCTG GGAGACATCA TAGTGCTAGTACTATGTCAAAGCAACAGTCCACACTTTGTCCAATGGTTTTTTCACTGCC TGACCTTTAA AAGGCCATCGATATTCTTTGCTCTTGCCAAAATTGCACTATTATAGGACTTGTATTGTTA TTTAAATTAC TGGATTCTAAGGAATTTCTTATCTGACAGAGCATCAGAACCAGAGGCTTGGTCCCACAGG CCACGGACCA ATGGCCTGCAGCCGTGACAACACTCCTGTCATATTGGAGTCCAAAACTTGAATTCTGGGT TGAATTTTTT AAAAATCAGGTACCACTTGATTTCATATGGGAAATTGAAGCAGGAAATATTGAGGGCTTC TTGATCACAG AAAACTCAGAAGAGATAGTAATGCTCAGGACAGGAGCGGCAGCCCCAGAACAGGCCACTC ATTTAGAATT CTAGTGTTTCAAAACACTTTTGTGTGTTGTATGGTCAATAACATTTTTCATTACTGATGG TGTCATTCAC CCATTAGGTAAACATTCCCTTTTAAATGTTTGTTTGTTTTTTGAGACAGGATCTCACTCT GTTGCCAGGG CTGTAGTGCAGTGGTGTGATCATAGCTCACTGCAACCTCCACCTCCCAGGCTCAAGCCTC CCGAATAGCT GGGACTACAGGCGCACACCACCATCCCCGGCTAATTTTTGTATTTTTTGTAGAGACGGGG TTTTGCCATG TTGCCAAGGCTGGTTTCAAACTCCTGGACTCAAGAAATCCACCCACCTCAGCCTCCCAAA GTGCTAGGAT TACAGGCATGAGCCACTGCGCCCAGCCCTTATAAATTTTTGTATAGACATTCCTTTGGTT GGAAGAATAT T T AT AG G C AAT AC AGT C AAAGT T T C AAAAT AG CAT C AC AC AAAAC AT GT T TAT AAAT GAAC AG GAT GT AA T GT ACAT AGAT GACAT T AAGAAAAT TT GT AT GAAAT AAT T T AGT CAT CAT GAAAT AT T T AGT T GT CAT AT AAAAACCCACTGTTTGAGAATGATGCTACTCTGATCTAATGAATGTGAACATGTAGATGT TTTGTGTGTA T T T T T T T AAAT GAAAAC T C AAAAT AAGACAAGT AAT T T GT T GAT AAAT AT T T T T AAAGAT AAC T C AG CAT GTTTGTAAAGCAGGATACATTTTACTAAAAGGTTCATTGGTTCCAATCACAGCTCATAGG TAGAGCAAAG AAAGGGTGGATGGATTGAAAAGATTAGCCTCTGTCTCGGTGGCAGGTTCCCACCTCGCAA GCAATTGGAA ACAAAACTTTTGGGGAGTTTTATTTTGCATTAGGGTGTGTTTTATGTTAAGCAAAACATA CTTTAGAAAC AAATGAAAAAGGCAATTGAAAATCCCAGCTATTTCACCTAGATGGAATAGCCACCCTGAG CAGAACTTTG TGATGCTTCATTCTGTGGAATTTTGTGCTTGCTACTGTATAGTGCATGTGGTGTAGGTTA CTCTAACTGG T T T T GT C GAC GT AAACAT T T AAAGT GT TAT AT T T T T T AT AAAAAT GT T TAT T T T T AAT GAT AT GAGAAAA ATTTTGTTAGGCCACAAAAACACTGCACTGTGAACATTTTAGAAAAGGTATGTCAGACTG GGATTAATGA CAGCATGATTTTCAATGACTGTAAATTGCGATAAGGAAATGTACTGATTGCCAATACACC CCACCCTCAT TACATCATCAGGACTTGAAGCCAAGGGTTAACCCAGCAAGCTACAAAGAGGGTGTGTCAC ACTGAAACTC AATAGTTGAGTTTGGCTGTTGTTGCAGGAAAATGATTATAACTAAAAGCTCTCTGATAGT GCAGAGACTT ACCAGAAGACACAAGGAATTGTACTGAAGAGCTATTACAATCCAAATATTGCCGTTTCAT AAATGTAATA AGTAATACTAATT CACAGAGTATT GTAAAT GGT GGAT GACAAAAGAAAAT CT GCT CT GT GGAAAGAAAGA ACTGTCTCTACCAGGGTCAAGAGCATGAACGCATCAATAGAAAGAACTCGGGGAAACATC CCATCAACAG GACTACACACTTGTATATACATTCTTGAGAACACTGCAATGTGAAAATCACGTTTGCTAT TTATAAACTT GTCCTTAGATTAATGTGTCTGGACAGATTGTGGGAGTAAGTGATTCTTCTAAGAATTAGA TACTTGTCAC TGCCTATACCTGCAGCTGAACTGAATGGTACTTCGTATGTTAATAGTTGTTCTGATAAAT CATGCAATTA AAGTAAAGT GAT GCAA

[0144] NM_002524.5 Homo sapiens NRAS proto-oncogene, GTPase (NRAS), mRNA (SEQ ID NO: 13)

GGGGCCGGAAGTGCCGCTCCTTGGTGGGGGCTGTTCATGGCGGTTCCGGGGTCTCCA ACATTTTTCCCGG CTGTGGTCCTAAATCTGTCCAAAGCAGAGGCAGTGGAGCTTGAGGTTCTTGCTGGTGTGA AATGACTGAG TACAAACTGGTGGTGGTTGGAGCAGGTGGTGTTGGGAAAAGCGCACTGACAATCCAGCTA ATCCAGAACC ACTTTGTAGATGAATATGATCCCACCATAGAGGATTCTTACAGAAAACAAGTGGTTATAG ATGGTGAAAC CTGTTTGTTGGACATACTGGATACAGCTGGACAAGAAGAGTACAGTGCCATGAGAGACCA ATACATGAGG ACAGGCGAAGGCTTCCTCTGTGTATTTGCCATCAATAATAGCAAGTCATTTGCGGATATT AACCTCTACA GGGAGCAGATTAAGCGAGTAAAAGACTCGGATGATGTACCTATGGTGCTAGTGGGAAACA AGTGTGATTT GCCAACAAGGACAGTTGATACAAAACAAGCCCACGAACTGGCCAAGAGTTACGGGATTCC ATTCATTGAA ACCTCAGCCAAGACCAGACAGGGTGTTGAAGATGCTTTTTACACACTGGTAAGAGAAATA CGCCAGTACC GAAT GAAAAAACT CAACAGCAGT GATGAT GGGACT CAGGGTT GTAT GGGATT GCCAT GT GT GGT GAT GTA ACAAGATACTTTTAAAGTTTTGTCAGAAAAGAGCCACTTTCAAGCTGCACTGACACCCTG GTCCTGACTT CCCTGGAGGAGAAGTATTCCTGTTGCTGTCTTCAGTCTCACAGAGAAGCTCCTGCTACTT CCCCAGCTCT CAGTAGTTTAGTACAATAATCTCTATTTGAGAAGTTCTCAGAATAACTACCTCCTCACTT GGCTGTCTGA CCAGAGAATGCACCTCTTGTTACTCCCTGTTATTTTTCTGCCCTGGGTTCTTCCACAGCA CAAACACACC TCTGCCACCCCAGGTTTTTCATCTGAAAAGCAGTTCATGTCTGAAACAGAGAACCAAACC GCAAACGTGA AATTCTATTGAAAACAGTGTCTTGAGCTCTAAAGTAGCAACTGCTGGTGATTTTTTTTTT CTTTTTACTG TTGAACTTAGAACTATGCTAATTTTTGGAGAAATGTCATAAATTACTGTTTTGCCAAGAA TATAGTTATT ATTGCTGTTTGGTTTGTTTATAATGTTATCGGCTCTATTCTCTAAACTGGCATCTGCTCT AGATTCATAA ATACAAAAATGAATACTGAATTTTGAGTCTATCCTAGTCTTCACAACTTTGACGTAATTA AATCCAACTT TCACAGTGAAGTGCCTTTTTCCTAGAAGTGGTTTGTAGACTTCCTTTATAATATTTCAGT GGAATAGATG TCTCAAAAATCCTTATGCATGAAATGAATGTCTGAGATACGTCTGTGACTTATCTACCAT TGAAGGAAAG CTATATCTATTTGAGAGCAGATGCCATTTTGTACATGTATGAAATTGGTTTTCCAGAGGC CTGTTTTGGG GCTTTCCCAGGAGAAAGATGAAACTGAAAGCACATGAATAATTTCACTTAATAATTTTTA CCTAATCTCC ACTTTTTTCATAGGTTACTACCTATACAATGTATGTAATTTGTTTCCCCTAGCTTACTGA TAAACCTAAT ATTCAATGAACTTCCATTTGTATTCAAATTTGTGTCATACCAGAAAGCTCTACATTTGCA GATGTTCAAA TATTGTAAAACTTTGGTGCATTGTTATTTAATAGCTGTGATCAGTGATTTTCAAACCTCA AATATAGTAT ATTAACAAATTACATTTTCACTGTATATCATGGTATCTTAATGATGTATATAATTGCCTT CAATCCCCTT CTCACCCCACCCTCTACAGCTTCCCCCACAGCAATAGGGGCTTGATTATTTCAGTTGAGT AAAGCATGGT GCTAATGGACCAGGGTCACAGTTTCAAAACTTGAACAATCCAGTTAGCATCACAGAGAAA GAAATTCTTC TGCATTTGCTCATTGCACCAGTAACTCCAGCTAGTAATTTTGCTAGGTAGCTGCAGTTAG CCCTGCAAGG AAAGAAGAGGTCAGTTAGCACAAACCCTTTACCATGACTGGAAAACTCAGTATCACGTAT TTAAACATTT TTTTTTCTTTTAGCCATGTAGAAACTCTAAATTAAGCCAATATTCTCATTTGAGAATGAG GATGTCTCAG CTGAGAAACGTTTTAAATTCTCTTTATTCATAATGTTCTTTGAAGGGTTTAAAACAAGAT GTTGATAAAT CTAAGCTGATGAGTTTGCTCAAAACAGGAAGTTGAAATTGTTGAGACAGGAATGGAAAAT ATAATTAATT GATACCTATGAGGATTTGGAGGCTTGGCATTTTAATTTGCAGATAATACCCTGGTAATTC TCATGAAAAA TAGACTTGGATAACTTTTGATAAAAGACTAATTCCAAAATGGCCACTTTGTTCCTGTCTT TAATATCTAA ATACTTACTGAGGTCCTCCATCTTCTATATTATGAATTTTCATTTATTAAGCAAATGTCA TATTACCTTG AAATTCAGAAGAGAAGAAACATATACTGTGTCCAGAGTATAATGAACCTGCAGAGTTGTG CTTCTTACTG CTAATTCTGGGAGCTTTCACAGTACTGTCATCATTTGTAAATGGAAATTCTGCTTTTCTG TTTCTGCTCC TTCTGGAGCAGTGCTACTCTGTAATTTTCCTGAGGCTTATCACCTCAGTCATTTCTTTTT TAAATGTCTG TGACTGGCAGTGATTCTTTTTCTTAAAAATCTATTAAATTTGATGTCAAATTAGGGAGAA AGATAGTTAC

TCATCTTGGGCTCTTGTGCCAATAGCCCTTGTATGTATGTACTTAGAGTTTTCCAAG TATGTTCTAAGCA CAGAAGTTTCTAAATGGGGCCAAAATTCAGACTTGAGTATGTTCTTTGAATACCTTAAGA AGTTACAATT AGCCGGGCATGGTGGCCCGTGCCTGTAGTCCCAGCTACTTGAGAGGCTGAGGCAGGAGAA TCACTTCAAC CCAGGAGGTGGAGGTTACAGTGAGCAGAGATCGTGCCACTGCACTCCAGCCTGGGTGACA AGAGAGACTT GTCTCCAAAAAAAAAGTTACACCTAGGTGTGAATTTTGGCACAAAGGAGTGACAAACTTA TAGTTAAAAG CTGAATAACTTCAGTGTGGTATAAAACGTGGTTTTTAGGCTATGTTTGTGATTGCTGAAA AGAATTCTAG TTTACCTCAAAATCCTTCTCTTTCCCCAAATTAAGTGCCTGGCCAGCTGTCATAAATTAC ATATTCCTTT TGGTTTTTTTAAAGGTTACATGTTCAAGAGTGAAAATAAGATGTTCTGTCTGAAGGCTAC CATGCCGGAT CTGTAAATGAACCTGTTAAATGCTGTATTTGCTCCAACGGCTTACTATAGAATGTTACTT AATACAATAT CATACTTATTACAATTTTTACTATAGGAGTGTAATAGGTAAAATTAATCTCTATTTTAGT GGGCCCATGT TTAGTCTTTCACCATCCTTTAAACTGCTGTGAATTTTTTTGTCATGACTTGAAAGCAAGG ATAGAGAAAC ACTTTAGAGATATGTGGGGTTTTTTTACCATTCCAGAGCTTGTGAGCATAATCATATTTG CTTTATATTT ATAGTCATGAACTCCTAAGTTGGCAGCTACAACCAAGAACCAAAAAATGGTGCGTTCTGC TTCTTGTAAT TCATCTCTGCTAATAAATTATAAGAAGCAAGGAAAATTAGGGAAAATATTTTATTTGGAT GGTTTCTATA AACAAGGGACTATAATTCTTGTACATTATTTTTCATCTTTGCTGTTTCTTTGAGCAGTCT AATGTGCCAC ACAAT T AT CT AAGGT AT T T GT T T T CTAT AAGAAT T GT T T T AAAAGT AT T CT T GT TAG CAGAGT AGT T GT A TTATATTTCAAAACGTAAGATGATTTTTAAAAGCCTGAGTACTGACCTAAGATGGAATTG TATGAACTCT GCTCTGGAGGGAGGGGAGGATGTCCGTGGAAGTTGTAAGACTTTTATTTTTTTGTGCCAT CAAATATAGG TAAAAATAATTGTGCAATTCTGCTGTTTAAACAGGAACTATTGGCCTCCTTGGCCCTAAA TGGAAGGGCC GAT AT T T T AAGT T GAT T AT T T T AT T GT AAAT T AAT C CAAC CT AGT T CT T T T T AAT T T GGT T GAAT GT T T T TTCTTGTTAAATGATGTTTAAAAAATAAAAACTGGAAGTTCTTGGCTTAGTCATAA

[0145] NM 006218.4 Homo sapiens phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), mRNA (SEQ ID NO: 14)

AGTTCCGGTGCCGCCGCTGCGGCCGCTGAGGTGTCGGGCTGCTGCTGCCGCGGCCGC TGGGACTGGGGCT GGGGCCGCCGGCGAGGCAGGGCTCGGGCCCGGCCGGGCAGCTCCGGAGCGGCGGGGGAGA GGGGCCGGGA GGCGGGGGCCGTGCCGCCCGCTCTCCTCTCCCTCGGCGCCGCCGCCGCCGCCCGCGGGGC TGGGACCCGA TGCGGTTAGAGCCGCGGAGCCTGGAAGAGCCCCGAGCGTTTCTGCTTTGGGACAACCATA CATCTAATTC CTTAAAGTAGTTTTATATGTAAAACTTGCAAAGAATCAGAACAATGCCTCCACGACCATC ATCAGGTGAA CTGTGGGGCATCCACTTGATGCCCCCAAGAATCCTAGTAGAATGTTTACTACCAAATGGA ATGATAGTGA CTTTAGAATGCCTCCGTGAGGCTACATTAATAACCATAAAGCATGAACTATTTAAAGAAG CAAGAAAATA CCCCCTCCATCAACTTCTTCAAGATGAATCTTCTTACATTTTCGTAAGTGTTACTCAAGA AGCAGAAAGG GAAGAATTTTTTGATGAAACAAGACGACTTTGTGACCTTCGGCTTTTTCAACCCTTTTTA AAAGTAATTG AACCAGTAGGCAACCGTGAAGAAAAGATCCTCAATCGAGAAATTGGTTTTGCTATCGGCA TGCCAGTGTG T GAAT T T GAT AT GGT T AAAGAT C C AGAAGT AC AG GAC T T C C GAAGAAAT AT T C T GAAC GT T T GT AAAGAA GCTGTGGATCTTAGGGACCTCAATTCACCTCATAGTAGAGCAATGTATGTCTATCCTCCA AATGTAGAAT CTTCACCAGAATTGCCAAAGCACATATATAATAAATTAGATAAAGGGCAAATAATAGTGG TGATCTGGGT AATAGTTTCTCCAAATAATGACAAGCAGAAGTATACTCTGAAAATCAACCATGACTGTGT ACCAGAACAA GTAATT GCT GAAGCAAT CAGGAAAAAAACT CGAAGTAT GTT GCTAT CCT CT GAACAACTAAAACT CT GT G TTTTAGAATATCAGGGCAAGTATATTTTAAAAGTGTGTGGATGTGATGAATACTTCCTAG AAAAATATCC TCTGAGTCAGTATAAGTATATAAGAAGCTGTATAATGCTTGGGAGGATGCCCAATTTGAT GTTGATGGCT AAAGAAAGCCTTTATTCTCAACTGCCAATGGACTGTTTTACAATGCCATCTTATTCCAGA CGCATTTCCA CAGCTACACCATATATGAATGGAGAAACATCTACAAAATCCCTTTGGGTTATAAATAGTG CACTCAGAAT AAAAATTCTTTGTGCAACCTACGTGAATGTAAATATTCGAGACATTGATAAGATCTATGT TCGAACAGGT ATCTACCATGGAGGAGAACCCTTATGTGACAATGTGAACACTCAAAGAGTACCTTGTTCC AATCCCAGGT GGAATGAATGGCTGAATTATGATATATACATTCCTGATCTTCCTCGTGCTGCTCGACTTT GCCTTTCCAT TTGCTCTGTTAAAGGCCGAAAGGGTGCTAAAGAGGAACACTGTCCATTGGCATGGGGAAA TATAAACTTG TTTGATTACACAGACACTCTAGTATCTGGAAAAATGGCTTTGAATCTTTGGCCAGTACCT CATGGATTAG AAGATTTGCTGAACCCTATTGGTGTTACTGGATCAAATCCAAATAAAGAAACTCCATGCT TAGAGTTGGA GTTTGACTGGTTCAGCAGTGTGGTAAAGTTCCCAGATATGTCAGTGATTGAAGAGCATGC CAATTGGTCT GTATCCCGAGAAGCAGGATTTAGCTATTCCCACGCAGGACTGAGTAACAGACTAGCTAGA GACAATGAAT TAAGGGAAAAT GACAAAGAACAGCT CAAAGCAATTT CTACACGAGAT CCT CT CT CT GAAAT CACT GAGCA GGAGAAAGATTTTCTATGGAGTCACAGACACTATTGTGTAACTATCCCCGAAATTCTACC CAAATTGCTT CTGTCTGTTAAATGGAATTCTAGAGATGAAGTAGCCCAGATGTATTGCTTGGTAAAAGAT TGGCCTCCAA TCAAACCTGAACAGGCTATGGAACTTCTGGACTGTAATTACCCAGATCCTATGGTTCGAG GTTTTGCTGT TCGGTGCTTGGAAAAATATTTAACAGATGACAAACTTTCTCAGTATTTAATTCAGCTAGT ACAGGTCCTA AAATATGAACAATATTTGGATAACTTGCTTGTGAGATTTTTACTGAAGAAAGCATTGACT AATCAAAGGA TTGGGCACTTTTTCTTTTGGCATTTAAAATCTGAGATGCACAATAAAACAGTTAGCCAGA GGTTTGGCCT GCTTTTGGAGTCCTATTGTCGTGCATGTGGGATGTATTTGAAGCACCTGAATAGGCAAGT CGAGGCAATG GAAAAGCT CATTAACTTAACT GACATT CT CAAACAGGAGAAGAAGGAT GAAACACAAAAGGTACAGAT GA AGTTTTTAGTTGAGCAAATGAGGCGACCAGATTTCATGGATGCTCTACAGGGCTTTCTGT CTCCTCTAAA CCCTGCTCATCAACTAGGAAACCTCAGGCTTGAAGAGTGTCGAATTATGTCCTCTGCAAA AAGGCCACTG

TGGTTGAATTGGGAGAACCCAGACATCATGTCAGAGTTACTGTTTCAGAACAATGAG ATCATCTTTAAAA ATGGGGATGATTTACGGCAAGATATGCTAACACTTCAAATTATTCGTATTATGGAAAATA TCTGGCAAAA TCAAGGTCTTGATCTTCGAATGTTACCTTATGGTTGTCTGTCAATCGGTGACTGTGTGGG ACTTATTGAG GTGGTGCGAAATTCTCACACTATTATGCAAATTCAGTGCAAAGGCGGCTTGAAAGGTGCA CTGCAGTTCA ACAGCCACACACTACAT CAGT GGCT CAAAGACAAGAACAAAGGAGAAATATAT GAT G GAG C GATT GAG CT GTTTACACGTTCATGTGCTGGATACTGTGTAGCTACCTTCATTTTGGGAATTGGAGATCG TCACAATAGT AACATCATGGTGAAAGACGATGGACAACTGTTTCATATAGATTTTGGACACTTTTTGGAT CACAAGAAGA AAAAAT T T GGT T AT AAAC GAGAAC GT GT GC CAT T T GT T T T GACACAGGAT T T CT T AAT AGT GAT T AGT AA AGGAGCCCAAGAATGCACAAAGACAAGAGAATTTGAGAGGTTTCAGGAGATGTGTTACAA GGCTTATCTA GCTATTCGACAGCATGCCAATCTCTTCATAAATCTTTTCTCAATGATGCTTGGCTCTGGA ATGCCAGAAC TACAATCTTTTGATGACATTGCATACATTCGAAAGACCCTAGCCTTAGATAAAACTGAGC AAGAGGCTTT GGAGTATTT CAT GAAACAAAT GAAT GAT GCACAT CAT GGT GGCT GGACAACAAAAAT GGATT GGAT CTT C CACACAATTAAACAGCAT GCATT GAACT GAAAAGATAACT GAGAAAAT GAAAGCT CACT CT GGATT CCAC ACTGCACTGTTAATAACTCTCAGCAGGCAAAGACCGATTGCATAGGAATTGCACAATCCA TGAACAGCAT TAGAATTTACAGCAAGAACAGAAATAAAATACTATATAATTTAAATAATGTAAACGCAAA CAGGGTTTGA TAGCACTTAAACTAGTTCATTTCAAAATTAAGCTTTAGAATAATGCGCAATTTCATGTTA TGCCTTAAGT C C AAAAAG GT AAAC T T T GAAGAT TGTTTGTATCTTTTTT TAAAAAACAAAACAAAAC AAAAAT C C C C AAA ATATATAGAAATGATGGAGAAGGAAAAAGTGATGGTTTTTTTTGTCTTGCAAATGTTCTA TGTTTTGAAA TGTGGACACAACAAAGGCTGTTATTGCATTAGGTGTAAGTAAACTGGAGTTTATGTTAAA TTACATTGAT TGGAAAAGAATGAAAATTTCTTATTTTTCCATTGCTGTTCAATTTATAGTTTGAAGTGGG TTTTTGACTG CTTGTTTAATGAAGAAAAATGCTTGGGGTGGAAGGGACTCTTGAGATTTCACCAGAGACT TTTTCTTTTT AATAAATCAAACCTTTTGATGATTTGAGGTTTTATCTGCAGTTTTGGAAGCAGTCACAAA TGAGACCTGT TATAAGGTGGTATTTTTTTTTTTCTTCTGGACAGTATTTAAAGGATCTTATTCTTATTTC CCAGGGAAAT TCTGGGCTCCCACAAAGTAAAAAAAAAAAAAAATCATAGAAAAAGAATGAGCAGGAATAG TTCTTATTCC AGAATTGTACAGTATTCACCTTAAGTTGATTTTTTTTCTCCTTCTGCAATTGAACTGAAT ACATTTTTCA T G CAT GT T T T C C AGAAAAT AGAAGT AT T AAT GT TAT T AAAAAGAT TATTTTTTTTAT T AAAG G C T AT T T A TAT T AT AGAAAC TAT CAT T AAT AT AT AT T C T T T AT T TAG AT GAT C T GT C C CAT AGT CAT G CAT T GT T T T G CACCCCAAATTTTTTATTGTTCATAGCAGCATGGTCAGCTTTCTTCTTGATCTATAGATG AGGCTCAGGC ACTATCCCATTTATACCAATAACCAGTGTATAACTACTTAAGGAAAACATAAAAACTTCA TCTTCTTTCC TTTTATTTCTTATGTGAATCTCCCGTCTTCCATTCTCTTTTATAATTGAGAATGTCTCAA TCATATGAAA TTAGTTACCAGAATTAACACAATTTAGACTATCTTCCTGATTCCTTAAACCCCTTTACTG AAGTATACTC ATGAATAATACTTTAAAATATGGGGGAATAGAAACCATGAACTTTTTACCTTTTTAAACT ATTTATCCAT ATCTCCAAAGTAGAACATTAAACCATTTTAAGATATGTCTCATTCCCAAGTAGTCAGAGC TCACTCTCCA ACTTTATTAAATACTATTTGAGCACAGGACACATTCTTAAACATTTTGAAAAACATTAAC CCAAGATGTA GAGGCTACTGCTAGTCGTCATTCTAGAATCTGATATTTTACTCTGTATTTGAAATGAATG ATTAATGTCC TAGGAAATTAGCTTTAGCAGATGTCCAGGTGCCACATCAAAAAAGTGCAATAATTATTGA CAGTTTTTTA GATTAGGCATATTATTGGAAAACAACTTTATAAAGAGTGAACATTGTATACTCTAGTAAA ACAGCATCAC TTTAAAAATATTCATTTATGAAATCTGTTACCTATAGTTGAAGTCTTGAGTAGTGAACAA GGGACTCTAA TACCAATACTCTTAATATCTGGCTATTTTAGATCCCTTAAAGGGCATAATTATTGGAAAT TTAGGTATTT CACTAAAGCATGTATATAATATTGCCAACAAGAAAAGTAAATTTGAAGATTAAGGGAACT TACTTCTGCA AACTGTCTTGCGATAGTTAAGCAGAATTTAAACTCTGTTTTAAGCAGGAAACCAGAAAGA TTATTTTGCA GT T GT AGAAGAT T T CAT AACT T AT T AAAACT T AT T AACAT TTTGTGTTGTT T AGAT AT AGGCAGT T GAT A CATACTAACATCCCAGCCTTTTCAATATCAGGGTTAAATTATAGGAAAACTCAGTAAAAT GGTACAAATC TGAAAGTTTGATGGTAGAAACTGAAGATTTAACAGAGAACTGTGTTTTACCCGAGTGCCA AAAATGCTGT GAGCCTCCTTGCACAAAATTTATACCACTTTTGCATTTTTATCTATCAGTCCAGATAGTT GTCTCCCCTC CTTCTCCCAGGACCTCTCCACCATTAAAATGCACAAACCACATGGCCGATTTCACCATTT ACATTTATTT TCAAAAGTTACTACAACCAAATTAATTCTATTAGAAGAAATGTAGACAAATTCTATAAAG ACTATAGATT GT GACCTAAGAAAGAAAT GAGGCAAAGAACCAAACATT GAATTAAAT GCTACAT GGGT GACTAAGAT CT G TTTCAAGTCAGTGATAATATAGCCACTTCTGGGTACTTCAGTATCAGAGATCAGTTCTCG TGGTTTAGAC AGTTCCTATCTATAGCTGACTATCCTTGTCCTTGAATATGGTGTAACTGACTATTGGCTC TACAGTTTTA TTGGGCCACTTAAGAAATATTTCCTTGAATAATTATTTTGAGAAAAAGTCTAAAAGTAAT AAAAATAATT TTAAACACACTGTAGTAAGAAATGACTGTTGGAAAATTATGCTTTCACTTTCTACCATAT TCTCAGCTAT ACAAAACCATTTATTTTGAAGATTTTTAGACTACTGTTAATTTGAAATCTGTTACTCTTA TTGTGGAATT TGTTTTTTTAAAAAAGATGTTTCTAATTGGATTTTTAAAAGAAGAATGGAATTTGGTTGC TATTTTACAA TAGAACCTAAGCTTTTTGTGGTTCTTAGTGTCCTATGTAAAACTTAGTGTCAAAGTAATC AACTTTGAGA TTTTCCCTTCTATTCTGCTTTATATTAAAAGCCCATTAGAAAATGGGAACCTGGTGAATA TATAATGAAT TGTAAAATATTTTAATGTGTAACTTTTTCAACTGTGAAACTGACTTGATTTTTTGATGAA AACAGCTGCT GAT AAAGT AT T T T GT GT AAAGT GT AGT T CT TAT T AAT CAGGAAAAT GAT GACT T GAT T AGACT GT AT AT G CCCTCTTGGATTTTATTTTAAATGGATTGGTGACTTTCACATAGGTAAAACACAGTCCAT CTGTATTCTT TTTTCCATCAAAAATCGAGTGATTTGGAATTATAAAAAAATTGTGAGCAGCCTATTTGAA AGGCATCATG GAAAT T T C AC AG C AC AAT AAC AC G GAT T T GT T T T T T C T T AAT GAT GT AAAT C C GT T T AAT T C AT AC T T T G ATCAATAGCCCATGCTTGCCAACTCTGAAGAAATTTAATTTCCAGCAGTATTTTAAAGCT AGCCTGTTAA CTTTTTCTGAATATTTAAAGTTCCTCTTTTTTCTATGTCTGCACAAACTGCAGACCTGGG CTGGACCCAC AT AC T C AAGAGT C C AC C T T AAGAAAT T AT T T T GAT GT C C AAGAC AT C AC T AAAAT AT T T AAGT T T AAAGA TAATATGTGGTGTTAATAGATTGTGGTGCTTTTACTATTTAAAGACAACTTTCATACTTC AGATGTTTTT GAGAAGAGGGGAATGTGAGGGGAGGGGGCAGAACAGGGAGGAGTTGTTTGAATGAATTAC ATTCTTTATA TCCATCCTGCTCATTTGGGGCATGTCTTTAAGAGAAGGCTGAAAGTTGTGAGAGTATATT GTATACCGTA AGAGAATCAACTCTTCATCATGGATGGGATTGTGAAGGCTGAACTATAAAATTCAGCATT GACAGCATCC TCAATTAATAATTCTTGGTGACAGAATAATACAGCTGGGCTGTTTTTTAAAATATAAACA ATACCATTTT TAATTATTACATTAAAAATTGTAAATATATCTATGTGCCATGGCCTGGGAAGCCTGCTTT CTTTTTTCAT AAAAATTATTTTTACTGTATGAAAAGATCATGGGGTTTAGCTCAAAATATCTGTGGTCCT GATAAAATTG GATT GGTAACT CTACCT CAGAAGGAAAAT GGGAAAAAAAAATAGAT GAGT CACAATT CAATACTT CAAGC TCAGAAACTGTGCAGATCACTGAATTTTAGATTTATAAAGTCAGAGTTGGCATGCCTTGT TTTTAATGAT ATGGAAGACCTTAAGAAAAAAACTTGGCTGAAGTTTAATCGTTGGTCCAGCCATTTGAAA AAGGCAATAG TTTGAGGAGGTTCCCGAATTCGGCATTTGAAATTCATTTTGTTCTCTCTTCTTCATTATT AGTGCATTTG GTGTGTGTATACTTGCACACAATTCTGTTTGTGTACACACTGCTTGCTTAGCCCTAGTCA AGAGGCATCT TTTATAAAAGGTGTAAAGAAATATCAAGGTTCTAAAATTCGGAAGAGTTTAGAATTTATT AGGAGTTTCC CAAGTTGGGATGTTAGTCTTTAAATAAACTTCATGCACCTATTCCACTTAAGGTTTTGCA CCTCCTTTTT ATTAGTGCAGTGCCATTTCTTCTGCTTGATTTTAGGTATGTTAATATTCCAGCCTTGCTA GTTAGCATAA AGTGACAGGTGTGAGCCATGAGGAAATTTTCTGACTTAATTTGTACACAACTACATATAA GAGTTTTAGT GGAGGAAAAAAATTAGTCCCTTGTGCGTATACAGTAGTTAGGTAAATGATTTTTCTACCA ACAGTATACT CCATTCCTCATGTAGGTAAGTACAGAAAAGGTTTTTAAATGTATTTTTTTAGCCAGTTAA AGTCTATGAA TCTATCTGCAACCTTATTTAATCTGTCACTATAATAATTTTGTGGTTATGCTAAGAACCA TGTATACTTT TAGGTATTCTTATTTTTGTCAATTTTTCTAGGTTGGCAAGGAGGCAGAAAACCTTCATTG TTTCATATTA AAAT AT AAT T AGAC T AAAC T T AAT T CT AGT AT GAAT T T C C AAAAT CAT T AT C T AT T T AT T T CAT T T T T AT TTAATTTTGTTTTTATTTCATTTTTAAAAGTCCCTTGTTCAATTTAACTTATGTTCCTAA GAGAGGTTGG AGAACTTGGCCTTCATCTGATTTCAAAAATGTTTTGAGTTTCAAATGAAGTTAATGGTTT CAGTGTGATT CAGTCCTCAGACCTAATTGGGTTGAATAAAATCTAAAAGAATATACCCTTTTGGAGCATA ACATTTTAAT ACCTTGGGGAATGTGGCACTACCAAAAGAAGACTACTAACACGTCAGATGTTCACCTGGA AGCTTTATCA AGAAATTCGAACCACCCTTTTGGCCCCATTAATTGTAGCAAGTTTATTTCTCTATATTTT GTCATTCAGT GAATTGAAGTCCTGTGGTATACTGCATTCATTAGAAGAAAAACGTTTTTAATGTCCTTTT AATGATGGCC CAGAAAGCATTT GACACAGCAAGAT GCAT GT GTTACTATATT GAGAATATAGAATAATAACAGTAT CACT AAATTTAAGACCTCTTCCCAGTCTTGCTGTTCCTAGCAAGAAGTTTGGCCTGTGACTGCA CTTACTGTTT ATGCTCATCAGAAACTGTCAATGTCTGCTTTTCTTTAACTCTGCAGTCTGTAACATCACG CTGTTTATTA AAAAAAAAAAGAAAAAT TA

[0146] NM 001406743.1 Homo sapiens ret proto-oncogene (RET), transcript variant 1, mRNA (SEQ ID NO: 15)

AGTCCCGCGACCGAAGCAGGGCGCGCAGCAGCGCTGAGTGCCCCGGAACGTGCGTCG CGCCCCCAGTGTC CGTCGCGTCCGCCGCGCCCCGGGCGGGGATGGGGCGGCCAGACTGAGCGCCGCACCCGCC ATCCAGACCC GCCGGCCCTAGCCGCAGTCCCTCCAGCCGTGGCCCCAGCGCGCACGGGCGATGGCGAAGG GGACGTCCGG TGCCGCGGGGCTGCGTCTGCTGTTGCTGCTGCTGCTGCCGCTGCTAGGCAAAGTGGCATT GGGCCTCTAC TTCTCGAGGGATGCTTACTGGGAGAAGCTGTATGTGGACCAGGCAGCCGGCACGCCCTTG CTGTACGTCC ATGCCCTGCGGGACGCCCCTGAGGAGGTGCCCAGCTTCCGCCTGGGCCAGCATCTCTACG GCACGTACCG CACACGGCTGCATGAGAACAACTGGATCTGCATCCAGGAGGACACCGGCCTCCTCTACCT TAACCGGAGC CTGGACCATAGCTCCTGGGAGAAGCTCAGTGTCCGCAACCGCGGCTTTCCCCTGCTCACC GTCTACCTCA AGGTCTTCCTGTCACCCACATCCCTTCGTGAGGGCGAGTGCCAGTGGCCAGGCTGTGCCC GGGTATACTT CTCCTTCTTCAACACCTCCTTTCCAGCCTGCAGCTCCCTCAAGCCCCGGGAGCTCTGCTT CCCAGAGACA AGGCCCTCCTTCCGCATTCGGGAGAACCGACCCCCAGGCACCTTCCACCAGTTCCGCCTG CTGCCTGTGC AGTTCTTGTGCCCCAACATCAGCGTGGCCTACAGGCTCCTGGAGGGTGAGGGTCTGCCCT TCCGCTGGGC CCCGGACAGCCTGGAGGTGAGCACGCGCTGGGCCCTGGACCGCGAGCAGCGGGAGAAGTA CGAGCTGGTG GCCGTGTGCACCGTGCACGCCGGCGCGCGCGAGGAGGTGGTGATGGTGCCCTTCCCGGTG ACCGTGTACG ACGAGGACGACTCGGCGCCCACCTTCCCCGCGGGCGTCGACACCGCCAGCGCCGTGGTGG AGTTCAAGGG GAAGGAGGACACCGTGGTGGCCACGCTGCGTGTCTTCGATGCAGACGTGGTACCTGCATC AGGGGAGCTG GTGAGGCGGTACACAAGCACGCTGCTCCCCGGGGACACCTGGGCCCAGCAGACCTTCCGG GTGGAACACT GGCCCAACGAGACCTCGGTCCAGGCCAACGGCAGCTTCGTGCGGGCGACCGTACATGACT ATAGGCTGGT TCTCAACCGGAACCTCTCCATCTCGGAGAACCGCACCATGCAGCTGGCGGTGCTGGTCAA TGACTCAGAC TTCCAGGGCCCAGGAGCGGGCGTCCTCTTGCTCCACTTCAACGTGTCGGTGCTGCCGGTC AGCCTGCACC TGCCCAGTACCTACTCCCTCTCCGTGAGCAGGAGGGCTCGCCGATTTGCCCAGATCGGGA AAGTCTGTGT GGAAAACTGCCAGGCATTCAGTGGCATCAACGTCCAGTACAAGCTGCATTCCTCTGGTGC CAACTGCAGC ACGCTAGGGGTGGTCACCTCAGCCGAGGACACCTCGGGGATCCTGTTTGTGAATGACACC AAGGCCCTGC GGCGGCCCAAGTGTGCCGAACTTCACTACATGGTGGTGGCCACCGACCAGCAGACCTCTA GGCAGGCCCA GGCCCAGCTGCTTGTAACAGTGGAGGGGTCATATGTGGCCGAGGAGGCGGGCTGCCCCCT GTCCTGTGCA GTCAGCAAGAGACGGCTGGAGTGTGAGGAGTGTGGCGGCCTGGGCTCCCCAACAGGCAGG TGTGAGTGGA GGCAAGGAGATGGCAAAGGGATCACCAGGAACTTCTCCACCTGCTCTCCCAGCACCAAGA CCTGCCCCGA CGGCCACTGCGATGTTGTGGAGACCCAAGACATCAACATTTGCCCTCAGGACTGCCTCCG GGGCAGCATT GTTGGGGGACACGAGCCTGGGGAGCCCCGGGGGATTAAAGCTGGCTATGGCACCTGCAAC TGCTTCCCTG AGGAGGAGAAGTGCTTCTGCGAGCCCGAAGACATCCAGGATCCACTGTGCGACGAGCTGT GCCGCACGGT GATCGCAGCCGCTGTCCTCTTCTCCTTCATCGTCTCGGTGCTGCTGTCTGCCTTCTGCAT CCACTGCTAC CACAAGTTTGCCCACAAGCCACCCATCTCCTCAGCTGAGATGACCTTCCGGAGGCCCGCC CAGGCCTTCC CGGTCAGCTACTCCTCTTCCGGTGCCCGCCGGCCCTCGCTGGACTCCATGGAGAACCAGG TCTCCGTGGA TGCCTTCAAGATCCTGGAGGATCCAAAGTGGGAATTCCCTCGGAAGAACTTGGTTCTTGG AAAAACTCTA GGAGAAGGCGAATTTGGAAAAGTGGTCAAGGCAACGGCCTTCCATCTGAAAGGCAGAGCA GGGTACACCA CGGTGGCCGTGAAGATGCTGAAAGAGAACGCCTCCCCGAGTGAGCTGCGAGACCTGCTGT CAGAGTTCAA CGTCCTGAAGCAGGTCAACCACCCACATGTCATCAAATTGTATGGGGCCTGCAGCCAGGA TGGCCCGCTC CTCCTCATCGTGGAGTACGCCAAATACGGCTCCCTGCGGGGCTTCCTCCGCGAGAGCCGC AAAGTGGGGC CTGGCTACCTGGGCAGTGGAGGCAGCCGCAACTCCAGCTCCCTGGACCACCCGGATGAGC GGGCCCTCAC CATGGGCGACCTCATCTCATTTGCCTGGCAGATCTCACAGGGGATGCAGTATCTGGCCGA GATGAAGCTC GTTCATCGGGACTTGGCAGCCAGAAACATCCTGGTAGCTGAGGGGCGGAAGATGAAGATT TCGGATTTCG GCTTGTCCCGAGATGTTTATGAAGAGGATTCCTACGTGAAGAGGAGCCAGGGTCGGATTC CAGTTAAATG GATGGCAATTGAATCCCTTTTTGATCATATCTACACCACGCAAAGTGATGTATGGTCTTT TGGTGTCCTG CTGTGGGAGATCGTGACCCTAGGGGGAAACCCCTATCCTGGGATTCCTCCTGAGCGGCTC TTCAACCTTC TGAAGACCGGCCACCGGATGGAGAGGCCAGACAACTGCAGCGAGGAGATGTACCGCCTGA TGCTGCAATG CTGGAAGCAGGAGCCGGACAAAAGGCCGGTGTTTGCGGACATCAGCAAAGACCTGGAGAA GATGATGGTT AAGAGGAGAGACTACTTGGACCTTGCGGCGTCCACTCCATCTGACTCCCTGATTTATGAC GACGGCCTCT CAGAGGAGGAGACACCGCTGGTGGACTGTAATAATGCCCCCCTCCCTCGAGCCCTCCCTT CCACATGGAT TGAAAACAAACTCTATGGCATGTCAGACCCGAACTGGCCTGGAGAGAGTCCTGTACCACT CACGAGAGCT GATGGCACTAACACTGGGTTTCCAAGATATCCAAATGATAGTGTATATGCTAACTGGATG CTTTCACCCT CAGCGGCAAAATTAATGGACACGTTTGATAGTTAACATTTCTTTGTGAAAGATGCACAAC ACTCCTCCAG TCTTGTGGGGGCAGCTTTTGGGAAGTCTCAGCAGCTCTTCTGGCTGTGTTGTCAGCACTG TAACTTCGCA GAAAAGAGTCGGATTACCAAAACACTGCCTGCTCTTCAGACTTAAAGCACTGATAGGACT TAAAATAGTC TCATTCAAATACTGTATTTTATATAGGCATTTCACAAAAACAGCAAAATTGTGGCATTTT GTGAGGCCAA GGCTTGGATGCGTGTGTAATAGAGCCTTGTGGTGTGTGCGCACACACCCAGAGGGAGAGT TTGAAAAATG CTTATTGGACACGTAACCTGGCTCTAATTTGGGCTGTTTTTCAGATACACTGTGATAAGT TCTTTTACAA ATATCTATAGACATGGTAAACTTTTGGTTTTCAGATATGCTTAATGATAGTCTTACTAAA TGCAGAAATA AGAATAAACTTTCTCAAATTATTAAAAATGCCTACACAGTAAGTGTGAATTGCTGCAACA GGTTTGTTCT CAGGAGGGTAAGAACTCCAGGTCTAAACAGCTGACCCAGTGATGGGGAATTTATCCTTGA CCAATTTATC CTTGACCAATAACCTAATTGTCTATTCCTGAGTTATAAAAGTCCCCATCCTTATTAGCTC TACTGGAATT T T CAT ACAC GT AAAT GCAGAAGT T ACT AAGT AT T AAGT AT T ACT GAGT AT T AAGT AGT AAT CT GT CAGT T AT T AAAAT T T GT AAAAT C TAT T TAT GAAAG GT CAT T AAAC C AGAT CAT GTTCCTTTTTTT GT AAT C AAG G T GACT AAGAAAAT CAGT T GT GT AAAT AAAAT CAT GT AT CAT AAAA

[0147] NM 002944.3 Homo sapiens ROS proto-oncogene 1, receptor tyrosine kinase

(ROS1), transcript variant 1, mRNA (SEQ ID NO: 16)

GCACTTCTAAGAACTAACCTTTAGTCACTGGGTGACTTTATGGGAGTAAAAGGAAGC TGTTATGAAATAG CTCTTATGGAACTGTTACAAGCTTTCAAGCATTCAAAGGTCTAAATGAAAAAGGCTAAGT ATTATTTCAA AAGGCAAGTATATCCTAATATAGCAAAACAAACAAAGCAAAATCCATCAGCTACTCCTCC AATTGAAGTG ATGAAGCCCAAATAATTCATATAGCAAAATGGAGAAAATTAGACCGGCCATCTAAAAATC TGCCATTGGT GAAGTGATGAAGAACATTTACTGTCTTATTCCGAAGCTTGTCAATTTTGCAACTCTTGGC TGCCTATGGA

TTTCTGTGGTGCAGTGTACAGTTTTAAATAGCTGCCTAAAGTCGTGTGTAACTAATC TGGGCCAGCAGCT TGACCTTGGCACACCACATAATCTGAGTGAACCGTGTATCCAAGGATGTCACTTTTGGAA CTCTGTAGAT CAGAAAAACTGTGCTTTAAAGTGTCGGGAGTCGTGTGAGGTTGGCTGTAGCAGCGCGGAA GGTGCATATG AAGAGGAAGTACTGGAAAATGCAGACCTACCAACTGCTCCCTTTGCTTCTTCCATTGGAA GCCACAATAT GACATTACGAT GGAAAT CT GCAAACTT CT CT GGAGTAAAATACAT CATT CAGT GGAAATAT GCACAACTT

CTGGGAAGCTGGACTTATACTAAGACTGTGTCCAGACCGTCCTATGTGGTCAAGCCC CTGCACCCCTTCA CTGAGTACATTTTCCGAGTGGTTTGGATCTTCACAGCGCAGCTGCAGCTCTACTCCCCTC CAAGTCCCAG TTACAGGACTCATCCTCATGGAGTTCCTGAAACTGCACCTTTGATTAGGAATATTGAGAG CTCAAGTCCC GACACTGTGGAAGTCAGCTGGGATCCACCTCAATTCCCAGGTGGACCTATTTTGGGTTAT AACTTAAGGC TGATCAGCAAAAATCAAAAATTAGATGCAGGGACACAGAGAACCAGTTTCCAGTTTTACT CCACTTTACC AAATACTATCTACAGGTTTTCTATTGCAGCAGTAAATGAAGTTGGTGAGGGTCCAGAAGC AGAATCTAGT ATTACCACTTCATCTTCAGCAGTTCAACAAGAGGAACAGTGGCTCTTTTTATCCAGAAAA ACTTCTCTAA GAAAGAGATCTTTAAAACATTTAGTAGATGAAGCACATTGCCTTCGGTTGGATGCTATAT ACCATAATAT TACAGGAATATCTGTTGATGTCCACCAGCAAATTGTTTATTTCTCTGAAGGAACTCTCAT ATGGGCGAAG AAGGCTGCCAACATGTCTGATGTATCTGACCTGAGAATTTTTTACAGAGGTTCAGGATTA ATTTCTTCTA TCTCCATAGATTGGCTTTATCAAAGAATGTATTTCATCATGGATGAACTGGTATGTGTCT GTGATTTAGA GAACTGCTCAAACATCGAGGAAATTACTCCACCCTCTATTAGTGCACCTCAAAAAATTGT GGCTGATTCA TACAATGGGTATGTCTTTTACCTCCTGAGAGATGGCATTTATAGAGCAGACCTTCCTGTA CCATCTGGCC GGTGTGCAGAAGCTGTGCGTATTGTGGAGAGTTGCACGTTAAAGGACTTTGCAATCAAGC CACAAGCCAA GCGAATCATTTACTTCAATGACACTGCCCAAGTCTTCATGTCAACATTTCTGGATGGCTC TGCTTCCCAT CTCATCCTACCTCGCATCCCCTTTGCTGATGTGAAAAGTTTTGCTTGTGAAAACAATGAC TTTCTTGTCA CAGATGGCAAGGTCATTTTCCAACAGGATGCTTTGTCTTTTAATGAATTCATCGTGGGAT GTGACCTGAG TCACATAGAAGAATTTGGGTTTGGTAACTTGGTCATCTTTGGCTCATCCTCCCAGCTGCA CCCTCTGCCA GGCCGCCCGCAGGAGCTTTCGGTGCTGTTTGGCTCTCACCAGGCTCTTGTTCAATGGAAG CCTCCTGCCC TTGCCATAGGAGCCAATGTCATCCTGATCAGTGATATTATTGAACTCTTTGAATTAGGCC CTTCTGCCTG GCAGAACTGGACCTATGAGGTGAAAGTATCCACCCAAGACCCTCCTGAAGTCACTCATAT TTTCTTGAAC ATAAGT GGAACCAT GCT GAAT GTACCT GAGCT GCAGAGT GCTAT GAAATACAAGGTTT CT GT GAGAGCAA GTTCTCCAAAGAGGCCAGGCCCCTGGTCAGAGCCCTCAGTGGGTACTACCCTGGTGCCAG CTAGTGAACC ACCATTTATCATGGCTGTGAAAGAAGATGGGCTTTGGAGTAAACCATTAAATAGCTTTGG CCCAGGAGAG TTCTTATCCTCTGATATAGGAAATGTGTCAGACATGGATTGGTATAACAACAGCCTCTAC TACAGTGACA CGAAAGGCGACGTTTTTGTGTGGCTGCTGAATGGGACGGATATCTCAGAGAATTATCACC TACCCAGCAT TGCAGGAGCAGGGGCTTTAGCTTTTGAGTGGCTGGGTCACTTTCTCTACTGGGCTGGAAA GACATATGTG ATACAAAGGCAGTCTGTGTTGACGGGACACACAGACATTGTTACCCACGTGAAGCTATTG GTGAATGACA TGGTGGTGGATTCAGTTGGTGGATATCTCTACTGGACCACACTCTATTCAGTGGAAAGCA CCAGACTAAA TGGGGAAAGTTCCCTTGTACTACAGACACAGCCTTGGTTTTCTGGGAAAAAGGTAATTGC TCTAACTTTA GACCTCAGTGATGGGCTCCTGTATTGGTTGGTTCAAGACAGTCAATGTATTCACCTGTAC ACAGCTGTTC TTCGGGGACAGAGCACTGGGGATACCACCATCACAGAATTTGCAGCCTGGAGTACTTCTG AAATTTCCCA GAATGCACTGATGTACTATAGTGGTCGGCTGTTCTGGATCAATGGCTTTAGGATTATCAC AACTCAAGAA ATAGGTCAGAAAACCAGTGTCTCTGTTTTGGAACCAGCCAGATTTAATCAGTTCACAATT ATTCAGACAT CCCTTAAGCCCCTGCCAGGGAACTTTTCCTTTACCCCTAAGGTTATTCCAGATTCTGTTC AAGAGTCTTC ATTTAGGATTGAAGGAAATGCTTCAAGTTTTCAAATCCTGTGGAATGGTCCCCCTGCGGT AGACTGGGGT GTAGTTTTCTACAGTGTAGAATTTAGTGCTCATTCTAAGTTCTTGGCTAGTGAACAACAC TCTTTACCTG TATTTACTGTGGAAGGACTGGAACCTTATGCCTTATTTAATCTTTCTGTCACTCCTTATA CCTACTGGGG AAAGGGCCCCAAAACATCTCTGTCACTTCGAGCACCTGAAACAGTTCCATCAGCACCAGA GAACCCCAGA ATATTTATATTACCAAGTGGAAAATGCTGCAACAAGAATGAAGTTGTGGTGGAATTTAGG TGGAACAAAC CTAAGCATGAAAATGGGGTGTTAACAAAATTTGAAATTTTCTACAATATATCCAATCAAA GTATTACAAA CAAAACATGTGAAGACTGGATTGCTGTCAATGTCACTCCCTCAGTGATGTCTTTTCAACT TGAAGGCATG AGTCCCAGATGCTTTATTGCCTTCCAGGTTAGGGCCTTTACATCTAAGGGGCCAGGACCA TATGCTGACG TTGTAAAGTCTACAACATCAGAAATCAACCCATTTCCTCACCTCATAACTCTTCTTGGTA ACAAGATAGT TTTTTTAGATATGGATCAAAATCAAGTTGTGTGGACGTTTTCAGCAGAAAGAGTTATCAG TGCCGTTTGC TACACAGCTGATAATGAGATGGGATATTATGCTGAAGGGGACTCACTCTTTCTTCTGCAC TTGCACAATC GCTCTAGCTCTGAGCTTTTCCAAGATTCACTGGTTTTTGATATCACAGTTATTACAATTG ACTGGATTTC AAGGCACCTCTACTTTGCACTGAAAGAATCACAAAATGGAATGCAAGTATTTGATGTTGA TCTTGAACAC AAGGTGAAATATCCCAGAGAGGTGAAGATTCACAATAGGAATTCAACAATAATTTCTTTT TCTGTATATC CTCTTTTAAGTCGCTTGTATTGGACAGAAGTTTCCAATTTTGGCTACCAGATGTTCTACT ACAGTATTAT CAGTCACACCTTGCACCGAATTCTGCAACCCACAGCTACAAACCAACAAAACAAAAGGAA TCAATGTTCT TGTAATGTGACTGAATTTGAGTTAAGTGGAGCAATGGCTATTGATACCTCTAACCTAGAG AAACCATTGA TATACTTTGCCAAAGCACAAGAGATCTGGGCAATGGATCTGGAAGGCTGTCAGTGTTGGA GAGTTATCAC AGTACCTGCTATGCTCGCAGGAAAAACCCTTGTTAGCTTAACTGTGGATGGAGATCTTAT ATACTGGATC ATCACAGCAAAGGACAGCACACAGATTTATCAGGCAAAGAAAGGAAATGGGGCCATCGTT TCCCAGGTGA AGGCCCTAAGGAGTAGGCATATCTTGGCTTACAGTTCAGTTATGCAGCCTTTTCCAGATA AAGCGTTTCT GTCTCTAGCTTCAGACACTGTGGAACCAACTATACTTAATGCCACTAACACTAGCCTCAC AATCAGATTA CCTCTGGCCAAGACAAACCTCACATGGTATGGCATCACCAGCCCTACTCCAACATACCTG GTTTATTATG CAGAAGTTAATGACAGGAAAAACAGCTCTGACTTGAAATATAGAATTCTGGAATTTCAGG ACAGTATAGC T C T T AT T GAAGAT T T AC AAC CAT T T T C AAC AT AC AT GAT AC AGAT AG C T GT AAAAAAT TAT TAT T C AGAT CCTTTGGAACATTTACCACCAGGAAAAGAGATTTGGGGAAAAACTAAAAATGGAGTACCA GAGGCAGTGC AGCTCATTAATACAACTGTGCGGTCAGACACCAGCCTCATTATATCTTGGAGAGAATCTC ACAAGCCAAA TGGACCTAAAGAATCAGTCCGTTATCAGTTGGCAATCTCACACCTGGCCCTAATTCCTGA AACTCCTCTA AGACAAAGTGAATTTCCAAATGGAAGGCTCACTCTCCTTGTTACTAGACTGTCTGGTGGA AATATTTATG TGTTAAAGGTTCTTGCCTGCCACTCTGAGGAAATGTGGTGTACAGAGAGTCATCCTGTCA CTGTGGAAAT GTTTAACACACCAGAGAAACCTTATTCCTTGGTTCCAGAGAACACTAGTTTGCAATTTAA TTGGAAGGCT CCATTGAATGTTAACCTCATCAGATTTTGGGTTGAGCTACAGAAGTGGAAATACAATGAG TTTTACCATG TTAAAACTTCATGCAGCCAAGGTCCTGCTTATGTCTGTAATATCACAAATCTACAACCTT ATACTTCATA TAATGTCAGAGTAGTGGTGGTTTATAAGACGGGAGAAAATAGCACCTCACTTCCAGAAAG CTTTAAGACA AAAGCTGGAGTCCCAAATAAACCAGGCATTCCCAAATTACTAGAAGGGAGTAAAAATTCA ATACAGTGGG AGAAAGCT GAAGATAAT GGAT GTAGAATTACATACTATAT CCTT GAGATAAGAAAGAGCACTT CAAATAA TTTACAGAACCAGAATTTAAGGTGGAAGATGACATTTAATGGATCCTGCAGTAGTGTTTG CACATGGAAG TCCAAAAACCTGAAAGGAATATTTCAGTTCAGAGTAGTAGCTGCAAATAATCTAGGGTTT GGTGAATATA GT G GAAT C AGT GAGAAT AT T AT AT T AGT T G GAGAT GAT T T T T G GAT AC C AGAAAC AAGT T T CAT AC T T AC TATTATAGTTGGAATATTTCTGGTTGTTACAATCCCACTGACCTTTGTCTGGCATAGAAG ATTAAAGAAT CAAAAAAGTGCCAAGGAAGGGGTGACAGTGCTTATAAACGAAGACAAAGAGTTGGCTGAG CTGCGAGGTC TGGCAGCCGGAGTAGGCCTGGCTAATGCCTGCTATGCAATACATACTCTTCCAACCCAAG AGGAGATTGA AAATCTTCCTGCCTTCCCTCGGGAAAAACTGACTCTGCGTCTCTTGCTGGGAAGTGGAGC CTTTGGAGAA GT GTAT GAAGGAACAGCAGT GGACATCTTAGGAGTT GGAAGT GGAGAAAT CAAAGTAGCAGT GAAGACTT TGAAGAAGGGTTCCACAGACCAGGAGAAGATTGAATTCCTGAAGGAGGCACATCTGATGA GCAAATTTAA TCATCCCAACATTCTGAAGCAGCTTGGAGTTTGTCTGCTGAATGAACCCCAATACATTAT CCTGGAACTG ATGGAGGGAGGAGACCTTCTTACTTATTTGCGTAAAGCCCGGATGGCAACGTTTTATGGT CCTTTACTCA CCTTGGTTGACCTTGTAGACCTGTGTGTAGATATTTCAAAAGGCTGTGTCTACTTGGAAC GGATGCATTT CATTCACAGGGATCTGGCAGCTAGAAATTGCCTTGTTTCCGTGAAAGACTATACCAGTCC ACGGATAGTG AAGATTGGAGACTTTGGACTCGCCAGAGACATCTATAAAAATGATTACTATAGAAAGAGA GGGGAAGGCC TGCTCCCAGTTCGGTGGATGGCTCCAGAAAGTTTGATGGATGGAATCTTCACTACTCAAT CTGATGTATG GTCTTTTGGAATTCTGATTTGGGAGATTTTAACTCTTGGTCATCAGCCTTATCCAGCTCA TTCCAACCTT GATGTGTTAAACTATGTGCAAACAGGAGGGAGACTGGAGCCACCAAGAAATTGTCCTGAT GATCTGTGGA ATTTAATGACCCAGTGCTGGGCTCAAGAACCCGACCAAAGACCTACTTTTCATAGAATTC AGGACCAACT T C AGT T AT T C AGAAAT T T T T T C T T AAAT AG CAT T TAT AAGT C C AGAGAT GAAG C AAAC AAC AGT G GAGT C ATAAATGAAAGCTTTGAAGGTGAAGATGGCGATGTGATTTGTTTGAATTCAGATGACATT ATGCCAGTTG CTTTAATGGAAACGAAGAACCGAGAAGGGTTAAACTATATGGTACTTGCTACAGAATGTG GCCAAGGTGA AGAAAAGTCTGAGGGTCCTCTAGGCTCCCAGGAATCTGAATCTTGTGGTCTGAGGAAAGA AGAGAAGGAA CCACATGCAGACAAAGATTTCTGCCAAGAAAAACAAGTGGCTTACTGCCCTTCTGGCAAG CCTGAAGGCC TGAACTATGCCTGTCTCACTCACAGTGGATATGGAGATGGGTCTGATTAATAGCGTTGTT TGGGAAATAG AGAGTT GAGATAAACACT CT CATT CAGTAGTTACT GAAAGAAAACT CT GCTAGAAT GAT AAAT GT CAT GG TGGTCTATAACTCCAAATAAACAATGCAACGTTCCTGATTTCTAATCTTGGTTCTGAGAG CCATTTGGTT TCAGTTGTAGCAATCCCCATACCAGCTGCCTGACTTTCAGTAGAATTATGAGATGAACAC TAAGCATGTG GAAAGCTTAGGAAGACTCAGAAGTCTGGAAGGGAAACACTGCTCTCCCTTCTCCCTTGAG GTGCTTTAGG CTCTTACCCACCTTTCAGTTTGGGCTGTAATAAAAATATCTTGGCCACATGTTTAGAGAC AGAATAGGTG T GTT CAGCGATATAAAGAAGAGGCTAAGGAGTAGGCT CAGGGGGGT CAACT GAACTACAGATAAT CT CAA ATGGGACCAAGGAAATGAGAAATAATTTCACACATACAGAAGAAACCAGCACCTGTGACT TGAGAAATCA CTTGGAAAGCTGTTACTGCAATGATATATATATTATCTTTTTTTAATTTTTTTTTTTTTT TTTTGAGACG AAGTCTTGCTCTGTTGCCCAGGCTGGAGTTCAATGGCACGATCTCGGCACTGCAAACTCC ACCTCCTGGG

TTCAAGCAATTCTCGTGCCTCAGCCTCCTAAGTAGCTGGGATTACAGGCGTGTGCCA CCACGCCCGGCTA ATTTTTGTATTTTTAGTAGAGATGAGGTTTCACCATATTGGCCAGGCTGGTCTAGAACTC CTGACCTCGG GATCCACCTGCCTTGGCCTCCCAAAGTGCTGGATTACAGGTGTGAGCCACCATGCCTAGC CGATATATAT TGTCTTTAATCACTACTGTAAAATATTTTGTAGTTTTGAGGCTTACAACAGTAGATTCAG TCATGTTGAA AATAAGACTGTGAAGATCTTTTAAGTCCTGAAGTTTTGCATTCTGTAATCTTCAGTTGTA TAAAATCACT CTGACTTGTGTGCTATTATGGAAATTAACTAGTATAAAGATTGCTATTTGCCATATCTAT TTTATGTATA AAAT AC T T AAGAT TAG AT T T T GT AT CAAAT T AT G C T T AAAAT T AAAT AT AAAT GAT T AT AC AAT GT T AA

[0148] NM_000455.5 Homo sapiens serine/threonine kinase 11 (STK11), transcript variant 1, mRNA (SEQ ID NO: 17)

GAGGTAAACAAGATGGCGGCGGCGTGTCGGGCGCGGAAGGGGGAGGCGGCCCGGGGC GCCCGCGAGTGAG GCGCGGGGCGGCGAAGGGAGCGCGGGTGGCGGCACTTGCTGCCGCGGCCTTGGATGGGCT GGGCCCCCCT CGCCGCTCCGCCTCCTCCACACGCGCGGCGGCCGCGGCGAGGGGGACGCGCCGCCCGGGG CCCGGCACCT TCGGGAACCCCCCGGCCCGGAGCCTGCGGCCTGCGCCGCCTCGGCCGCCGGGAGCCCCGT GGAGCCCCCG CCGCCGCGCCGCCCCGCGGACCGGACGCTGAGGGCACTCGGGGCGGGGCGCGCGCTCGGG CAGACGTTTG CGGGGAGGGGGGCGCCTGCCGGGCCCCGGCGACCACCTTGGGGGTCGCGGGCCGGCTCGG GGGGCGCCCA GTGCGGGCCCTCGCGGGCGCCGGGCAGCGACCAGCCCTGAGCGGAGCTGTTGGCCGCGGC GGGAGGCCTC CCGGACGCCCCCAGCCCCCCGAACGCTCGCCCGGGCCGGCGGGAGTCGGCGCCCCCCGGG AGGTCCGCTC GGTCGTCCGCGGCGGAGCGTTTGCTCCTGGGACAGGCGGTGGGACCGGGGCGTCGCCGGA GACGCCCCCA GCGAAGTTGGGCTCTCCAGGTGTGGGGGTCCCGGGGGGTAGCGACGTCGCGGACCCGGCC TGTGGGATGG GCGGCCCGGAGAAGACTGCGCTCGGCCGTGTTCATACTTGTCCGTGGGCCTGAGGTCCCC GGAGGATGAC CTAGCACTGAAAAGCCCCGGCCGGCCTCCCCAGGGTCCCCGAGGACGAAGTTGACCCTGA CCGGGCCGTC TCCCAGTTCTGAGGCCCGGGTCCCACTGGAACTCGCGTCTGAGCCGCCGTCCCGGACCCC CGGTGCCCGC CGGTCCGCAGACCCTGCACCGGGCTTGGACTCGCAGCCGGGACTGACGTGTAGAACAATC GTTTCTGTTG GAAGAAGGGTTTTTCCCTTCCTTTTGGGGTTTTTGTTGCCTTTTTTTTTTCTTTTTTCTT TGTAAAATTT TGGAGAAGGGAAGTCGGAACACAAGGAAGGACCGCTCACCCGCGGACTCAGGGCTGGCGG CGGGACTCCA GGACCCTGGGTCCAGCATGGAGGTGGTGGACCCGCAGCAGCTGGGCATGTTCACGGAGGG CGAGCTGATG TCGGTGGGTATGGACACGTTCATCCACCGCATCGACTCCACCGAGGTCATCTACCAGCCG CGCCGCAAGC GGGCCAAGCTCATCGGCAAGTACCTGATGGGGGACCTGCTGGGGGAAGGCTCTTACGGCA AGGTGAAGGA GGTGCTGGACTCGGAGACGCTGTGCAGGAGGGCCGTCAAGATCCTCAAGAAGAAGAAGTT GCGAAGGATC CCCAACGGGGAGGCCAACGTGAAGAAGGAAATTCAACTACTGAGGAGGTTACGGCACAAA AATGTCATCC AGCT GGT GGAT GT GTTATACAACGAAGAGAAGCAGAAAAT GTATAT GGT GAT GGAGTACT GCGT GT GT GG CATGCAGGAAATGCTGGACAGCGTGCCGGAGAAGCGTTTCCCAGTGTGCCAGGCCCACGG GTACTTCTGT CAGCTGATTGACGGCCTGGAGTACCTGCATAGCCAGGGCATTGTGCACAAGGACATCAAG CCGGGGAACC TGCTGCTCACCACCGGTGGCACCCTCAAAATCTCCGACCTGGGCGTGGCCGAGGCACTGC ACCCGTTCGC GGCGGACGACACCTGCCGGACCAGCCAGGGCTCCCCGGCTTTCCAGCCGCCCGAGATTGC CAACGGCCTG GACACCTTCTCCGGCTTCAAGGTGGACATCTGGTCGGCTGGGGTCACCCTCTACAACATC ACCACGGGTC TGTACCCCTTCGAAGGGGACAACATCTACAAGTTGTTTGAGAACATCGGGAAGGGGAGCT ACGCCATCCC GGGCGACTGTGGCCCCCCGCTCTCTGACCTGCTGAAAGGGATGCTTGAGTACGAACCGGC CAAGAGGTTC TCCATCCGGCAGATCCGGCAGCACAGCTGGTTCCGGAAGAAACATCCTCCGGCTGAAGCA CCAGTGCCCA TCCCACCGAGCCCAGACACCAAGGACCGGTGGCGCAGCATGACTGTGGTGCCGTACTTGG AGGACCTGCA CGGCGCGGACGAGGACGAGGACCTCTTCGACATCGAGGATGACATCATCTACACTCAGGA CTTCACGGTG CCCGGACAGGTCCCAGAAGAGGAGGCCAGTCACAATGGACAGCGCCGGGGCCTCCCCAAG GCCGTGTGTA TGAACGGCACAGAGGCGGCGCAGCTGAGCACCAAATCCAGGGCGGAGGGCCGGGCCCCCA ACCCTGCCCG CAAGGCCTGCTCCGCCAGCAGCAAGATCCGCCGGCTGTCGGCCTGCAAGCAGCAGTGAGG CTGGCCGCCT GCAGCCCGTGTCCAGGAGCCCCGCCAGGTGCCCGCGCCAGGCCCTCAGTCTTCCTGCCGG TTCCGCCCGC CCTCCCGGAGAGGTGGCCGCCATGCTTCTGTGCCGACCACGCCCCAGGACCTCCGGAGCG CCCTGCAGGG CCGGGCAGGGGGACAGCAGGGACCGGGCGCAGCCCTCCCCCCTCGGCCGCCCGGCAGTGC ACGCGGCTTG TTGACTTCGCAGCCCCGGGCGGAGCCTTCCCGGGCGGGCGTGGGAGGAGGGAGGCGGCCT CCATGCACTT TATGTGGAGACTACTGGCCCCGCCCGTGGCCTCGTGCTCCGCAGGGCGCCCAGCGCCGTC CGGCGGCCCC GCCGCAGACCAGCTGGCGGGTGTGGAGACCAGGCTCCTGACCCCGCCATGCATGCAGCGC CACCTGGAAG CCGCGCGGCCGCTTTGGTTTTTTGTTTGGTTGGTTCCATTTTCTTTTTTTCTTTTTTTTT TTAAGAAAAA ATAAAAGGTGGATTTGAGCTGTGGCTGTGAGGGGTGTTTGGGAGCTGCTGGGTGGCAGGG GGGCTGTGGG GTCGGGCTCACGTCGCGGCCGCCTTTGCGCTCTCGGGTCACCCTGCTTTGGCGGCCCGGC CGGAGGGCAG GACCCTCACCTCTCCCCCAAGGCCACTGCGCTCTTGGGACCCCAGAGAAAACCCGGAGCA AGCAGGAGTG TGCGGTCAATATTTATATCATCCAGAAAAGAAAAACACGAGAAACGCCATCGCGGGATGG TGCAGACGCG GCGGGGACTCGGAGGGTGCCGTGCGGGCGAGGCCGCCCAAATTTGGCAATAAATAAAGCT TGGGAAGCTT GGA

[0149] NM 000546.6 Homo sapiens tumor protein p53 (TP53), transcript variant 1, mRNA (SEQ ID NO: 18)

CTCAAAAGTCTAGAGCCACCGTCCAGGGAGCAGGTAGCTGCTGGGCTCCGGGGACAC TTTGCGTTCGGGC TGGGAGCGTGCTTTCCACGACGGTGACACGCTTCCCTGGATTGGCAGCCAGACTGCCTTC CGGGTCACTG CCATGGAGGAGCCGCAGTCAGATCCTAGCGTCGAGCCCCCTCTGAGTCAGGAAACATTTT CAGACCTATG GAAACTACTTCCTGAAAACAACGTTCTGTCCCCCTTGCCGTCCCAAGCAATGGATGATTT GATGCTGTCC CCGGACGATATTGAACAATGGTTCACTGAAGACCCAGGTCCAGATGAAGCTCCCAGAATG CCAGAGGCTG CTCCCCCCGTGGCCCCTGCACCAGCAGCTCCTACACCGGCGGCCCCTGCACCAGCCCCCT CCTGGCCCCT GTCATCTTCTGTCCCTTCCCAGAAAACCTACCAGGGCAGCTACGGTTTCCGTCTGGGCTT CTTGCATTCT GGGACAGCCAAGTCTGTGACTTGCACGTACTCCCCTGCCCTCAACAAGATGTTTTGCCAA CTGGCCAAGA CCTGCCCTGTGCAGCTGTGGGTTGATTCCACACCCCCGCCCGGCACCCGCGTCCGCGCCA TGGCCATCTA CAAGCAGTCACAGCACATGACGGAGGTTGTGAGGCGCTGCCCCCACCATGAGCGCTGCTC AGATAGCGAT GGTCTGGCCCCTCCTCAGCATCTTATCCGAGTGGAAGGAAATTTGCGTGTGGAGTATTTG GATGACAGAA

ACACTTTTCGACATAGTGTGGTGGTGCCCTATGAGCCGCCTGAGGTTGGCTCTGACT GTACCACCATCCA

CTACAACTACATGTGTAACAGTTCCTGCATGGGCGGCATGAACCGGAGGCCCATCCT CACCATCATCACA

CTGGAAGACTCCAGTGGTAATCTACTGGGACGGAACAGCTTTGAGGTGCGTGTTTGT GCCTGTCCTGGGA

GAGACCGGCGCACAGAGGAAGAGAATCTCCGCAAGAAAGGGGAGCCTCACCACGAGC TGCCCCCAGGGAG

CACTAAGCGAGCACTGCCCAACAACACCAGCTCCTCTCCCCAGCCAAAGAAGAAACC ACTGGATGGAGAA

TATTTCACCCTTCAGATCCGTGGGCGTGAGCGCTTCGAGATGTTCCGAGAGCTGAAT GAGGCCTTGGAAC

TCAAGGATGCCCAGGCTGGGAAGGAGCCAGGGGGGAGCAGGGCTCACTCCAGCCACC TGAAGTCCAAAAA

GGGTCAGTCTACCTCCCGCCATAAAAAACTCATGTTCAAGACAGAAGGGCCTGACTC AGACTGACATTCT

CCACTTCTTGTTCCCCACTGACAGCCTCCCACCCCCATCTCTCCCTCCCCTGCCATT TTGGGTTTTGGGT

CTTTGAACCCTTGCTTGCAATAGGTGTGCGTCAGAAGCACCCAGGACTTCCATTTGC TTTGTCCCGGGGC

TCCACTGAACAAGTTGGCCTGCACTGGTGTTTTGTTGTGGGGAGGAGGATGGGGAGT AGGACATACCAGC

TTAGATTTTAAGGTTTTTACTGTGAGGGATGTTTGGGAGATGTAAGAAATGTTCTTG CAGTTAAGGGTTA

GTTTACAATCAGCCACATTCTAGGTAGGGGCCCACTTCACCGTACTAACCAGGGAAG CTGTCCCTCACTG

TTGAATTTTCTCTAACTTCAAGGCCCATATCTGTGAAATGCTGGCATTTGCACCTAC CTCACAGAGTGCA

TTGTGAGGGTTAATGAAATAATGTACATCTGGCCTTGAAACCACCTTTTATTACATG GGGTCTAGAACTT

GACCCCCTTGAGGGTGCTTGTTCCCTCTCCCTGTTGGTCGGTGGGTTGGTAGTTTCT ACAGTTGGGCAGC

TGGTTAGGTAGAGGGAGTTGTCAAGTCTCTGCTGGCCCAGCCAAACCCTGTCTGACA ACCTCTTGGTGAA

CCTTAGTACCTAAAAGGAAATCTCACCCCATCCCACACCCTGGAGGATTTCATCTCT TGTATATGATGAT

CTGGATCCACCAAGACTTGTTTTATGCTCAGGGTCAATTTCTTTTTTCTTTTTTTTT TTTTTTTTTCTTT

TTCTTTGAGACTGGGTCTCGCTTTGTTGCCCAGGCTGGAGTGGAGTGGCGTGATCTT GGCTTACTGCAGC

CTTTGCCTCCCCGGCTCGAGCAGTCCTGCCTCAGCCTCCGGAGTAGCTGGGACCACA GGTTCATGCCACC

ATGGCCAGCCAACTTTTGCATGTTTTGTAGAGATGGGGTCTCACAGTGTTGCCCAGG CTGGTCTCAAACT

CCTGGGCTCAGGCGATCCACCTGTCTCAGCCTCCCAGAGTGCTGGGATTACAATTGT GAGCCACCACGTC

CAGCTGGAAGGGTCAACATCTTTTACATTCTGCAAGCACATCTGCATTTTCACCCCA CCCTTCCCCTCCT

[0150] NM_002529.4 Homo sapiens neurotrophic receptor tyrosine kinase 1 (NTRK1), transcript variant 2, mRNA (SEQ ID NO: 19)

GGAGGCCTGGCAGCTGCAGCTGGGAGCGCACAGACGGCTGCCCCGCCTGAGCGAGGC GGGCGCCGCCGCG ATGCTGCGAGGCGGACGGCGCGGGCAGCTTGGCTGGCACAGCTGGGCTGCGGGGCCGGGC AGCCTGCTGG

CTTGGCTGATACTGGCATCTGCGGGCGCCGCACCCTGCCCCGATGCCTGCTGCCCCC ACGGCTCCTCGGG ACTGCGATGCACCCGGGATGGGGCCCTGGATAGCCTCCACCACCTGCCCGGCGCAGAGAA CCTGACTGAG

CTCTACATCGAGAACCAGCAGCATCTGCAGCATCTGGAGCTCCGTGATCTGAGGGGC CTGGGGGAGCTGA GAAACCTCACCATCGTGAAGAGTGGTCTCCGTTTCGTGGCGCCAGATGCCTTCCATTTCA CTCCTCGGCT

CAGTCGCCTGAATCTCTCCTTCAACGCTCTGGAGTCTCTCTCCTGGAAAACTGTGCA GGGCCTCTCCTTA CAGGAACTGGTCCTGTCGGGGAACCCTCTGCACTGTTCTTGTGCCCTGCGCTGGCTACAG CGCTGGGAGG

AGGAGGGACTGGGCGGAGTGCCTGAACAGAAGCTGCAGTGTCATGGGCAAGGGCCCC TGGCCCACATGCC CAATGCCAGCTGTGGTGTGCCCACGCTGAAGGTCCAGGTGCCCAATGCCTCGGTGGATGT GGGGGACGAC GTGCTGCTGCGGTGCCAGGTGGAGGGGCGGGGCCTGGAGCAGGCCGGCTGGATCCTCACA GAGCTGGAGC

AGTCAGCCACGGTGATGAAATCTGGGGGTCTGCCATCCCTGGGGCTGACCCTGGCCA ATGTCACCAGTGA CCTCAACAGGAAGAACGTGACGTGCTGGGCAGAGAACGATGTGGGCCGGGCAGAGGTCTC TGTTCAGGTC

AACGTCTCCTTCCCGGCCAGTGTGCAGCTGCACACGGCGGTGGAGATGCACCACTGG TGCATCCCCTTCT CTGTGGATGGGCAGCCGGCACCGTCTCTGCGCTGGCTCTTCAATGGCTCCGTGCTCAATG AGACCAGCTT CATCTTCACTGAGTTCCTGGAGCCGGCAGCCAATGAGACCGTGCGGCACGGGTGTCTGCG CCTCAACCAG CCCACCCACGTCAACAACGGCAACTACACGCTGCTGGCTGCCAACCCCTTCGGCCAGGCC TCCGCCTCCA TCATGGCTGCCTTCATGGACAACCCTTTCGAGTTCAACCCCGAGGACCCCATCCCTGTCT CCTTCTCGCC GGTGGACACTAACAGCACATCTGGAGACCCGGTGGAGAAGAAGGACGAAACACCTTTTGG GGTCTCGGTG GCTGTGGGCCTGGCCGTCTTTGCCTGCCTCTTCCTTTCTACGCTGCTCCTTGTGCTCAAC AAATGTGGAC GGAGAAACAAGTTTGGGATCAACCGCCCGGCTGTGCTGGCTCCAGAGGATGGGCTGGCCA TGTCCCTGCA TTTCATGACATTGGGTGGCAGCTCCCTGTCCCCCACCGAGGGCAAAGGCTCTGGGCTCCA AGGCCACATC ATCGAGAACCCACAATACTTCAGTGATGCCTGTGTTCACCACATCAAGCGCCGGGACATC GTGCTCAAGT GGGAGCTGGGGGAGGGCGCCTTTGGGAAGGTCTTCCTTGCTGAGTGCCACAACCTCCTGC CTGAGCAGGA CAAGATGCTGGTGGCTGTCAAGGCACTGAAGGAGGCGTCCGAGAGTGCTCGGCAGGACTT CCAGCGTGAG GCTGAGCTGCTCACCATGCTGCAGCACCAGCACATCGTGCGCTTCTTCGGCGTCTGCACC GAGGGCCGCC CCCTGCTCATGGTCTTTGAGTATATGCGGCACGGGGACCTCAACCGCTTCCTCCGATCCC ATGGACCTGA TGCCAAGCTGCTGGCTGGTGGGGAGGATGTGGCTCCAGGCCCCCTGGGTCTGGGGCAGCT GCTGGCCGTG GCTAGCCAGGTCGCTGCGGGGATGGTGTACCTGGCGGGTCTGCATTTTGTGCACCGGGAC CTGGCCACAC GCAACTGTCTAGTGGGCCAGGGACTGGTGGTCAAGATTGGTGATTTTGGCATGAGCAGGG ATATCTACAG CACCGACTATTACCGTGTGGGAGGCCGCACCATGCTGCCCATTCGCTGGATGCCGCCCGA GAGCATCCTG TACCGTAAGTTCACCACCGAGAGCGACGTGTGGAGCTTCGGCGTGGTGCTCTGGGAGATC TTCACCTACG GCAAGCAGCCCTGGTACCAGCTCTCCAACACGGAGGCAATCGACTGCATCACGCAGGGAC GTGAGTTGGA GCGGCCACGTGCCTGCCCACCAGAGGTCTACGCCATCATGCGGGGCTGCTGGCAGCGGGA GCCCCAGCAA CGCCACAGCATCAAGGATGTGCACGCCCGGCTGCAAGCCCTGGCCCAGGCACCTCCTGTC TACCTGGATG TCCTGGGCTAGGGGGCCGGCCCAGGGGCTGGGAGTGGTTAGCCGGAATACTGGGGCCTGC CCTCAGCATC CCCCATAGCTCCCAGCAGCCCCAGGGTGATCTCAAAGTATCTAATTCACCCTCAGCATGT GGGAAGGGAC AGGTGGGGGCTGGGAGTAGAGGATGTTCCTGCTTCTCTAGGCAAGGTCCCGTCATAGCAA TTATATTTAT TATCCCTTG

[0151] NM 023110.3 Homo sapiens fibroblast growth factor receptor 1 (FGFR1), transcript variant 1, mRNA (SEQ ID NO: 20)

GCATAGCGCTCGGAGCGCTCTTGCGGCCACAGGCGCGGCGTCCTCGGCGGCGGGCGG CAGCTAGCGGGAG CCGGGACGCCGGTGCAGCCGCAGCGCGCGGAGGAACCCGGGTGTGCCGGGAGCTGGGCGG CCACGTCCGG ACGGGACCGAGACCCCTCGTAGCGCATTGCGGCGACCTCGCCTTCCCCGGCCGCGAGCGC GCCGCTGCTT GAAAAGCCGCGGAACCCAAGGACTTTTCTCCGGTCCGAGCTCGGGGCGCCCCGCAGGGCG CACGGTACCC GTGCTGCAGTCGGGCACGCCGCGGCGCCGGGGCCTCCGCAGGGCGATGGAGCCCGGTCTG CAAGGAAAGT GAGGCGCCGCCGCTGCGTTCTGGAGGAGGGGGGCACAAGGTCTGGAGACCCCGGGTGGCG GACGGGAGCC CTCCCCCCGCCCCGCCTCCGGGGCACCAGCTCCGGCTCCATTGTTCCCGCCCGGGCTGGA GGCGCCGAGC ACCGAGCGCCGCCGGGAGTCGAGCGCCGGCCGCGGAGCTCTTGCGACCCCGCCAGGACCC GAACAGAGCC CGGGGGCGGCGGGCCGGAGCCGGGGACGCGGGCACACGCCCGCTCGCACAAGCCACGGCG GACTCTCCCG AGGCGGAACCTCCACGCCGAGCGAGGGTCAGTTTGAAAAGGAGGATCGAGCTCACTGTGG AGTATCCATG GAGATGTGGAGCCTTGTCACCAACCTCTAACTGCAGAACTGGGATGTGGAGCTGGAAGTG CCTCCTCTTC TGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAA CAAGCCCAGC CCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGC TTCGCTGTCG GCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAG CAACCGCACC CGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTAT GCTTGCGTAA CCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCC CCTCCTCGGA GGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACC AAACCGTATG CCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCG GCTGCCAAGA CAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAA ATGGCAAAGA ATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCAT AATGGACTCT GTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATC AACCACACAT ACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCG CCAACAAAAC AGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCA CATCCAGTGG CTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAG ATCTTGAAGA CTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCT TTGAGGACGC AGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTT GACCGTTCTG GAAGCCCTGGAAGAGAGGCCGGCAGTGATGACCTCGCCCCTGTACCTGGAGATCATCATC TATTGCACAG GGGCCTTCCTCATCTCCTGCATGGTGGGGTCGGTCATCGTCTACAAGATGAAGAGTGGTA CCAAGAAGAG TGACTTCCACAGCCAGATGGCTGTGCACAAGCTGGCCAAGAGCATCCCTCTGCGCAGACA GGTAACAGTG TCTGCTGACTCCAGTGCATCCATGAACTCTGGGGTTCTTCTGGTTCGGCCATCACGGCTC TCCTCCAGTG GGACTCCCATGCTAGCAGGGGTCTCTGAGTATGAGCTTCCCGAAGACCCTCGCTGGGAGC TGCCTCGGGA CAGACTGGTCTTAGGCAAACCCCTGGGAGAGGGCTGCTTTGGGCAGGTGGTGTTGGCAGA GGCTATCGGG CTGGACAAGGACAAACCCAACCGTGTGACCAAAGTGGCTGTGAAGATGTTGAAGTCGGAC GCAACAGAGA AAGACTT GT CAGACCT GAT CT CAGAAAT GGAGAT GAT GAAGAT GAT CGGGAAGCATAAGAATAT CAT CAA CCTGCTGGGGGCCTGCACGCAGGATGGTCCCTTGTATGTCATCGTGGAGTATGCCTCCAA GGGCAACCTG CGGGAGTACCTGCAGGCCCGGAGGCCCCCAGGGCTGGAATACTGCTACAACCCCAGCCAC AACCCAGAGG AGCAGCTCTCCTCCAAGGACCTGGTGTCCTGCGCCTACCAGGTGGCCCGAGGCATGGAGT ATCTGGCCTC CAAGAAGTGCATACACCGAGACCTGGCAGCCAGGAATGTCCTGGTGACAGAGGACAATGT GATGAAGATA GCAGACTTTGGCCTCGCACGGGACATTCACCACATCGACTACTATAAAAAGACAACCAAC GGCCGACTGC CTGTGAAGTGGATGGCACCCGAGGCATTATTTGACCGGATCTACACCCACCAGAGTGATG TGTGGTCTTT CGGGGTGCTCCTGTGGGAGATCTTCACTCTGGGCGGCTCCCCATACCCCGGTGTGCCTGT GGAGGAACTT TTCAAGCTGCTGAAGGAGGGTCACCGCATGGACAAGCCCAGTAACTGCACCAACGAGCTG TACATGATGA TGCGGGACTGCTGGCATGCAGTGCCCTCACAGAGACCCACCTTCAAGCAGCTGGTGGAAG ACCTGGACCG CATCGTGGCCTTGACCTCCAACCAGGAGTACCTGGACCTGTCCATGCCCCTGGACCAGTA CTCCCCCAGC TTTCCCGACACCCGGAGCTCTACGTGCTCCTCAGGGGAGGATTCCGTCTTCTCTCATGAG CCGCTGCCCG AGGAGCCCTGCCTGCCCCGACACCCAGCCCAGCTTGCCAATGGCGGACTCAAACGCCGCT GACTGCCACC CACACGCCCTCCCCAGACTCCACCGTCAGCTGTAACCCTCACCCACAGCCCCTGCTGGGC CCACCACCTG TCCGTCCCTGTCCCCTTTCCTGCTGGCAGGAGCCGGCTGCCTACCAGGGGCCTTCCTGTG TGGCCTGCCT TCACCCCACTCAGCTCACCTCTCCCTCCACCTCCTCTCCACCTGCTGGTGAGAGGTGCAA AGAGGCAGAT CTTTGCTGCCAGCCACTTCATCCCCTCCCAGATGTTGGACCAACACCCCTCCCTGCCACC AGGCACTGCC TGGAGGGCAGGGAGTGGGAGCCAATGAACAGGCATGCAAGTGAGAGCTTCCTGAGCTTTC TCCTGTCGGT TTGGTCTGTTTTGCCTTCACCCATAAGCCCCTCGCACTCTGGTGGCAGGTGCCTTGTCCT CAGGGCTACA GCAGTAGGGAGGTCAGTGCTTCGTGCCTCGATTGAAGGTGACCTCTGCCCCAGATAGGTG GTGCCAGTGG CTTATTAATTCCGATACTAGTTTGCTTTGCTGACCAAATGCCTGGTACCAGAGGATGGTG AGGCGAAGGC CAGGTTGGGGGCAGTGTTGTGGCCCTGGGGCCCAGCCCCAAACTGGGGGCTCTGTATATA GCTATGAAGA AAACACAAAGT GT AT AAAT CT GAGT AT AT AT T T ACAT GT CT T T T T AAAAGGGT C GT TAG CAGAGAT T TAG CCATCGGGTAAGATGCTCCTGGTGGCTGGGAGGCATCAGTTGCTATATATTAAAAACAAA AAAGAAAAAA AAGGAAAATGTTTTTAAAAAGGTCATATATTTTTTGCTACTTTTGCTGTTTTATTTTTTT AAATTATGTT CTAAACCTATTTTCAGTTTAGGTCCCTCAATAAAAATTGCTGCTGCTTCATTTATCTATG GGCTGTATGA AAAGGGTGGGAATGTCCACTGGAAAGAAGGGACACCCACGGGCCCTGGGGCTAGGTCTGT CCCGAGGGCA CCGCATGCTCCCGGCGCAGGTTCCTTGTAACCTCTTCTTCCTAGGTCCTGCACCCAGACC TCACGACGCA CCTCCTGCCTCTCCGCTGCTTTTGGAAAGTCAGAAAAAGAAGATGTCTGCTTCGAGGGCA GGAACCCCAT CCATGCAGTAGAGGCGCTGGGCAGAGAGTCAAGGCCCAGCAGCCATCGACCATGGATGGT TTCCTCCAAG GAAACCGGTGGGGTTGGGCTGGGGAGGGGGCACCTACCTAGGAATAGCCACGGGGTAGAG CTACAGTGAT TAAGAGGAAAGCAAGGGCGCGGTTGCTCACGCCTGTAATCCCAGCACTTTGGGACACCGA GGTGGGCAGA TCACTTCAGGTCAGGAGTTTGAGACCAGCCTGGCCAACTTAGTGAAACCCCATCTCTACT AAAAATGCAA AAATTATCCAGGCATGGTGGCACACGCCTGTAATCCCAGCTCCACAGGAGGCTGAGGCAG AATCCCTTGA AGCTGGGAGGCGGAGGTTGCAGTGAGCCGAGATTGCGCCATTGCACTCCAGCCTGGGCAA CAGAGAAAAC AAAAAGGAAAACAAATGATGAAGGTCTGCAGAAACTGAAACCCAGACATGTGTCTGCCCC CTCTATGTGG GCATGGTTTTGCCAGTGCTTCTAAGTGCAGGAGAACATGTCACCTGAGGCTAGTTTTGCA TTCAGGTCCC TGGCTTCGTTTCTTGTTGGTATGCCTCCCCAGATCGTCCTTCCTGTATCCATGTGACCAG ACTGTATTTG TTGGGACTGTCGCAGATCTTGGCTTCTTACAGTTCTTCCTGTCCAAACTCCATCCTGTCC CTCAGGAACG GGGGGAAAATTCTCCGAATGTTTTTGGTTTTTTGGCTGCTTGGAATTTACTTCTGCCACC TGCTGGTCAT CACTGTCCTCACTAAGTGGATTCTGGCTCCCCCGTACCTCATGGCTCAAACTACCACTCC TCAGTCGCTA TATTAAAGCTTATATTTTGCTGGATTACTGCTAAATACAAAAGAAAGTTCAATATGTTTT CATTTCTGTA GGGAAAATGGGATTGCTGCTTTAAATTTCTGAGCTAGGGATTTTTTGGCAGCTGCAGTGT TGGCGACTAT TGTAAAATTCTCTTTGTTTCTCTCTGTAAATAGCACCTGCTAACATTACAATTTGTATTT ATGTTTAAAG AAGGCATCATTTGGTGAACAGAACTAGGAAATGAATTTTTAGCTCTTAAAAGCATTTGCT TTGAGACCGC ACAGGAGTGTCTTTCCTTGTAAAACAGTGATGATAATTTCTGCCTTGGCCCTACCTTGAA GCAATGTTGT GT GAAGGGAT GAAGAAT CTAAAAGT CTT CATAAGT CCTT GGGAGAGGT GCTAGAAAAATATAAGGCACTA TCATAATTACAGTGATGTCCTTGCTGTTACTACTCAAATCACCCACAAATTTCCCCAAAG ACTGCGCTAG CT GT CAAAT AAAAGACAGT GAAAT T GA

[0152] NM 001354870.1 Homo sapiens MYC proto-oncogene, bHLH transcription factor (MYC), transcript variant 2, mRNA (SEQ ID NO: 21)

GGAGTTTATTCATAACGCGCTCTCCAAGTATACGTGGCAATGCGTTGCTGGGTTATT TTAATCATTCTAG GCATCGTTTTCCTCCTTATGCCTCTATCATTCCTCCCTATCTACACTAACATCCCACGCT CTGAACGCGC GCCCATTAATACCCTTCTTTCCTCCACTCTCCCTGGGACTCTTGATCAAAGCGCGGCCCT TTCCCCAGCC TTAGCGAGGCGCCCTGCAGCCTGGTACGCGCGTGGCGTGGCGGTGGGCGCGCAGTGCGTT CTCGGTGTGG AGGGCAGCTGTTCCGCCTGCGATGATTTATACTCACAGGACAAGGATGCGGTTTGTCAAA CAGTACTGCT ACGGAGGAGCAGCAGAGAAAGGGAGAGGGTTTGAGAGGGAGCAAAAGAAAATGGTAGGCG CGCGTAGTTA ATTCATGCGGCTCTCTTACTCTGTTTACATCCTAGAGCTAGAGTGCTCGGCTGCCCGGCT GAGTCTCCTC CCCACCTTCCCCACCCTCCCCACCCTCCCCATAAGCGCCCCTCCCGGGTTCCCAAAGCAG AGGGCGTGGG GGAAAAGAAAAAAGATCCTCTCTCGCTAATCTCCGCCCACCGGCCCTTTATAATGCGAGG GTCTGGACGG CTGAGGACCCCCGAGCTGTGCTGCTCGCGGCCGCCACCGCCGGGCCCCGGCCGTCCCTGG CTCCCCTCCT GCCTCGAGAAGGGCAGGGCTTCTCAGAGGCTTGGCGGGAAAAAGAACGGAGGGAGGGATC GCGCTGAGTA TAAAAGCCGGTTTTCGGGGCTTTATCTAACTCGCTGTAGTAATTCCAGCGAGAGGCAGAG GGAGCGAGCG GGCGGCCGGCTAGGGTGGAAGAGCCGGGCGAGCAGAGCTGCGCTGCGGGCGTCCTGGGAA GGGAGATCCG GAGCGAATAGGGGGCTTCGCCTCTGGCCCAGCCCTCCCGCTGATCCCCCAGCCAGCGGTC CGCAACCCTT GCCGCATCCACGAAACTTTGCCCATAGCAGCGGGCGGGCACTTTGCACTGGAACTTACAA CACCCGAGCA AGGACGCGACTCTCCCGACGCGGGGAGGCTATTCTGCCCATTTGGGGACACTTCCCCGCC GCTGCCAGGA CCCGCTTCTCTGAAAGGCTCTCCTTGCAGCTGCTTAGACGCTGGATTTTTTTCGGGTAGT GGAAAACCAG CCTCCCGCGACGATGCCCCTCAACGTTAGCTTCACCAACAGGAACTATGACCTCGACTAC GACTCGGTGC AGCCGTATTTCTACTGCGACGAGGAGGAGAACTTCTACCAGCAGCAGCAGCAGAGCGAGC TGCAGCCCCC GGCGCCCAGCGAGGATATCTGGAAGAAATTCGAGCTGCTGCCCACCCCGCCCCTGTCCCC TAGCCGCCGC TCCGGGCTCTGCTCGCCCTCCTACGTTGCGGTCACACCCTTCTCCCTTCGGGGAGACAAC GACGGCGGTG GCGGGAGCTTCTCCACGGCCGACCAGCTGGAGATGGTGACCGAGCTGCTGGGAGGAGACA TGGTGAACCA GAGTTTCATCTGCGACCCGGACGACGAGACCTTCATCAAAAACATCATCATCCAGGACTG TATGTGGAGC GGCTTCTCGGCCGCCGCCAAGCTCGTCTCAGAGAAGCTGGCCTCCTACCAGGCTGCGCGC AAAGACAGCG GCAGCCCGAACCCCGCCCGCGGCCACAGCGTCTGCTCCACCTCCAGCTTGTACCTGCAGG ATCTGAGCGC CGCCGCCTCAGAGTGCATCGACCCCTCGGTGGTCTTCCCCTACCCTCTCAACGACAGCAG CTCGCCCAAG TCCTGCGCCTCGCAAGACTCCAGCGCCTTCTCTCCGTCCTCGGATTCTCTGCTCTCCTCG ACGGAGTCCT CCCCGCAGGGCAGCCCCGAGCCCCTGGTGCTCCATGAGGAGACACCGCCCACCACCAGCA GCGACTCTGA GGAGGAACAAGAAGATGAGGAAGAAATCGATGTTGTTTCTGTGGAAAAGAGGCAGGCTCC TGGCAAAAGG TCAGAGTCTGGATCACCTTCTGCTGGAGGCCACAGCAAACCTCCTCACAGCCCACTGGTC CTCAAGAGGT GCCACGTCTCCACACATCAGCACAACTACGCAGCGCCTCCCTCCACTCGGAAGGACTATC CTGCTGCCAA GAGGGTCAAGTTGGACAGTGTCAGAGTCCTGAGACAGATCAGCAACAACCGAAAATGCAC CAGCCCCAGG TCCTCGGACACCGAGGAGAATGTCAAGAGGCGAACACACAACGTCTTGGAGCGCCAGAGG AGGAACGAGC TAAAACGGAGCTTTTTTGCCCTGCGTGACCAGATCCCGGAGTTGGAAAACAATGAAAAGG CCCCCAAGGT AGTTATCCTTAAAAAAGCCACAGCATACATCCTGTCCGTCCAAGCAGAGGAGCAAAAGCT CATTTCTGAA GAGGACTTGTTGCGGAAACGACGAGAACAGTTGAAACACAAACTTGAACAGCTACGGAAC TCTTGTGCGT AAGGAAAAGTAAGGAAAACGATTCCTTCTAACAGAAATGTCCTGAGCAATCACCTATGAA CTTGTTTCAA ATGCATGATCAAATGCAACCTCACAACCTTGGCTGAGTCTTGAGACTGAAAGATTTAGCC ATAATGTAAA CTGCCTCAAATTGGACTTTGGGCATAAAAGAACTTTTTTATGCTTACCATCTTTTTTTTT TCTTTAACAG AT T T GT AT T T AAGAAT T GT T T T T AAAAAAT T T T AAGAT T T ACACAAT GT T T CT CT GT AAAT AT T GC CAT T AAATGTAAATAACTTTAATAAAACGTTTATAGCAGTTACACAGAATTTCAATCCTAGTAT ATAGTACCTA GTATTATAGGTACTATAAACCCTAATTTTTTTTATTTAAGTACATTTTGCTTTTTAAAGT TGATTTTTTT CTATTGTTTTTAGAAAAAATAAAATAACTGGCAAATATATCATTGAGCCAAATCTTAAGT TGTGAATGTT TTGTTTCGTTTCTTCCCCCTCCCAACCACCACCATCCCTGTTTGTTTTCATCAATTGCCC CTTCAGAGGG TGGTCTTAAGAAAGGCAAGAGTTTTCCTCTGTTGAAATGGGTCTGGGGGCCTTAAGGTCT TTAAGTTCTT GGAGGTTCTAAGATGCTTCCTGGAGACTATGATAACAGCCAGAGTTGACAGTTAGAAGGA ATGGCAGAAG GCAGGTGAGAAGGTGAGAGGTAGGCAAAGGAGATACAAGAGGTCAAAGGTAGCAGTTAAG TACACAAAGA GGCATAAGGACTGGGGAGTTGGGAGGAAGGTGAGGAAGAAACTCCTGTTACTTTAGTTAA CCAGTGCCAG TCCCCTGCTCACTCCAAACCCAGGAATTCTGCCCAGTTGATGGGGACACGGTGGGAACCA GCTTCTGCTG CCTTCACAACCAGGCGCCAGTCCTGTCCATGGGTTATCTCGCAAACCCCAGAGGATCTCT GGGAGGAATG CTACTATTAACCCTATTTCACAAACAAGGAAATAGAAGAGCTCAAAGAGGTTATGTAACT TATCTGTAGC CACGCAGATAATACAAAGCAGCAATCTGGACCCATTCTGTTCAAAACACTTAACCCTTCG CTATCATGCC TTGGTTCATCTGGGTCTAATGTGCTGAGATCAAGAAGGTTTAGGACCTAATGGACAGACT CAAGTCATAA CAATGCTAAGCTCTATTTGTGTCCCAAGCACTCCTAAGCATTTTATCCCTAACTCTACAT CAACCCCATG AAGGAGATACTGTTGATTTCCCCATATTAGAAGTAGAGAGGGAAGCTGAGGCACACAAAG ACTCATCCAC ATGCCCAAGATTCACTGATAGGGAAAAGTGGAAGCGAGATTTGAACCCAGGCTGTTTACT CCTAACCTGT CCAAGCCACCTCTCAGACGACGGTAGGAATCAGCTGGCTGCTTGTGAGTACAGGAGTTAC AGTCCAGTGG GTTATGTTTTTTAAGTCTCAACATCTAAGCCTGGTCAGGCATCAGTTCCCCTTTTTTTGT GATTTATTTT GTTTTTATTTTGTTGTTCATTGTTTAATTTTTCCTTTTACAATGAGAAGGTCACCATCTT GACTCCTACC TTAGCCATTTGTTGAATCAGACTCATGACGGCTCCTGGGAAGAAGCCAGTTCAGATCATA AAATAAAACA TATTTATTCTTTGTCATGGGAGTCATTATTTTAGAAACTACAAACTCTCCTTGCTTCCAT CCTTTTTTAC ATACTCATGACACATGCTCATCCTGAGTCCTTGAAAAGGTATTTTTGAACATGTGTATTA ATTATAAGCC TCTGAAAACCTATGGCCCAAACCAGAAATGATGTTGATTATATAGGTAAATGAAGGATGC TATTGCTGTT CTAATTACCTCATTGTCTCAGTCTCAAAGTAGGTCTTCAGCTCCCTGTACTTTGGGATTT TAATCTACCA C C AC C CAT AAAT C AAT AAAT AAT TACTTTCTTTGA

[0153] NM 000314.8 Homo sapiens phosphatase and tensin homolog (PTEN), transcript variant 1, mRNA (SEQ ID NO: 22)

GTTCTCTCCTCTCGGAAGCTGCAGCCATGATGGAAGTTTGAGAGTTGAGCCGCTGTG AGGCGAGGCCGGG CTCAGGCGAGGGAGATGAGAGACGGCGGCGGCCGCGGCCCGGAGCCCCTCTCAGCGCCTG TGAGCAGCCG CGGGGGCAGCGCCCTCGGGGAGCCGGCCGGCCTGCGGCGGCGGCAGCGGCGGCGTTTCTC GCCTCCTCTT CGTCTTTTCTAACCGTGCAGCCTCTTCCTCGGCTTCTCCTGAAAGGGAAGGTGGAAGCCG TGGGCTCGGG CGGGAGCCGGCTGAGGCGCGGCGGCGGCGGCGGCACCTCCCGCTCCTGGAGCGGGGGGGA GAAGCGGCGG CGGCGGCGGCCGCGGCGGCTGCAGCTCCAGGGAGGGGGTCTGAGTCGCCTGTCACCATTT CCAGGGCTGG GAACGCCGGAGAGTTGGTCTCTCCCCTTCTACTGCCTCCAACACGGCGGCGGCGGCGGCT GGCACATCCA GGGACCCGGGCCGGTTTTAAACCTCCCGTGCGCCGCCGCCGCACCCCCCGTGGCCCGGGC TCCGGAGGCC GCCGGCGGAGGCAGCCGTTCGGAGGATTATTCGTCTTCTCCCCATTCCGCTGCCGCCGCT GCCAGGCCTC TGGCTGCTGAGGAGAAGCAGGCCCAGTCGCTGCAACCATCCAGCAGCCGCCGCAGCAGCC ATTACCCGGC TGCGGTCCAGAGCCAAGCGGCGGCAGAGCGAGGGGCATCAGCTACCGCCAAGTCCAGAGC CATTTCCATC CTGCAGAAGAAGCCCCGCCACCAGCAGCTTCTGCCATCTCTCTCCTCCTTTTTCTTCAGC CACAGGCTCC CAGACATGACAGCCATCATCAAAGAGATCGTTAGCAGAAACAAAAGGAGATATCAAGAGG ATGGATTCGA CTTAGACTTGACCTATATTTATCCAAACATTATTGCTATGGGATTTCCTGCAGAAAGACT TGAAGGCGTA TAG AG GAAC AAT AT T GAT GAT GT AGT AAG GT T T T T G GAT T C AAAG C AT AAAAAC CAT T AC AAGAT AT AC A ATCTTTGTGCTGAAAGACATTATGACACCGCCAAATTTAATTGCAGAGTTGCACAATATC CTTTTGAAGA CCATAACCCACCACAGCTAGAACTTATCAAACCCTTTTGTGAAGATCTTGACCAATGGCT AAGTGAAGAT GACAAT CAT GTT GCAGCAATT CACT GTAAAGCT GGAAAGGGACGAACT GGT GTAAT GATAT GT GCATATT TATTACATCGGGGCAAATTTTTAAAGGCACAAGAGGCCCTAGATTTCTATGGGGAAGTAA GGACCAGAGA CAAAAAGGGAGTAACTATTCCCAGTCAGAGGCGCTATGTGTATTATTATAGCTACCTGTT AAAGAATCAT CTGGATTATAGACCAGTGGCACTGTTGTTTCACAAGATGATGTTTGAAACTATTCCAATG TTCAGTGGCG GAACTTGCAATCCTCAGTTTGTGGTCTGCCAGCTAAAGGTGAAGATATATTCCTCCAATT CAGGACCCAC ACGACGGGAAGACAAGTTCATGTACTTTGAGTTCCCTCAGCCGTTACCTGTGTGTGGTGA TATCAAAGTA GAGTTCTTCCACAAACAGAACAAGATGCTAAAAAAGGACAAAATGTTTCACTTTTGGGTA AATACATTCT T CATACCAGGACCAGAGGAAACCT CAGAAAAAGTAGAAAAT GGAAGT CTAT GT GAT CAAGAAAT CGATAG CATTTGCAGTATAGAGCGTGCAGATAATGACAAGGAATATCTAGTACTTACTTTAACAAA AAATGATCTT GACAAAGCAAATAAAGACAAAGCCAACCGATACTTTTCTCCAAATTTTAAGGTGAAGCTG TACTTCACAA AAACAGTAGAGGAGCCGTCAAATCCAGAGGCTAGCAGTTCAACTTCTGTAACACCAGATG TTAGTGACAA TGAACCTGATCATTATAGATATTCTGACACCACTGACTCTGATCCAGAGAATGAACCTTT TGATGAAGAT CAGCATACACAAATTACAAAAGTCTGAATTTTTTTTTATCAAGAGGGATAAAACACCATG AAAATAAACT TGAATAAACTGAAAATGGACCTTTTTTTTTTTAATGGCAATAGGACATTGTGTCAGATTA CCAGTTATAG GAACAATTCTCTTTTCCTGACCAATCTTGTTTTACCCTATACATCCACAGGGTTTTGACA CTTGTTGTCC AGTTGAAAAAAGGTTGTGTAGCTGTGTCATGTATATACCTTTTTGTGTCAAAAGGACATT TAAAATTCAA TTAGGATTAATAAAGATGGCACTTTCCCGTTTTATTCCAGTTTTATAAAAAGTGGAGACA GACTGATGTG TATACGTAGGAATTTTTTCCTTTTGTGTTCTGTCACCAACTGAAGTGGCTAAAGAGCTTT GTGATATACT GGTTCACATCCTACCCCTTTGCACTTGTGGCAACAGATAAGTTTGCAGTTGGCTAAGAGA GGTTTCCGAA GGGTTTTGCTACATTCTAATGCATGTATTCGGGTTAGGGGAATGGAGGGAATGCTCAGAA AGGAAATAAT TTTATGCTGGACTCTGGACCATATACCATCTCCAGCTATTTACACACACCTTTCTTTAGC ATGCTACAGT TATTAATCTGGACATTCGAGGAATTGGCCGCTGTCACTGCTTGTTGTTTGCGCATTTTTT TTTAAAGCAT ATT GGT GCTAGAAAAGGCAGCTAAAGGAAGT GAAT CT GTATT GGGGTACAGGAAT GAACCTT CT GCAACA T CTTAAGAT CCACAAAT GAAGGGATATAAAAATAAT GT CATAGGTAAGAAACACAGCAACAAT GACTTAA CCATATAAATGTGGAGGCTATCAACAAAGAATGGGCTTGAAACATTATAAAAATTGACAA TGATTTATTA AATATGTTTTCTCAATTGTAACGACTTCTCCATCTCCTGTGTAATCAAGGCCAGTGCTAA AATTCAGATG CTGTTAGTACCTACATCAGTCAACAACTTACACTTATTTTACTAGTTTTCAATCATAATA CCTGCTGTGG ATGCTTCATGTGCTGCCTGCAAGCTTCTTTTTTCTCATTAAATATAAAATATTTTGTAAT GCTGCACAGA AATTTTCAATTTGAGATTCTACAGTAAGCGTTTTTTTTCTTTGAAGATTTATGATGCACT TATTCAATAG CTGTCAGCCGTTCCACCCTTTTGACCTTACACATTCTATTACAATGAATTTTGCAGTTTT GCACATTTTT TAAATGTCATTAACTGTTAGGGAATTTTACTTGAATACTGAATACATATAATGTTTATAT TAAAAAGGAC ATTTGTGTTAAAAAGGAAATTAGAGTTGCAGTAAACTTTCAATGCTGCACACAAAAAAAA GACATTTGAT TTTTCAGTAGAAATTGTCCTACATGTGCTTTATTGATTTGCTATTGAAAGAATAGGGTTT TTTTTTTTTT _{TTTTTTTTTTTTTTTT7V} ^ _{T GT GCAGT GTT G} ^ _{T CATTT CTT CATAGT GCT CCCCCGAGTT GGGACTAGG} GCTTCAATTTCACTTCTTAAAAAAAATCATCATATATTTGATATGCCCAGACTGCATACG ATTTTAAGCG GAGTACAACTACTATTGTAAAGCTAATGTGAAGATATTATTAAAAAGGTTTTTTTTTCCA GAAATTTGGT GTCTTCAAATTATACCTTCACCTTGACATTTGAATATCCAGCCATTTTGTTTCTTAATGG TATAAAATTC CATTTTCAATAACTTATTGGTGCTGAAATTGTTCACTAGCTGTGGTCTGACCTAGTTAAT TTACAAATAC AGATTGAATAGGACCTACTAGAGCAGCATTTATAGAGTTTGATGGCAAATAGATTAGGCA GAACTTCATC T AAAAT AT T CT T AGT AAAT AAT GTT GACAC GT T T T C CAT AC CT T GT CAGT T T CAT T CAACAAT T T T T AAA TTTTTAACAAAGCTCTTAGGATTTACACATTTATATTTAAACATTGATATATAGAGTATT GATTGATTGC TCATAAGTTAAATTGGTAAAGTTAGAGACAACTATTCTAACACCTCACCATTGAAATTTA TATGCCACCT TGTCTTTCATAAAAGCTGAAAATTGTTACCTAAAATGAAAATCAACTTCATGTTTTGAAG ATAGTTATAA ATATTGTTCTTTGTTACAATTTCGGGCACCGCATATTAAAACGTAACTTTATTGTTCCAA TATGTAACAT GGAGGGCCAGGTCATAAATAATGACATTATAATGGGCTTTTGCACTGTTATTATTTTTCC TTTGGAATGT GAAGGTCTGAATGAGGGTTTTGATTTTGAATGTTTCAATGTTTTTGAGAAGCCTTGCTTA CATTTTATGG T GTAGT CATT GGAAAT GGAAAAAT GGCATTATATATATTATATATATAAATATATATTATACATACT CT C CTTACTTTATTTCAGTTACCATCCCCATAGAATTTGACAAGAATTGCTATGACTGAAAGG TTTTCGAGTC CTAATTAAAACTTTATTTATGGCAGTATTCATAATTAGCCTGAAATGCATTCTGTAGGTA ATCTCTGAGT TTCTGGAATATTTTCTTAGACTTTTTGGATGTGCAGCAGCTTACATGTCTGAAGTTACTT GAAGGCATCA CTTTTAAGAAAGCTTACAGTTGGGCCCTGTACCATCCCAAGTCCTTTGTAGCTCCTCTTG AACATGTTTG CCATACTTTTAAAAGGGTAGTTGAATAAATAGCATCACCATTCTTTGCTGTGGCACAGGT TATAAACTTA AGTGGAGTTTACCGGCAGCATCAAATGTTTCAGCTTTAAAAAATAAAAGTAGGGTACAAG TTTAATGTTT AGTTCTAGAAATTTTGTGCAATATGTTCATAACGATGGCTGTGGTTGCCACAAAGTGCCT CGTTTACCTT TAAATACTGTTAATGTGTCATGCATGCAGATGGAAGGGGTGGAACTGTGCACTAAAGTGG GGGCTTTAAC TGTAGTATTTGGCAGAGTTGCCTTCTACCTGCCAGTTCAAAAGTTCAACCTGTTTTCATA TAGAATATAT ATACTAAAAAATTTCAGTCTGTTAAACAGCCTTACTCTGATTCAGCCTCTTCAGATACTC TTGTGCTGTG CAGCAGT GGCT CT GT GT GTAAAT GCTAT GCACT GAGGATACACAAAAATACCAATAT GAT GT GTACAGGA TAATGCCTCATCCCAATCAGATGTCCATTTGTTATTGTGTTTGTTAACAACCCTTTATCT CTTAGTGTTA TAAACTCCACTTAAAACTGATTAAAGTCTCATTCTTGTCATTGTGTGGGTGTTTTATTAA ATGAGAGTTT ATAATTCAAATTGCTTAAGTCCATTGAAGTTTTAATTAATGGGCAGCCAAATGTGAATAC AAAGTTTTCA GTTTTTTTTTTTCCTGCTGTCCTTCAAAGCCTACTGTTTAAAAAAAAAAAAAAAAAAAAA CATGGCCTGA GAGTAGAGTATCTGTCTACTCATGTTTAATTAAGGAAAAACACTTATTTTTAGGGCTTTA GTCATCACTT CATAAATTGTATAAGCACATTAAATAGCGTTCTAGTCCTGAAAAAGTCCAAGATTCTTAG AAAATTGTGC AT AT T T T TAT TAT GAC AGAT GT T T GAAGAT AAT T C C C C AGAAT G GAT T T GAT AC T T T AGAT T T C AAT T T T GTGGCTTTTGTCTATTATTCTGTACTCTGCCATCAGCATATGGAAAGCTTCATTTACTCA TCATGACTTG TGCCATATAAAAATTGATATTTCGGAATAGTCTAAAGGACTTTTTGTACTTGAATTTAAT CATGTTGTTT CTAATATTCTTAAAAGCTTGAAGACTAAAGCATATCCTTTCAACAAAGCATAGTAAGGTA ATAAGAAAGT GTAGT T T GT ACAAGT GT T AAAAAAATAAAGT AGACAAT GT T ACAGT GGGACT T AT TAT T T CAAGT T TACA T T T T CT C CAT GT AAT T T T T T AAAAAGT AAAT GAAAAAAT GT GCAAT AAT GT AAAAT AT GAAGT GT AT GT G TACACACATTTTATTTTTCGGTATCTTGGGTATACGTATGGTTGAAAACTATACTGGAGT CTAAAAGTAT T CT AAT T T AT AAGAAGACAT T T T GGT GAT GT T T GAAAAAT AGAAAT GT GCT AGT TTTGTTTT TAT AT CAT GTCCTTTGTACGTTGTAATATGAGCTGGCTTGGTTCAGTAAATGCCATCACCATTTCCAT TGAGAATTTA AAACTCACCAGTGTTTAATATGCAGGCTTCCAAAGGCTTATGAAAAAAATCAAGACCCTT AAATCTAGTT AATTTGCTGCTAACATGAAACTCTTTGGTTCTTTTATTTTTGCCAGATAATTAGACACAC ATCTAAAGCT TAGTCTTAAATGGCTTAAGTGTAGCTATTGATTAGTGCTGTTGCTAGTTCAGAAAGAAAT GTTTGTGAAT GGAAACAAGAATATTCAGTCCAAACTGTTGTAAGGACAGTACCTGAAAACCAGGAAACAG GATAATGGAA AAAGTCTTTTAAAGATGAAATGTTGGAGCCAACTTTCTTATAGAATTAATTGTATGTGGC TATAGAAAGC CTAATGATTGTTGCTTATTTTTGAGAGCATATTATTCTTTTATGACCATAATCTTGCTGT TTTTCCATCT TCCAAAAGATCTTCCTTCTAATATGTATATCAGAATGTGGGTAGCCAGTCAGACAAATTC ATATTGGTTG GTAGCTTTAAAAAGTTTGTAATGTGAAGACAGGAAAGGACAAAATAGTTTGCTTTGGTGG TAGTACTCTG GTTGTTAAGCTAGGTATTTTGAGACTACTTCCCCATCACAACAACAATAAAATAATCACT CATAATCCTA TCACCTGGAGACATAGCCATCGTTAATATGTTAGTGACTATACAATCATGTTTTCTTCTG TATATCCATG TATATTCTTTAAAAATGAAATTTATACTGTACCTGATCTCAAAGCTTTTTAGCTTAGTAT ATCTGTCATG AATTTGTAGGATGTTCCATTGCATCAGAAAACGGACAGTGATTTGATTACTTTCTAATGC CACAGATGCA GATTACATGTAGTTATTGAGAATCCTTTCGAATTCAGTGGCTTAATCATGAATGTCTAAA TATTGTTGAC AT TAG GAT GAT AC AT GTAAAT T AAAGT TAG AT TTGTTTAG C AT AGAC AAG C T T AAC AT T GT AGAT GT T T C T CT T CAAAAAT CAT CT T AAACAT T T GCAT T T GGAAT T GT GT T AAAT AGAAT GT GT GAAACACT GT AT TAG TAAACTTCATCACCTTTCTACTTCCTTATAGTTTGAACTTTTCAGTTTTTGTAGTTCCCA AACAGTTGCT CAATTTAGAGCAAATTAATTTAACACCTGCCAAAAAAAGGCTGCTGTTGGCTTATCAGTT GTCTTTAAAT TCAAATGCTCATGTGACTTTTATCACATCAAAAAATATTTCATTAATGATTCACCTTTAG CTCTGAAAAT TACCGCGTTTAGTAATTATAGTGGGCTTATAAAAACATGCAACTCTTTTTGATAGTTATT TGAGAATTTT GGTGAAAAATATTTAGCTGAGGGCAGTATAGAACTTATAAACCAATATATTGATATTTTT AAAACATTTT TACATATAAGTAAACTGCCATCTTTGAGCATAACTACATTTAAAAATAAAGCTGCATATT TTTAAATCAA GT GT T T AAC AAGAAT T T AT AT T T T T T AT T T T T T AAAAT T AAAAAT AAT T T AT AT T T C C T C T GT T G C AT GA GGATTCTCATCTGTGCTTATAATGGTTAGAGATTTTATTTGTGTGGAATGAAGTGAGGCT TGTAGTCATG GTTCTAGTGTTTCAGTTTGCCAAGTCTGTTTACTGCAGTGAAATTCATCAAATGTTTCAG TGTGGTTTTC TGTAGCCTATCATTTACTGGCTATTTTTTTATGTACACCTTTAGGATTTTCTGCCTACTC TATCCAGTTG TCCAAATGATATCCTACATTTTACAAATGCCCTTTCAGTTTCTATTTTCTTTTTCCATTA AATTGCCCTC ATGTCCTAATGTGCAGTTTGTAAGTGTGTGTGTGTGTGTCTGTGTGTGTGTGAATTTGAT TTTCAAGAGT GCTAGACTTCCAATTTGAGAGATTAAATAATTTAATTCAGGCAAACATTTTTCATTGGAA TTTCACAGTT CATTGTAATGAAAATGTTAATCCTGGATGACCTTTGACATACAGTAATGAATCTTGGATA TTAATGAATT TGTTAGTAGCATCTTGATGTGTGTTTTAATGAGTTATTTTCAAAGTTGTGCATTAAACCA AAGTTGGCAT ACTGGAAGTGTTTATATCAAGTTCCATTTGGCTACTGATGGACAAAAAATAGAAATGCCT TCCTATGGAG AGTATTTTTCCTT T AAAAAAT T AAAAAG GT T AAT TATTTTGACTA [0154] NM 001285439.2 Homo sapiens RPTOR independent companion of MTOR complex 2 (RICTOR), transcript variant 2, mRNA (SEQ ID NO: 23)

GTTGTGACTGAAACCCGTCAATATGGCGGCGATCGGCCGCGGCCGCTCTCTGAAGAA CCTCCGAGTACGA GGGCGGAATGACAGCGGCGAGGAGAACGTCCCGCTGGATCTGACCCGAGAACCTTCTGAT AACTTAAGAG AGATTCTCCAAAATGTGGCCAGATTGCAGGGAGTATCAAATATGAGAAAGCTAGGCCATC TGAATAACTT TACTAAGCTTCTTTGTGATATTGGCCACAGTGAAGAAAAACTGGGCTTTCACTATGAGGA TATCATAATT TGTTTGCGGTTAGCTTTATTAAATGAAGCAAAAGAAGTGCGAGCAGCAGGGCTACGAGCG CTTCGATATC TCATCCAAGACTCCAGTATTCTCCAGAAGGTGCTAAAATTGAAAGTGGACTATTTAATAG CTAGGTGCAT TGACATACAACAGAGCAACGAGGTAGAGAGGACACAAGCACTTCGATTAGTCAGAAAGAT GATTACTGTG AATGCTTCCTTGTTTCCTAGTTCTGTGACCAACTCATTAATTGCAGTTGGAAATGATGGA CTTCAAGAAA GAGACAGAATGGTCCGAGCATGCATTGCCATTATCTGTGAACTAGCACTTCAGAATCCAG AGGTGGTGGC CCTTCGAGGTGGACTAAACACCATCTTGAAAAATGTGATCGATTGCCAATTAAGTCGAAT AAATGAGGCC CTAATTACTACAATTTTGCACCTTCTTAATCATCCAAAGACTCGACAGTATGTGCGAGCT GATGTAGAAT TAGAGAGAATTTTAGCACCCTATACTGATTTTCACTACAGACATAGTCCAGATACAGCTG AAGGACAGCT CAAAGAAGACAGAGAAGCACGATTTCTAGCCAGTAAAATGGGAATCATAGCAACATTCCG ATCATGGGCA GGTATTATTAATTTATGTAAACCTGGAAATTCTGGGATCCAGTCTCTAATAGGAGTACTT TGCATACCAA ATATGGAAATAAGGCGAGGTCTACTTGAAGTGCTTTATGATATATTTCGTCTTCCTCTAC CTGTTGTGAC TGAGGAGTTCATAGAAGCACTACTCAGTGTAGATCCAGGGAGGTTCCAAGACAGTTGGAG GCTTTCAGAT

GGCTTTGTGGCAGCTGAGGCAAAAACTATTCTTCCTCATCGTGCCAGATCCAGGCCA GACCTCATGGATA ATTATTTGGCACTGATACTCTCTGCATTTATTCGTAATGGACTTTTAGAGGGTCTAGTTG AAGTGATAAC AAACAGTGATGATCATATCTCAGTTAGAGCTACCATCCTTTTAGGAGAGCTTTTACATAT GGCAAACACA ATTCTTCCTCATTCACATAGCCATCATTTACACTGCTTGCCAACCCTAATGAATATGGCT GCATCCTTTG ATATCCCCAAGGAAAAGAGACTGCGAGCCAGTGCAGCCTTGAACTGTTTAAAACGCTTCC ATGAAATGAA GAAACGAGGACCTAAGCCTTATAGTCTTCATTTAGACCACATTATTCAGAAAGCAATTGC AACACACCAG AAACGGGATCAGTATCTCCGAGTTCAGAAAGATATATTTATCCTTAAGGATACAGAGGAA GCTCTTTTAA TTAACCTTAGAGATAGCCAAGTCCTTCAACATAAAGAGAATCTTGAATGGAATTGGAATC TTATAGGGAC CATTCTTAAGTGGCCAAATGTAAATCTAAGAAACTATAAAGATGAACAGTTACACAGGTT TGTACGAAGA CTACTTTATTTTTACAAGCCCAGCAGTAAATTATATGCCAACCTGGATCTGGATTTTGCC AAGGCCAAAC AGCTCACGGTTGTAGGTTGCCAGTTTACAGAATTTCTTCTTGAATCTGAAGAGGATGGGC AAGGCTACTT AGAAGATCTAGTAAAGGATATTGTTCAGTGGCTCAATGCTTCATCTGGAATGAAACCCGA AAGAAGTCTT CAAAATAATGGTTTATTGACCACCCTTAGTCAACACTACTTTTTATTTATTGGAACACTT TCTTGCCACC

CTCATGGAGTTAAAATGCTGGAAAAATGCAGTGTATTTCAGTGTCTCCTTAATCTTT GCTCCTTGAAAAA CCAAGATCACTTGCTAAAACTTACTGTTTCTAGCTTGGACTATAGCAGAGATGGATTGGC TAGAGTCATC CTTTCCAAAATTTTAACTGCAGCTACTGATGCCTGCAGACTCTATGCAACAAAACATTTA AGGGTATTAT TGAGAGCTAATGTTGAATTCTTTAATAATTGGGGAATTGAGTTGTTAGTGACCCAGCTAC ATGATAAAAA CAAAACGATTTCCTCTGAAGCTCTTGATATCCTCGATGAAGCATGTGAAGACAAGGCCAA TCTTCATGCT CTCATTCAGATGAAACCAGCGTTATCCCACCTTGGAGACAAGGGTTTGCTTCTCCTGCTG AGATTTCTCT CCATTCCAAAAGGATTTTCCTATCTGAATGAAAGAGGTTATGTAGCAAAACAATTGGAAA AGTGGCACAG GGAATACAACTCCAAATATGTTGACTTGATTGAGGAACAACTCAATGAAGCACTTACTAC TTACCGGAAG CCTGTTGATGGTGATAACTATGTTCGTCGGAGTAACCAAAGATTACAGCGTCCTCACGTC TACCTGCCTA TACACCTTTATGGACAACTAGTACACCATAAAACAGGCTGCCATTTGTTGGAAGTACAGA ATATTATTAC AGAACTCTGTCGTAATGTTCGTACACCAGATTTGGATAAGTGGGAAGAAATTAAAAAACT GAAAGCATCT CTTTGGGCCTTGGGAAATATCGGCTCATCAAATTGGGGTCTCAATTTGCTACAGGAAGAA AACGTGATTC CAGATATACTAAAACTTGCAAAACAGTGTGAAGTTCTTTCCATCAGAGGGACCTGTGTAT ATGTACTTGG GCT CATAGCTAAAACCAAACAAGGCTGT GATATT CTAAAAT GT CACAACT GGGAT GCT GT GAGGCATAGT

CGCAAACATCTGTGGCCAGTGGTTCCAGATGATGTGGAACAACTCTGTAATGAACTT TCATCTATCCCAA GCACTCTAAGTTTGAACTCGGAGTCAACCAGCTCTAGACATAATAGTGAAAGTGAATCTG TGCCATCGAG TATGTTCATATTGGAGGATGACCGGTTTGGCAGCAGCTCTACTAGCACATTTTTCCTTGA TATCAATGAA GATACAGAGCCAACATTTTATGACCGATCTGGACCCATAAAGGATAAAAATTCATTCCCT TTCTTTGCTT CTAGTAAACTTGTGAAGAATCGTATCTTAAATTCGCTTACTTTGCCTAACAAAAAACATC GTAGTAGCAG TGATCCAAAAGGAGGGAAATTATCATCTGAAAGTAAGACAAGCAACAGGCGAATCAGAAC ACTTACGGAG C C CAGT GT T GAT T T T AAT CAT AGT GAT GAT T T T ACAC C CAT AT C CACT GT ACAGAAAACAT T ACAAT TAG AGACTTCATTTATGGGGAATAAGCACATTGAAGACACTGGTAGTACACCAAGCATTGGAG AAAATGACTT AAAAT T CAC CAAGAAT T T T GGT ACAGAGAAT CACAGAGAAAAT ACAAGC C GAGAGAGGT T AGT AGT AGAA AGTTCAACGAGCTCACATATGAAGATACGTAGCCAAAGTTTCAATACAGACACTACAACA AGTGGCATAA GTT CAAT GAGCT CAAGT CCTT CACGAGAGACAGTAGGT GTAGAT GCTACAACTAT GGACACAGACT GT GG AAGCATGAGTACTGTGGTAAGTACTAAAACTATTAAGACAAGCCACTATTTGACGCCACA GTCTAACCAT CTGTCTCTCTCCAAATCAAATTCGGTGTCCCTGGTGCCTCCAGGTTCTTCTCATACGCTT CCTAGAAGAG CACAGTCCCTTAAAGCACCCTCTATTGCTACAATTAAAAGTCTAGCAGATTGTAACTTTA GTTACACAAG TTCTAGAGATGCTTTTGGCTATGCTACACTGAAAAGACTACAGCAACAAAGAATGCATCC ATCCTTATCT CACTCTGAAGCTTTGGCATCTCCAGCAAAAGATGTGCTATTTACTGATACCATCACCATG AAGGCCAACA GTTTTGAGTCCAGATTAACACCAAGCAGGATCGATTTTAAAAAGAAGCATGTCGGGGGAA TCAGGAGCTT AAGACCTACAATAACAAACAACCTTTTCAGGTTCATGAAAGCCTTAAGTTATGCATCATT AGATAAAGAA GATTTATTGAGTCCTATTAATCAAAATACCCTGCAACGATCTTCCTCAGTGCGGTCCATG GTGTCCAGTG CCACATATGGGGGTTCAGATGATTACATTGGTCTTGCTCTCCCGGTGGATATAAATGATA TATTCCAGGT AAAGGATATTCCCTATTTTCAGACAAAAAACATACCACCACATGATGATCGAGGTGCAAG AGCATTTGCC CATGATGCAGGAGGTCTTCCATCTGGAACTGGAGGTCTTGTAAAAAATTCTTTTCACTTG CTACGACAGC AGATGAGTCTTACGGAAATAATGAATTCAATCCATTCAGATGCCTCTCTGTTTTTAGAAA GTACAGAAGA CACTGGACTACAGGAACATACAGATGATAACTGCCTTTATTGTGTCTGTATTGAAATTCT GGGTTTCCAG CCCAGCAACCAACTGAGTGCAATATGTAGTCATTCAGACTTTCAAGATATTCCATATTCT GATTGGTGTG AGCAGACTATCCATAATCCTTTAGAAGTGGTTCCCTCTAAGTTTTCGGGGATTTCTGGAT GCAGTGATGG GGTGTCTCAAGAAGGCTCAGCTAGCAGCACCAAAAGCACAGAATTGTTACTAGGTGTTAA AACAATTCCA GATGATACACCAATGTGCCGTATACTCCTTCGCAAAGAAGTTCTAAGATTAGTCATTAAT TTGAGTAGTT CAGTTTCAACTAAATGTCATGAGACTGGGCTTTTAACAATTAAGGAGAAGTATCCTCAAA CATTTGATGA CATATGCCTTTACTCTGAGGTTTCCCATTTGCTGTCACACTGCACATTCAGACTTCCGTG TCGGAGGTTC ATACAAGAATTATTTCAAGATGTACAGTTTCTACAAATGCATGAAGAAGCAGAGGCTGTG TTGGCAACAC CACCAAAGCAACCTATAGTTGATACATCTGCTGAATCCTGACCTCATATTTATGATGGAT ATAGATACAT ACTATATATATTCATATTTGTGGATTTCCTAAAAGCCTCAGAAAATACGACTGACTAGGC AGCAAAGACA GGAGTATCTTCTGTACACTGTTCCGCAGTTACTGGTACATGAACAGTTGGAACTGCTGAC TTTCCTAACC AAAACAACTTCCTTCTCTCCTTTGTTGAGCCTTTTGAGGGGTTCATGATTCATTACCACA GTTTTAAGAG TTTCAGTTACCATTGTATGCAAGAGCCAAGCACTGAATACCTACATAGGTTTTCTATTTT CTTTCATTTT AAAAGCATAATGACAGTGGAACAATAATGGGATATGCAGAAGCACCCTTCACAAGTTATT TCTGAATGAT TTTTAGGGTAAATAATACAGATGCCTTGTTTGTTAACTAACTTGTGGAAAGCAGGAATCA GTGTCTCTAA GGCTGCATCCTATTACCACAATGGGGTGTGCTATAACTGCTGGTATTAGAGAGGGAACTT TGGCCCTTTC ACGTTTTTCTTAATGTTTGTAACACTACTTCAGAGGTTTATAACCTCAAAGCAGAAGAAG AGCCTCAACA ACCCGGGACTTATAAGTTATTTTTATGTTACTAGACTTGCATAAAGATTCTTGTTTTCCA ACTCTTCATT TTGTTGCAATGTGTTATTACAGGATATATGAACCAATTAAGGTTTTTCACTACAGTTCTT GAATAAAATT T AAAAAT CAT TTTTTATTT T AAT T AAAAAT AT T T C C CAT T T AT AGAAT G CAT AT AT T T G C AAT G GAC T T C CACTTTCATCAACTTTCCATCTCATCGCTTTAAACAGGAACTTGAACAAGCACTGTTAGT TTAGACCTAA AGGATAGGAAAGCATTAAATAATACTTTGGATCTCCTGAGGAAAAGATAAGTTTGCTTGC AATTTACACA TTCCATGGGGAAAGAAGAGCCATATTTCCTTAAAAAAAACATTAATAAAGCTTGTTATTG AGAAAAATTG TAGTGAAAAGCCTTAAGTACCAAATTTTAAAGCAGCAGTAACTTAATTTTTATATCAGTG TTTTTGTTTT GCACAAACTAAATGCAGTGGTAGGTGGGTTTATGAGTATATTAATTGCCTTTATCCATTT GTGAAGTTAA GTTGATGAGGGCAAGGTTTTTGTTTGTTTAATTTGTATATGTCTAAAGGTATTTGGAACT TTTTACAGGA ATTAAACATATATGCAAATTTGTATATAAAAATAGCATGGCCATCATTTGAATGCTTGTA AATGAAAGGA TTATCTTTTTTGAGATCTATATATAAATAGAAATAGAAAATCCAGCTGGACTGATTAGGA TTCTTTTTTA AT T CAT T T GT GT AT AACAT T T T TAT TACAAT T ACACAT CAGT T T T GACACAGT CAT AGCAACAT T AAT AT TTTCCCATGATGCAGATCCTTTTTGTAATGGGCTTGTTCTTTGAGATCTCTGTAAAGAAC CCTGTGAACT AGAAAACATAACTCACAGAGATACTTTTTTAAAAAATTTATTTACTGGAACTGAAAGTTC CAGTTGGGAT GAAGCATTTCATCTCACTTCATAACACCTCTTTGACTGCACTTCAGTGAATTGTTCTTAT GTGCACTGTG TAGCAACTTACATTATAACAAAGCAGATAAGGGCTGTAAGCTGCTGCTTATGTTGAAAAG TGGTTCTTCA GAT T T T C T C T C AT AAAAT C C AGT T GAAGAT AAAT AAT TTTTTTATACTTTATCACT GAAC C C AAGT GT T T ATTTAAATGTCAACAGTACTTCTAAGAACGTTGCCTGTCATCGTGGTCTTTGGTCTTGGA TAACTAAACT GCCTTTCCAGAGAACCAAATGTCAGAGTTACTAGACCAAATAGTGGTTAAAACCTCCAAA GGAAGTAATG TAATCTTATTCATAATGGGATTAACATATTTTAGACATTCATTTTAAACACTACCTCAGT TAATATAGAG TAT AAAAAT CT GT GGT T T AAT C C CT CAAAAGT T AACAGT AAT TTTTTTTTT GT CT T ACACACACACACAC CCCCTCCCCCACCATCACTATCCCTGTACCCTCACCTTGGTCATCTATCCTGAAATAAGG CTTAGTTAGT ATTGGCCTGAATGTTTTGTGTTTTTTTTTTTGTTTTTTTTTTTTACTGTTACTTTGAAAA ATATGTATGT ATACCTTATCATATCTGCCTATATCACTTACTTTGGGGAGATACTCAGAGCTTTGTGGTT ATCAGTATAC TAAAAAAAAAAAAAAGTCTACGCTTAAATTTATAGTGCTATTTGGTTTCTCCATGATTTC ACTGACAGGT CTAATACATTTTCTTTGAGTACTTGTTTGTAAAAAGTAGACTTTATGGTGAAAAATACAT GCAGTGCCAA GTGATTAACTTAAGTGTTTAAAAATATTAAATTATAGCAGAAGAGGTTAGGAATGATATC AGCAGTAATA GAAAT AAT T GAGAAAAT CAT C TAT AAAT AAT AGAT AT T AC AGAC TAT AGAAT AC C AAAAT AAT GT C AAT A CTGTAGTTTTTAAAGATTTTAGGATTAATCTTAGTCCATATAAATTTGTACTATTGGTAA TTATTGAATA ATTGGGAGGAATCTGGGCAGTTGTGCTGGTTGTAAACTATGAATTTCTAATCGTAAAGTG AATTGTTATT TCTAATTGAACTTTTTTTCAAGAACAGATTTCAGCCTCACATACTAAGTAAATACTGATA AATAAGGAAA TTAGAAATTTAGTATTCATAATTAAATATGCTCTAAAATTTCCTATACTTTTATTTCCTG TTTATTCTTA GGTAGATTGGAAGGGGGAAACAGTCTGTTCTCCCTAATTAAATTTTTTCTAATAACGATT AGTAGAATAT GGACATTCTATATGACAGTGACATTAAAAGAGGCTCTTTGGAAGTATATACATTATTAAC ATAATGTGTA CAAGTCCTTTTGAAATGACAACTTTAATGGGTTTCAGCTCTTTTATCTAGAGCTTGAGAT AATTCAAGCT GAGTTTTTCAGGGCATATCACAACGGCCAAGTGTTCAGCAGTGGGATATCAATGCTTATT TACATTTTCC TACTGCTATTTATATAAAATGTTATTCCATTCAGAGGATGCCTTTTATCCCCACATTAAA GCACAGATCA TTAAGCAATAAAAACCAAATTGTCTGTCATTCAAATTATAACTGCAGTTATTTTTGCATG GTAAGAGTGA GGTGCTAATTTTGTGTGAGATGAACTTTGTAAACTACTTTGGGAAATGTTCTTTGGAAGT AAGGTTTTTT CTCCTTTAGTCTTATGCTTCCACTTTTGTCTCAGATTCACAATCCATTAAAACATGGGGA AAAAAGAAAA GGTAAAATTGAGAGACTTTTGTTAGAGGAGCTATTTGGAATGAACCAACATTTCAGATTT TCCAAAATGT AAGTTAGGAAGTCTCCATTGTCTCTGCATTAACAAAATACACTGTTACTATCTTAATCTC AAGAGTGTCA TTACAGTGAGAATCTCATTTAAAAGCATACCAGTGAAATTAATAGCAGTGCTTATCAAAG AACACTGAAA TCTGTGAGAATCTTTCTAGGAGCATTCTTTTCTTCTTTTAGTTCCAAGTTCCAGGGTATT TTTCATTCCT AGTAGGTTTATATGACTCACAGAATGTGGACTTTTTTCCTGTTTGGAGTATTTTTGTAAT GTAAGTATCG GATAGCTGCACCACAGCATGCATAAATTGCACATTTTGTTTTACTTTCTTTATAGAATAT TTAATTTCAA AAATATAATTTATGCCAAAAAAAGCATACCTTTCAATTTTGCTACTTGGTTGATTTAGCA CAAAATGCAA AGTCTTGGGGCAGAGAGGGGGAGTGAAAAAAATTTTATAGGTAATTGTTACAAAAATACC TGTCAGAAAC CCTAAAGCTGCATTGTAAAACAAATGGTGTAAACTAGTTTTGAAAAGTGGTAAGGAATTG TGAAAAAAAT CTCAGACTTAATGCTCTCTAACCACATGAGTTTCTTCTTTTTTATTTAGTAATACGCTGC TACATATTTG GAGGTTCTGGTGTTTGTAGGTCACTGAACAGACATTGAAATCTGATTTATATTGTATAAC TGTAACATAG AAAGAAAAAGT AT T TAT AT T T T T T CT GT AAGAAT AT T T CAT T GAGT T GT GT AT AAT T T AAAT AAGAT T T G TCCCCAAATGGTTTTGCTCACCTTGATTTTTTTTGTTGTGATTTTCTTGTTTTTGTATAA TGTGTATAGT TTATGTCAAGGGCATTAAAAGCCTCCTGAAGCATAATCTTATCAAAGGGATACATTGTTA ATAAAATGTA CTTAAAATTCTTAAA

[0155] Primers or probes can be designed so that they hybridize under stringent conditions to mutant nucleotide sequences of AKT1, ALK, B2M, BRAF, EGFR, ERBB2 (HER2), FGFR2, FGFR3, KEAP1, KRAS, MAP2K1 (MEK1), MET, NRAS, PIK3CA, RET, ROS1, STK11, TP53, NTRK1, FGFR1, MYC, PTEN, and RICTOR, but not to the respective wild-type nucleotide sequences. Primers or probes can also be prepared that are complementary and specific for the wild-type nucleotide sequence of AKT1, ALK, B2M, BRAF, EGFR, ERBB2 (HER2), FGFR2, FGFR3, KEAP1, KRAS, MAP2K1 (MEK1), MET, NRAS, PIK3CA, RET, ROS1, STK11, TP53, NTRK1, FGFR1, MYC, PTEN, and RICTOR, but not to any of the corresponding mutant nucleotide sequences. In some embodiments, the mutant nucleotide sequences of AKT1, ALK, B2M, BRAF, EGFR, ERBB2 (HER2), FGFR2, FGFR3, KEAP1, KRAS, MAP2K1 (MEK1), MET, NRAS, PIK3CA, RET, ROS1, STK11, TP53, NTRK1, FGFR1, MYC, PTEN, and RICTOR may be a frameshift mutation, a missense mutation, a deletion, an insertion, a nonsense mutation, an inversion, a translocation, a duplication, or a CNV that results in the altered expression and/or activity of AKT1, ALK, B2M, BRAF, EGFR, ERBB2 (HER2), FGFR2, FGFR3, KEAP1, KRAS, MAP2K1 (MEK1), MET, NRAS, PIK3CA, RET, ROS1, STK11, TP53, NTRK1, FGFR1, MYC, PTEN, and RICTOR. [0156] In some embodiments, detection can occur through any of a variety of mobility dependent analytical techniques based on the differential rates of migration between different nucleic acid sequences. Exemplary mobility-dependent analysis techniques include electrophoresis, chromatography, mass spectroscopy, sedimentation, gradient centrifugation, field-flow fractionation, multi-stage extraction techniques, and the like. In some embodiments, mobility probes can be hybridized to amplification products, and the identity of the target nucleic acid sequence determined via a mobility dependent analysis technique of the eluted mobility probes, as described in Published PCT Applications WO04/46344 and WOO 1/92579. In some embodiments, detection can be achieved by various microarrays and related software such as the Applied Biosystems Array System with the Applied Biosystems 1700 Chemiluminescent Microarray Analyzer and other commercially available array systems available from Affymetrix, Agilent, Illumina, and Amersham Biosciences, among others (see also Gerry et al., J. Mol. Biol. 292:251-62, 1999; De Bellis et al., Minerva Biotec 14:247-52, 2002; and Stears et al., Nat. Med. 9: 14045, including supplements, 2003).

[0157] It is also understood that detection can comprise reporter groups that are incorporated into the reaction products, either as part of labeled primers or due to the incorporation of labeled dNTPs during an amplification, or attached to reaction products, for example but not limited to, via hybridization tag complements comprising reporter groups or via linker arms that are integral or attached to reaction products. In some embodiments, unlabeled reaction products may be detected using mass spectrometry.

NGS Platforms

[0158] In some embodiments, high throughput, massively parallel sequencing employs sequencing-by-synthesis with reversible dye terminators. In other embodiments, sequencing is performed via sequencing-by-ligation. In yet other embodiments, sequencing is single molecule sequencing. Examples of Next Generation Sequencing techniques include, but are not limited to pyrosequencing, Reversible dye-terminator sequencing, SOLiD sequencing, Ion semiconductor sequencing, Helioscope single molecule sequencing etc.

[0159] The Ion Torrent™ (Life Technologies, Carlsbad, CA) amplicon sequencing system employs a flow-based approach that detects pH changes caused by the release of hydrogen ions during incorporation of unmodified nucleotides in DNA replication. For use with this system, a sequencing library is initially produced by generating DNA fragments flanked by sequencing adapters. In some embodiments, these fragments can be clonally amplified on particles by emulsion PCR. The particles with the amplified template are then placed in a silicon semiconductor sequencing chip. During replication, the chip is flooded with one nucleotide after another, and if a nucleotide complements the DNA molecule in a particular microwell of the chip, then it will be incorporated. A proton is naturally released when a nucleotide is incorporated by the polymerase in the DNA molecule, resulting in a detectable local change of pH. The pH of the solution then changes in that well and is detected by the ion sensor. If homopolymer repeats are present in the template sequence, multiple nucleotides will be incorporated in a single cycle. This leads to a corresponding number of released hydrogens and a proportionally higher electronic signal.

[0160] The 454TM GS FLX ™ sequencing system (Roche, Germany), employs a lightbased detection methodology in a large-scale parallel pyrosequencing system.

Pyrosequencing uses DNA polymerization, adding one nucleotide species at a time and detecting and quantifying the number of nucleotides added to a given location through the light emitted by the release of attached pyrophosphates. For use with the 454™ system, adapter-ligated DNA fragments are fixed to small DNA-capture beads in a water-in-oil emulsion and amplified by PCR (emulsion PCR). Each DNA-bound bead is placed into a well on a picotiter plate and sequencing reagents are delivered across the wells of the plate. The four DNA nucleotides are added sequentially in a fixed order across the picotiter plate device during a sequencing run. During the nucleotide flow, millions of copies of DNA bound to each of the beads are sequenced in parallel. When a nucleotide complementary to the template strand is added to a well, the nucleotide is incorporated onto the existing DNA strand, generating a light signal that is recorded by a CCD camera in the instrument.

[0161] Sequencing technology based on reversible dye-terminators: DNA molecules are first attached to primers on a slide and amplified so that local clonal colonies are formed. Four types of reversible terminator bases (RT-bases) are added, and non-incorporated nucleotides are washed away. Unlike pyrosequencing, the DNA can only be extended one nucleotide at a time. A camera takes images of the fluorescently labeled nucleotides, then the dye along with the terminal 3' blocker is chemically removed from the DNA, allowing the next cycle. [0162] Helicos's single-molecule sequencing uses DNA fragments with added polyA tail adapters, which are attached to the flow cell surface. At each cycle, DNA polymerase and a single species of fluorescently labeled nucleotide are added, resulting in templatedependent extension of the surface-immobilized primer-template duplexes. The reads are performed by the Helioscope sequencer. After acquisition of images tiling the full array, chemical cleavage and release of the fluorescent label permits the subsequent cycle of extension and imaging.

[0163] Sequencing by synthesis (SBS), like the "old style" dye-termination electrophoretic sequencing, relies on incorporation of nucleotides by a DNA polymerase to determine the base sequence. A DNA library with affixed adapters is denatured into single strands and grafted to a flow cell, followed by bridge amplification to form a high-density array of spots onto a glass chip. Reversible terminator methods use reversible versions of dye-terminators, adding one nucleotide at a time, detecting fluorescence at each position by repeated removal of the blocking group to allow polymerization of another nucleotide. The signal of nucleotide incorporation can vary with fluorescently labeled nucleotides, phosphate-driven light reactions and hydrogen ion sensing having all been used. Examples of SBS platforms include Illumina GA and HiSeq 2000. The MiSeq® personal sequencing system (Illumina, Inc.) also employs sequencing by synthesis with reversible terminator chemistry.

[0164] In contrast to the sequencing by synthesis method, the sequencing by ligation method uses a DNA ligase to determine the target sequence. This sequencing method relies on enzymatic ligation of oligonucleotides that are adjacent through local complementarity on a template DNA strand. This technology employs a partition of all possible oligonucleotides of a fixed length, labeled according to the sequenced position. Oligonucleotides are annealed and ligated and the preferential ligation by DNA ligase for matching sequences results in a dinucleotide encoded color space signal at that position (through the release of a fluorescently labeled probe that corresponds to a known nucleotide at a known position along the oligo). This method is primarily used by Life Technologies’ SOLiD™ sequencers. Before sequencing, the DNA is amplified by emulsion PCR. The resulting beads, each containing only copies of the same DNA molecule, are deposited on a solid planar substrate. [0165] SMRT™ sequencing is based on the sequencing by synthesis approach. The DNA is synthesized in zero-mode wave-guides (ZMWs)-small well-like containers with the capturing tools located at the bottom of the well. The sequencing is performed with use of unmodified polymerase (attached to the ZMW bottom) and fluorescently labeled nucleotides flowing freely in the solution. The wells are constructed in a way that only the fluorescence occurring at the bottom of the well is detected. The fluorescent label is detached from the nucleotide at its incorporation into the DNA strand, leaving an unmodified DNA strand.

Methods for Predicting the Risk of VTE Using ctDNA as a Biomarker

Pan Cancer

[0166] In one aspect, the present disclosure provides a method for preventing cancer associated thromboembolism (CAT) in a cancer patient in need thereof comprising (a) detecting ctDNA molecules in a biological sample obtained from the cancer patient, wherein the ctDNA molecules are detected at a variant allele fraction (VAF) detection limit of at least 0. l%-0.5% and (b) administering to the cancer patient an effective amount of anticoagulant therapy.

[0167] In another aspect, the present disclosure provides a method for preventing cancer associated thromboembolism (CAT) in a cancer patient in need thereof comprising administering to the cancer patient an effective amount of anticoagulant therapy, wherein a biological sample obtained from the cancer patient comprises detectable ctDNA molecules, wherein the ctDNA molecules are detected at a variant allele fraction (VAF) detection limit of at least 0. l%-0.5%.

[0168] Additionally or alternatively, in some embodiments of the methods disclosed herein, the ctDNA molecules are detected at a VAF detection limit of from about 0.1% to about 0.5%, from about 0.5% to about 2%, from about 2% to about 10% or from about 10% to about 99%. In certain embodiments, the ctDNA molecules are detected at a VAF detection limit of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%.

[0169] In any of the preceding embodiments of the methods disclosed herein, the cancer patient is diagnosed with or suffers from a cancer selected from the group consisting of nonsmall cell lung cancer, breast cancer, pancreatic cancer, melanoma, retinoblastoma, prostate cancer, esophagogastric cancer, histiocytosis, germ cell tumor, endometrial cancer, small cell lung cancer, soft tissue sarcoma, Gastrointestinal Stromal Tumor, ovarian cancer, mature B-Cell neoplasms, small bowel cancer, renal cell carcinoma, thyroid cancer, ampullary cancer, appendiceal cancer, sellar tumor, uterine sarcoma, bone cancer, nonmelanoma skin cancer, cervical cancer, mesothelioma, glioma, thymic tumor, gastrointestinal neuroendocrine tumor, salivary gland cancer, sex cord stromal tumor, anal cancer, mature T and NK neoplasms, peritoneal cancer, Head and neck cancer, choroid plexus tumor, leukemia, primary CNS melanocytic tumors, Myelodysplastic Syndromes, Peripheral Nervous System, mastocytosis, Wilms tumor, lymphatic cancer, vaginal cancer, Hodgkin lymphoma, adrenocortical carcinoma, brain tumors, embryonal tumors and NonHodgkin lymphoma. The cancer may be a Stage 1, Stage 2, Stage 3, or Stage 4 cancer. Additionally or alternatively, in some embodiments, the cancer patient has a Khorana Score > 2 or < 2 and/or has one or more organ sites of metastasis.

[0170] Additionally or alternatively, in some embodiments of the methods disclosed herein, the ctDNA molecules comprise one or more mutations (e.g., SNVs) in at least one cancer associated gene selected from the group consisting of AKT1, ALK, APC, AR, ARAF, ARID1 A, ARID2, ATM, B2M, BCL2, BCOR, BRAF, BRCA1, BRCA2, CARD11, CBFB, CCND1, CDH1, CDK4, CDKN2A, CIC, CREBBP, CTCF, CTNNB1, DICER1, DIS3, DNMT3A, EGFR, EIF1AX, EP300, ERBB2, ERBB3, ERCC2, ESRI, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, F0XA1, FOXL2, FOXO1, FUBP1, GATA3, GNA11, GNAQ, GNAS, H3F3A, HIST1H3B, HRAS, IDH1, IDH2, IKZF1, INPPL1, JAK1, KDM6A, KEAP1, KIT, KNSTRN, KRAS, MAP2K1, MAPK1, MAX, MED12, MET, MLH1, MSH2, MSH3, MSH6, MTOR, MYC, MYCN, MYD88, MYODI, NF1, NFE2L2, NOTCH1, NRAS, NTRK1, NTRK2, NTRK3, NUP93, PAK7, PDGFRA, PIK3CA, PIK3CB, PIK3R1, PIK3R2, PMS2, POLE, PPP2R1A, PPP6C, PRKCI, PTCHI, PTEN, PTPN11, RAC1, RAFI, RBI, RET, RHOA, RIT1, ROS1, RRAS2, RXRA, SETD2, SF3B1, SMAD3, SMAD4, SMARCA4, SMARCB1, SOS1, SPOP, STAT3, STK11, STK19, TCF7L2, TGFBR1, TGFBR2, TP53, TP63, TSC1, TSC2, U2AF1, VHL, XPO1, and TERT. In certain embodiments, the ctDNA molecules comprise 2-20 mutations in the at the least one cancer associated gene.

[0171] In any and all embodiments of the methods disclosed herein, the ctDNA molecules comprise one or more rearrangements in at least one cancer associated gene selected from the group consisting of ALK, BRAF, EGFR, ETV6, FGFR2, FGFR3, MET, NTRK1, RET and ROS1. The one or more rearrangements may comprise indels, CNVs, and/or gene fusions. Additionally or alternatively, in some embodiments, the ctDNA molecules comprise 2-20 rearrangements in the at the least one cancer associated gene.

[0172] In any of the preceding embodiments of the methods disclosed herein, the biological sample is whole blood, serum or plasma. In some embodiments, the biological sample has a cfDNA concentration ranging from about 3 pg/pL to 5.5 ng/pL. In some embodiments, the biological sample has a cfDNA concentration of about 3 pg/pL, about 4 pg/pL, about 5 pg/pL, about 6 pg/pL, about 7 pg/pL, about 8 pg/pL, about 9 pg/pL, about 10 pg/pL, about 15 pg/pL, about 20 pg/pL, about 25 pg/pL, about 30 pg/pL, about 35 pg/pL, about 40 pg/pL, about 45 pg/pL, about 50 pg/pL, about 55 pg/pL, about 60 pg/pL, about 65 pg/pL, about 70 pg/pL, about 75 pg/pL, about 80 pg/pL, about 85 pg/pL, about 90 pg/pL, about 100 pg/pL, about 125 pg/pL, about 150 pg/pL, about 175 pg/pL, about 200 pg/pL, about 225 pg/pL, about 250 pg/pL, about 275 pg/pL, about 300 pg/pL, about 325 pg/pL, about 350 pg/pL, about 375 pg/pL, about 400 pg/pL, about 425 pg/pL, about 450 pg/pL, about 475 pg/pL, about 500 pg/pL, about 525 pg/pL, about 550 pg/pL, about 575 pg/pL, about 600 pg/pL, about 625 pg/pL, about 650 pg/pL, about 675 pg/pL, about 700 pg/pL, about 725 pg/pL, about 750 pg/pL, about 775 pg/pL, about 800 pg/pL, about 825 pg/pL, about 850 pg/pL, about 875 pg/pL, about 900 pg/pL, about 925 pg/pL, about 950 pg/pL, about 975 pg/pL, about 1 ng/pL, about 1.25 ng/pL, about 1.5 ng/pL, about 1.75 ng/pL, about 2 ng/pL, about 2.25 ng/pL, about 2.5 ng/pL, about 2.75 ng/pL, about 3 ng/pL, about 3.25 ng/pL, about 3.5 ng/pL, about 3.75 ng/pL, about 4 ng/pL, about 4.25 ng/pL, about 4.5 ng/pL, about 4.75 ng/pL, about 5 ng/pL, about 5.25 ng/pL, or about 5.5 ng/pL.

[0173] Additionally or alternatively, in some embodiments, the anticoagulant therapy comprises one or more of apixaban, betrixaban, dabigatran, edoxaban, fondaparinux, heparin, rivaroxaban, warfarin, Xa inhibitors, statins, or enoxaparin. Examples of statins include, but are not limited to atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0174] In any of the foregoing embodiments of the methods disclosed herein, the cancer patient is chemotherapy-naive or has received/is receiving systemic chemotherapy. Systemic chemotherapy may comprise one or more of alkylating agents, antibiotics, antimetabolites, antimitotics, cyclin-dependent kinase inhibitors, epidermal growth factor receptor inhibitors, multikinase inhibitors, PARP inhibitors, platinum-based agents, selective estrogen receptor modulators (SERM), or VEGF inhibitors. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents, platinum agents, taxanes, vinca agents, anti-estrogen drugs, aromatase inhibitors, ovarian suppression agents, VEGF/VEGFR inhibitors, EGFZEGFR inhibitors, PARP inhibitors, cytostatic alkaloids, cytotoxic antibiotics, antimetabolites, endocrine/hormonal agents, bisphosphonate therapy agents and targeted biological therapy agents (e.g., therapeutic peptides described in US 6306832, WO 2012007137, WO 2005000889, WO 2010096603 etc.). In some embodiments, the at least one additional therapeutic agent is a chemotherapeutic agent. Specific chemotherapeutic agents include, but are not limited to, cyclophosphamide, fluorouracil (or 5 -fluorouracil or 5-FU), methotrexate, edatrexate (10-ethyl-10-deaza- aminopterin), thiotepa, carboplatin, cisplatin, taxanes, paclitaxel, protein-bound paclitaxel, docetaxel, vinorelbine, tamoxifen, raloxifene, toremifene, fulvestrant, gemcitabine, irinotecan, ixabepilone, temozolmide, topotecan, vincristine, vinblastine, eribulin, mutamycin, capecitabine, anastrozole, exemestane, letrozole, leuprolide, abarelix, buserlin, goserelin, megestrol acetate, risedronate, pamidronate, ibandronate, alendronate, denosumab, zoledronate, trastuzumab, tykerb, anthracyclines (e.g., daunorubicin and doxorubicin), bevacizumab, oxaliplatin, melphalan, etoposide, mechlorethamine, bleomycin, microtubule poisons, annonaceous acetogenins, or combinations thereof. [0175] Additionally or alternatively, in some embodiments of the methods disclosed herein, the cancer patient is immunotherapy-naive or has received/is receiving immunotherapy. Examples of immunotherapy include, but are not limited to, anti-PD-1 antibody, anti-PD-Ll antibody, anti-PD-L2 antibody, anti-CTLA-4 antibody, anti-TIM3 antibody, anti -4- IBB antibody, anti-CD73 antibody, anti-GITR antibody, and anti -LAG-3 antibody.

[0176] Additionally or alternatively, in certain embodiments of the methods disclosed herein, the cancer patient is radiotherapy-naive or has received/is receiving radiotherapy. The radiotherapy may comprise external radiotherapy, radiotherapy implants (brachytherapy), pre-targeted radioimmunotherapy, radiotherapy injections, radioisotope therapy, or intrabeam radiotherapy.

[0177] In any and all embodiments of the methods disclosed herein, the CAT is pulmonary embolism or lower extremity deep vein thrombosis (DVT). In some embodiments, lower extremity DVT includes thrombi involving a common iliac vein, an external iliac vein, a common femoral vein, a superficial femoral vein, a deep femoral vein, a popliteal vein, a peroneal vein, an anterior tibial vein, a posterior tibial vein, or a deep calf vein.

Lung Cancer

[0178] In one aspect, the present disclosure provides a method for preventing cancer associated thromboembolism (CAT) in a lung cancer patient in need thereof comprising detecting ctDNA molecules in a biological sample obtained from the lung cancer patient, wherein the ctDNA molecules comprise at least one alteration in at least one cancer- associated gene selected from the group consisting of AKT1, ALK, B2M, BRAF, EGFR, ERBB2 (HER2), FGFR2, FGFR3, KEAP1, KRAS, MAP2K1 (MEK1), MET, NRAS, PIK3CA, RET, ROS1, STK11, TP53, NTRK1, FGFR1, MYC, PTEN, and RICTOR; and administering to the lung cancer patient an effective amount of anticoagulant therapy. The lung cancer may be non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). In some embodiments, the lung cancer is Stage 1, Stage 2, Stage 3, or Stage 4.

[0179] In another aspect, the present disclosure provides a method for preventing cancer associated thromboembolism (CAT) in a lung cancer patient in need thereof comprising administering to the lung cancer patient an effective amount of anticoagulant therapy, wherein a biological sample obtained from the lung cancer patient comprises detectable ctDNA molecules comprising at least one alteration in at least one cancer-associated gene selected from the group consisting of AKT1, ALK, B2M, BRAF, EGFR, ERBB2 (HER2), FGFR2, FGFR3, KEAP1, KRAS, MAP2K1 (MEK1), MET, NRAS, PIK3CA, RET, ROS1, STK11, TP53, NTRK1, FGFR1, MYC, PTEN, and RICTOR. The lung cancer may be nonsmall cell lung cancer (NSCLC) or small cell lung cancer (SCLC). In certain embodiments, the lung cancer is Stage 1, Stage 2, Stage 3, or Stage 4.

[0180] Additionally or alternatively, in some embodiments, the anticoagulant therapy comprises one or more of apixaban, betrixaban, dabigatran, edoxaban, fondaparinux, heparin, rivaroxaban, warfarin, Xa inhibitors, statins, or enoxaparin. Examples of statins include, but are not limited to atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0181] In any of the preceding embodiments of the methods disclosed herein, the lung cancer patient has a Khorana Score < 2 or > 2. Additionally or alternatively, in certain embodiments, the at least one alteration is a SNV, an indel, a CNV, or a gene fusion.

[0182] Additionally or alternatively, in some embodiments of the methods disclosed herein, the at least one alteration is detected at a variant allele fraction (VAF) detection limit of 0. l%-0.5%. In certain embodiments, the detected ctDNA molecules comprise one alteration in the at the least one cancer associated gene. In other embodiments, the detected ctDNA molecules comprise 2-20 alterations in the at the least one cancer associated gene. Additionally or alternatively, in some embodiments of the methods disclosed herein, the ctDNA molecules are detected via polymerase chain reaction (PCR), real-time quantitative PCR (qPCR), droplet digital PCR (ddPCR), Reverse transcriptase-PCR (RT-PCR), microarray, RNA-Seq, or next-generation sequencing. In any of the preceding embodiments of the methods disclosed herein, the biological sample is whole blood, serum or plasma.

[0183] In any of the foregoing embodiments of the methods disclosed herein, the lung cancer patient is chemotherapy-naive or has received/is receiving systemic chemotherapy. Systemic chemotherapy may comprise one or more of alkylating agents, antibiotics, antimetabolites, antimitotics, cyclin-dependent kinase inhibitors, epidermal growth factor receptor inhibitors, multikinase inhibitors, PARP inhibitors, platinum-based agents, selective estrogen receptor modulators (SERM), or VEGF inhibitors. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents, platinum agents, taxanes, vinca agents, anti-estrogen drugs, aromatase inhibitors, ovarian suppression agents, VEGF/VEGFR inhibitors, EGFZEGFR inhibitors, PARP inhibitors, cytostatic alkaloids, cytotoxic antibiotics, antimetabolites, endocrine/hormonal agents, bisphosphonate therapy agents and targeted biological therapy agents (e.g., therapeutic peptides described in US 6306832, WO 2012007137, WO 2005000889, WO 2010096603 etc.). In some embodiments, the at least one additional therapeutic agent is a chemotherapeutic agent. Specific chemotherapeutic agents include, but are not limited to, cyclophosphamide, fluorouracil (or 5 -fluorouracil or 5-FU), methotrexate, edatrexate (10-ethyl-10-deaza- aminopterin), thiotepa, carboplatin, cisplatin, taxanes, paclitaxel, protein-bound paclitaxel, docetaxel, vinorelbine, tamoxifen, raloxifene, toremifene, fulvestrant, gemcitabine, irinotecan, ixabepilone, temozolmide, topotecan, vincristine, vinblastine, eribulin, mutamycin, capecitabine, anastrozole, exemestane, letrozole, leuprolide, abarelix, buserlin, goserelin, megestrol acetate, risedronate, pamidronate, ibandronate, alendronate, denosumab, zoledronate, trastuzumab, tykerb, anthracyclines (e.g., daunorubicin and doxorubicin), bevacizumab, oxaliplatin, melphalan, etoposide, mechlorethamine, bleomycin, microtubule poisons, annonaceous acetogenins, or combinations thereof.

[0184] Additionally or alternatively, in some embodiments of the methods disclosed herein, the lung cancer patient is immunotherapy-naive or has received/is receiving immunotherapy. Examples of immunotherapy include, but are not limited to, anti-PD-1 antibody, anti-PD-Ll antibody, anti-PD-L2 antibody, anti-CTLA-4 antibody, anti-TIM3 antibody, anti-4-lBB antibody, anti-CD73 antibody, anti-GITR antibody, and anti-LAG-3 antibody.

[0185] Additionally or alternatively, in certain embodiments of the methods disclosed herein, the lung cancer patient is radiotherapy -naive or has received/is receiving radiotherapy. The radiotherapy may comprise external radiotherapy, radiotherapy implants (brachytherapy), pre-targeted radioimmunotherapy, radiotherapy injections, radioisotope therapy, or intrabeam radiotherapy.

[0186] In any and all embodiments of the methods disclosed herein, the CAT is pulmonary embolism or lower extremity deep vein thrombosis (DVT). In some embodiments, lower extremity DVT includes thrombi involving a common iliac vein, an external iliac vein, a common femoral vein, a superficial femoral vein, a deep femoral vein, a popliteal vein, a peroneal vein, an anterior tibial vein, a posterior tibial vein, or a deep calf vein.

[0187] Additionally or alternatively, in certain embodiments of the methods disclosed herein, the at least one alteration comprises a SNV and/or an indel in one or more of AKT1, ALK, B2M, BRAF, EGFR, ERBB2 (HER2), FGFR2, FGFR3, KEAP1, KRAS, MAP2K1 (MEK1), MET, NRAS, PIK3CA, RET, ROS1, STK11 and TP53. In some embodiments of the methods disclosed herein, the at least one alteration comprises a gene fusion in one or more of ALK, EGFR, FGFR2, FGFR3, NTRK1, RET, and ROS1. Additionally or alternatively, in some embodiments, the at least one alteration comprises a CNV in one or more of B2M, EGFR, ERBB2 (HER2), FGFR1, KRAS, MET, MYC, NTRK1, PIK3CA, PTEN, RICTOR, STK11, and TP53.

Systems, Devices, and Methods for Predicting the Risk of VTE Across Multiple Cancer Types

[0188] Aspects of the operating environment as well as associated system components (e.g., hardware elements) in connection with various embodiments of the methods and systems described herein will now be discussed. Referring to FIG. 12A, an embodiment of a network environment is depicted. In brief overview, the network environment includes one or more clients 102a-102n (also generally referred to as local machine(s) 102, client(s) 102, client node(s) 102, client machine(s) 102, client computer(s) 102, client device(s) 102, endpoint(s) 102, or endpoint node(s) 102) in communication with one or more servers 106a- 106n (also generally referred to as server(s) 106, node 106, or remote machine(s) 106) via one or more networks 104. In some embodiments, a client 102 has the capacity to function as both a client node seeking access to resources provided by a server and as a server providing access to hosted resources for other clients 102a-102n.

[0189] Although FIG. 12A shows a network 104 between the clients 102 and the servers 106, the clients 102 and the servers 106 may be on the same network 104. In some embodiments, there are multiple networks 104 between the clients 102 and the servers 106. In one of these embodiments, a network 104’ (not shown) may be a private network and a network 104 may be a public network. In another of these embodiments, a network 104 may be a private network and a network 104’ a public network. In still another of these embodiments, networks 104 and 104’ may both be private networks. [0190] The network 104 may be connected via wired or wireless links. Wired links may include Digital Subscriber Line (DSL), coaxial cable lines, or optical fiber lines. The wireless links may include BLUETOOTH, Wi-Fi, Worldwide Interoperability for Microwave Access (WiMAX), an infrared channel or satellite band. The wireless links may also include any cellular network standards used to communicate among mobile devices, including standards that qualify as 1G, 2G, 3G, 4G, or 5G. The network standards may qualify as one or more generation of mobile telecommunication standards by fulfilling a specification or standards such as the specifications maintained by International Telecommunication Union. The 3G standards, for example, may correspond to the International Mobile Telecommunications-2000 (IMT-2000) specification, and the 4G standards may correspond to the International Mobile Telecommunications Advanced (IMT- Advanced) specification. Examples of cellular network standards include AMPS, GSM, GPRS, UMTS, LTE, LTE Advanced, Mobile WiMAX, and WiMAX-Advanced. Cellular network standards may use various channel access methods e.g. FDMA, TDMA, CDMA, or SDMA. In some embodiments, different types of data may be transmitted via different links and standards. In other embodiments, the same types of data may be transmitted via different links and standards.

[0191] The network 104 may be any type and/or form of network. The geographical scope of the network 104 may vary widely and the network 104 can be a body area network (BAN), a personal area network (PAN), a local-area network (LAN), e.g. Intranet, a metropolitan area network (MAN), a wide area network (WAN), or the Internet. The topology of the network 104 may be of any form and may include, e.g., any of the following: point-to-point, bus, star, ring, mesh, or tree. The network 104 may be an overlay network which is virtual and sits on top of one or more layers of other networks 104’. The network 104 may be of any such network topology as known to those ordinarily skilled in the art capable of supporting the operations described herein. The network 104 may utilize different techniques and layers or stacks of protocols, including, e.g., the Ethernet protocol, the internet protocol suite (TCP/IP), the ATM (Asynchronous Transfer Mode) technique, the SONET (Synchronous Optical Networking) protocol, or the SDH (Synchronous Digital Hierarchy) protocol. The TCP/IP internet protocol suite may include application layer, transport layer, internet layer (including, e.g., IPv6), or the link layer. The network 104 may be a type of a broadcast network, a telecommunications network, a data communication network, or a computer network.

[0192] In some embodiments, the system may include multiple, logically-grouped servers 106. In one of these embodiments, the logical group of servers may be referred to as a server farm 38 or a machine farm 38. In another of these embodiments, the servers 106 may be geographically dispersed. In other embodiments, a machine farm 38 may be administered as a single entity. In still other embodiments, the machine farm 38 includes a plurality of machine farms 38. The servers 106 within each machine farm 38 can be heterogeneous - one or more of the servers 106 or machines 106 can operate according to one type of operating system platform (e.g., WINDOWS NT, manufactured by Microsoft Corp, of Redmond, Washington), while one or more of the other servers 106 can operate on according to another type of operating system platform (e.g., Unix, Linux, or Mac OS X).

[0193] In one embodiment, servers 106 in the machine farm 38 may be stored in high- density rack systems, along with associated storage systems, and located in an enterprise data center. In this embodiment, consolidating the servers 106 in this way may improve system manageability, data security, the physical security of the system, and system performance by locating servers 106 and high performance storage systems on localized high performance networks. Centralizing the servers 106 and storage systems and coupling them with advanced system management tools allows more efficient use of server resources.

[0194] The servers 106 of each machine farm 38 do not need to be physically proximate to another server 106 in the same machine farm 38. Thus, the group of servers 106 logically grouped as a machine farm 38 may be interconnected using a wide-area network (WAN) connection or a metropolitan-area network (MAN) connection. For example, a machine farm 38 may include servers 106 physically located in different continents or different regions of a continent, country, state, city, campus, or room. Data transmission speeds between servers 106 in the machine farm 38 can be increased if the servers 106 are connected using a local-area network (LAN) connection or some form of direct connection. Additionally, a heterogeneous machine farm 38 may include one or more servers 106 operating according to a type of operating system, while one or more other servers 106 execute one or more types of hypervisors rather than operating systems. In these embodiments, hypervisors may be used to emulate virtual hardware, partition physical hardware, virtualize physical hardware, and execute virtual machines that provide access to computing environments, allowing multiple operating systems to run concurrently on a host computer. Native hypervisors may run directly on the host computer. Hypervisors may include VMware ESXZESXi, manufactured by VMWare, Inc., of Palo Alto, California; the Xen hypervisor, an open source product whose development is overseen by Citrix Systems, Inc.; the HYPER-V hypervisors provided by Microsoft or others. Hosted hypervisors may run within an operating system on a second software level. Examples of hosted hypervisors may include VMware Workstation and VIRTU ALBOX.

[0195] Management of the machine farm 38 may be de-centralized. For example, one or more servers 106 may comprise components, subsystems and modules to support one or more management services for the machine farm 38. In one of these embodiments, one or more servers 106 provide functionality for management of dynamic data, including techniques for handling failover, data replication, and increasing the robustness of the machine farm 38. Each server 106 may communicate with a persistent store and, in some embodiments, with a dynamic store.

[0196] Server 106 may be a file server, application server, web server, proxy server, appliance, network appliance, gateway, gateway server, virtualization server, deployment server, SSL VPN server, or firewall. In one embodiment, the server 106 may be referred to as a remote machine or a node. In another embodiment, a plurality of nodes 290 may be in the path between any two communicating servers.

[0197] Referring to FIG. 12B, a cloud computing environment is depicted. A cloud computing environment may provide client 102 with one or more resources provided by a network environment. The cloud computing environment may include one or more clients 102a-102n, in communication with the cloud 108 over one or more networks 104. Clients 102 may include, e.g., thick clients, thin clients, and zero clients. A thick client may provide at least some functionality even when disconnected from the cloud 108 or servers 106. A thin client or a zero client may depend on the connection to the cloud 108 or server 106 to provide functionality. A zero client may depend on the cloud 108 or other networks 104 or servers 106 to retrieve operating system data for the client device. The cloud 108 may include back end platforms, e.g., servers 106, storage, server farms or data centers. [0198] The cloud 108 may be public, private, or hybrid. Public clouds may include public servers 106 that are maintained by third parties to the clients 102 or the owners of the clients. The servers 106 may be located off-site in remote geographical locations as disclosed above or otherwise. Public clouds may be connected to the servers 106 over a public network. Private clouds may include private servers 106 that are physically maintained by clients 102 or owners of clients. Private clouds may be connected to the servers 106 over a private network 104. Hybrid clouds 108 may include both the private and public networks 104 and servers 106.

[0199] The cloud 108 may also include a cloud based delivery, e.g. Software as a Service (SaaS) 110, Platform as a Service (PaaS) 112, and Infrastructure as a Service (laaS) 114. laaS may refer to a user renting the use of infrastructure resources that are needed during a specified time period. laaS providers may offer storage, networking, servers or virtualization resources from large pools, allowing the users to quickly scale up by accessing more resources as needed. Examples of laaS can include infrastructure and services (e.g., EG-32) provided by OVH HOSTING of Montreal, Quebec, Canada, AMAZON WEB SERVICES provided by Amazon.com, Inc., of Seattle, Washington, RACKSPACE CLOUD provided by Rackspace US, Inc., of San Antonio, Texas, Google Compute Engine provided by Google Inc. of Mountain View, California, or RIGHTSCALE provided by RightScale, Inc., of Santa Barbara, California. PaaS providers may offer functionality provided by laaS, including, e.g., storage, networking, servers or virtualization, as well as additional resources such as, e.g., the operating system, middleware, or runtime resources. Examples of PaaS include WINDOWS AZURE provided by Microsoft Corporation of Redmond, Washington, Google App Engine provided by Google Inc., and HEROKU provided by Heroku, Inc. of San Francisco, California. SaaS providers may offer the resources that PaaS provides, including storage, networking, servers, virtualization, operating system, middleware, or runtime resources. In some embodiments, SaaS providers may offer additional resources including, e.g., data and application resources. Examples of SaaS include GOOGLE APPS provided by Google Inc., SALESFORCE provided by Salesforce.com Inc. of San Francisco, California, or OFFICE 365 provided by Microsoft Corporation. Examples of SaaS may also include data storage providers, e.g. DROPBOX provided by Dropbox, Inc. of San Francisco, California, Microsoft SKYDRIVE provided by Microsoft Corporation, Google Drive provided by Google Inc., or Apple ICLOUD provided by Apple Inc. of Cupertino, California.

[0200] Clients 102 may access laaS resources with one or more laaS standards, including, e.g, Amazon Elastic Compute Cloud (EC2), Open Cloud Computing Interface (OCCI), Cloud Infrastructure Management Interface (CIMI), or OpenStack standards. Some laaS standards may allow clients access to resources over HTTP, and may use Representational State Transfer (REST) protocol or Simple Object Access Protocol (SOAP). Clients 102 may access PaaS resources with different PaaS interfaces. Some PaaS interfaces use HTTP packages, standard Java APIs, JavaMail API, Java Data Objects (JDO), Java Persistence API (JPA), Python APIs, web integration APIs for different programming languages including, e.g, Rack for Ruby, WSGI for Python, or PSGI for Perl, or other APIs that may be built on REST, HTTP, XML, or other protocols. Clients 102 may access SaaS resources through the use of web-based user interfaces, provided by a web browser (e.g. GOOGLE CHROME, Microsoft INTERNET EXPLORER, or Mozilla Firefox provided by Mozilla Foundation of Mountain View, California). Clients 102 may also access SaaS resources through smartphone or tablet applications, including, e.g., Salesforce Sales Cloud, or Google Drive app. Clients 102 may also access SaaS resources through the client operating system, including, e.g., Windows file system for DROPBOX.

[0201] In some embodiments, access to laaS, PaaS, or SaaS resources may be authenticated. For example, a server or authentication server may authenticate a user via security certificates, HTTPS, or API keys. API keys may include various encryption standards such as, e.g., Advanced Encryption Standard (AES). Data resources may be sent over Transport Layer Security (TLS) or Secure Sockets Layer (SSL).

[0202] The client 102 and server 106 may be deployed as and/or executed on any type and form of computing device, e.g. a computer, network device or appliance capable of communicating on any type and form of network and performing the operations described herein. FIGs. 12C and 12D depict block diagrams of a computing device 100 useful for practicing an embodiment of the client 102 or a server 106. As shown in FIGs. 12C and 12D, each computing device 100 includes a central processing unit 121, and a main memory unit 122. As shown in FIG. 12C, a computing device 100 may include a storage device 128, an installation device 116, a network interface 118, an I/O controller 123, display devices 124a-124n, a keyboard 126 and a pointing device 127, e.g. a mouse. The storage device 128 may include, without limitation, an operating system, software, and a software of a genomic data processing system 120. As shown in FIG. 12D, each computing device 100 may also include additional optional elements, e.g. a memory port 103, a bridge 170, one or more input/output devices 130a-130n (generally referred to using reference numeral 130), and a cache memory 140 in communication with the central processing unit 121.

[0203] The central processing unit 121 is any logic circuitry that responds to and processes instructions fetched from the main memory unit 122. In many embodiments, the central processing unit 121 is provided by a microprocessor unit, e.g. : those manufactured by Intel Corporation of Mountain View, California; those manufactured by Motorola Corporation of Schaumburg, Illinois; the ARM processor and TEGRA system on a chip (SoC) manufactured by Nvidia of Santa Clara, California; the POWER7 processor, those manufactured by International Business Machines of White Plains, New York; or those manufactured by Advanced Micro Devices of Sunnyvale, California. The computing device 100 may be based on any of these processors, or any other processor capable of operating as described herein. The central processing unit 121 may utilize instruction level parallelism, thread level parallelism, different levels of cache, and multi-core processors. A multi-core processor may include two or more processing units on a single computing component. Examples of multi -core processors include the AMD PHENOM IIX2, INTEL CORE i5 and INTEL CORE i7.

[0204] Main memory unit or memory device 122 may include one or more memory chips capable of storing data and allowing any storage location to be directly accessed by the microprocessor 121. Main memory unit or device 122 may be volatile and faster than storage 128 memory. Main memory units or devices 122 may be Dynamic random access memory (DRAM) or any variants, including static random access memory (SRAM), Burst SRAM or SynchBurst SRAM (BSRAM), Fast Page Mode DRAM (FPM DRAM), Enhanced DRAM (EDRAM), Extended Data Output RAM (EDO RAM), Extended Data Output DRAM (EDO DRAM), Burst Extended Data Output DRAM (BEDO DRAM), Single Data Rate Synchronous DRAM (SDR SDRAM), Double Data Rate SDRAM (DDR SDRAM), Direct Rambus DRAM (DRDRAM), or Extreme Data Rate DRAM (XDR DRAM). In some embodiments, the main memory 122 or the storage 128 may be nonvolatile; e.g., non-volatile read access memory (NVRAM), flash memory non-volatile static RAM (nvSRAM), Ferroelectric RAM (FeRAM), Magnetoresistive RAM (MRAM), Phase- change memory (PRAM), conductive-bridging RAM (CBRAM), Silicon-Oxide-Nitride- Oxide-Silicon (SONOS), Resistive RAM (RRAM), Racetrack, Nano-RAM (NRAM), or Millipede memory. The main memory 122 may be based on any of the above described memory chips, or any other available memory chips capable of operating as described herein. In the embodiment shown in FIG. 12C, the processor 121 communicates with main memory 122 via a system bus 150 (described in more detail below). FIG. 12D depicts an embodiment of a computing device 100 in which the processor communicates directly with main memory 122 via a memory port 103. For example, in FIG. 12D the main memory 122 may be DRDRAM.

[0205] FIG. 12D depicts an embodiment in which the main processor 121 communicates directly with cache memory 140 via a secondary bus, sometimes referred to as a backside bus. In other embodiments, the main processor 121 communicates with cache memory 140 using the system bus 150. Cache memory 140 typically has a faster response time than main memory 122 and is typically provided by SRAM, BSRAM, or EDRAM. In the embodiment shown in FIG. 12D, the processor 121 communicates with various I/O devices 130 via a local system bus 150. Various buses may be used to connect the central processing unit 121 to any of the VO devices 130, including a PCI bus, a PCI-X bus, or a PCI-Express bus, or a NuBus. For embodiments in which the VO device is a video display 124, the processor 121 may use an Advanced Graphics Port (AGP) to communicate with the display 124 or the VO controller 123 for the display 124. FIG. 12D depicts an embodiment of a computer 100 in which the main processor 121 communicates directly with VO device 130b or other processors 12 V via HYPERTRANSPORT, RAPID IO, or INFINIBAND communications technology. FIG. 12D also depicts an embodiment in which local busses and direct communication are mixed: the processor 121 communicates with VO device 130a using a local interconnect bus while communicating with VO device 130b directly.

[0206] A wide variety of VO devices 130a-130n may be present in the computing device 100. Input devices may include keyboards, mice, trackpads, trackballs, touchpads, touch mice, multi-touch touchpads and touch mice, microphones, multi -array microphones, drawing tablets, cameras, single-lens reflex camera (SLR), digital SLR (DSLR), CMOS sensors, accelerometers, infrared optical sensors, pressure sensors, magnetometer sensors, angular rate sensors, depth sensors, proximity sensors, ambient light sensors, gyroscopic sensors, or other sensors. Output devices may include video displays, graphical displays, speakers, headphones, inkjet printers, laser printers, and 3D printers.

[0207] Devices 130a- 13 On may include a combination of multiple input or output devices, including, e.g., Microsoft KINECT, Nintendo Wiimote for the WII, Nintendo WII U GAMEPAD, or Apple IPHONE. Some devices 130a- 13 On allow gesture recognition inputs through combining some of the inputs and outputs. Some devices 130a- 13 On provides for facial recognition which may be utilized as an input for different purposes including authentication and other commands. Some devices 130a-130n provides for voice recognition and inputs, including, e.g., Microsoft KINECT, SIRI for IPHONE by Apple, Google Now or Google Voice Search.

[0208] Additional devices 130a- 13 On have both input and output capabilities, including, e.g., haptic feedback devices, touchscreen displays, or multi-touch displays. Touchscreen, multi-touch displays, touchpads, touch mice, or other touch sensing devices may use different technologies to sense touch, including, e.g., capacitive, surface capacitive, projected capacitive touch (PCT), in-cell capacitive, resistive, infrared, waveguide, dispersive signal touch (DST), in-cell optical, surface acoustic wave (SAW), bending wave touch (BWT), or force-based sensing technologies. Some multi-touch devices may allow two or more contact points with the surface, allowing advanced functionality including, e.g., pinch, spread, rotate, scroll, or other gestures. Some touchscreen devices, including, e.g., Microsoft PIXELSENSE or Multi-Touch Collaboration Wall, may have larger surfaces, such as on a table-top or on a wall, and may also interact with other electronic devices. Some I/O devices 130a-130n, display devices 124a-124n or group of devices may be augment reality devices. The I/O devices may be controlled by an I/O controller 123 as shown in FIG. 12C. The I/O controller may control one or more I/O devices, such as, e.g., a keyboard 126 and a pointing device 127, e.g., a mouse or optical pen. Furthermore, an I/O device may also provide storage and/or an installation medium 116 for the computing device 100. In still other embodiments, the computing device 100 may provide USB connections (not shown) to receive handheld USB storage devices. In further embodiments, an I/O device 130 may be a bridge between the system bus 150 and an external communication bus, e.g. a USB bus, a SCSI bus, a FireWire bus, an Ethernet bus, a Gigabit Ethernet bus, a Fibre Channel bus, or a Thunderbolt bus. [0209] In some embodiments, display devices 124a-124n may be connected to I/O controller 123. Display devices may include, e.g., liquid crystal displays (LCD), thin film transistor LCD (TFT-LCD), blue phase LCD, electronic papers (e-ink) displays, flexile displays, light emitting diode displays (LED), digital light processing (DLP) displays, liquid crystal on silicon (LCOS) displays, organic light-emitting diode (OLED) displays, activematrix organic light-emitting diode (AMOLED) displays, liquid crystal laser displays, time- multiplexed optical shutter (TMOS) displays, or 3D displays. Examples of 3D displays may use, e.g. stereoscopy, polarization filters, active shutters, or autostereoscopy. Display devices 124a-124n may also be a head-mounted display (HMD). In some embodiments, display devices 124a-124n or the corresponding I/O controllers 123 may be controlled through or have hardware support for OPENGL or DIRECTX API or other graphics libraries.

[0210] In some embodiments, the computing device 100 may include or connect to multiple display devices 124a-124n, which each may be of the same or different type and/or form. As such, any of the I/O devices 130a-130n and/or the I/O controller 123 may include any type and/or form of suitable hardware, software, or combination of hardware and software to support, enable or provide for the connection and use of multiple display devices 124a-124n by the computing device 100. For example, the computing device 100 may include any type and/or form of video adapter, video card, driver, and/or library to interface, communicate, connect or otherwise use the display devices 124a-124n. In one embodiment, a video adapter may include multiple connectors to interface to multiple display devices 124a-124n. In other embodiments, the computing device 100 may include multiple video adapters, with each video adapter connected to one or more of the display devices 124a-124n. In some embodiments, any portion of the operating system of the computing device 100 may be configured for using multiple displays 124a-124n. In other embodiments, one or more of the display devices 124a-124n may be provided by one or more other computing devices 100a or 100b connected to the computing device 100, via the network 104. In some embodiments software may be designed and constructed to use another computer’s display device as a second display device 124a for the computing device 100. For example, in one embodiment, an Apple iPad may connect to a computing device 100 and use the display of the device 100 as an additional display screen that may be used as an extended desktop. One ordinarily skilled in the art will recognize and appreciate the various ways and embodiments that a computing device 100 may be configured to have multiple display devices 124a-124n.

[0211] Referring again to FIG. 12C, the computing device 100 may comprise a storage device 128 (e.g. one or more hard disk drives or redundant arrays of independent disks) for storing an operating system or other related software, and for storing application software programs such as any program related to the software for the genomic data processing system 120. Examples of storage device 128 include, e.g, hard disk drive (HDD); optical drive including CD drive, DVD drive, or BLU-RAY drive; solid-state drive (SSD); USB flash drive; or any other device suitable for storing data. Some storage devices may include multiple volatile and non-volatile memories, including, e.g, solid state hybrid drives that combine hard disks with solid state cache. Some storage device 128 may be non-volatile, mutable, or read-only. Some storage device 128 may be internal and connect to the computing device 100 via a bus 150. Some storage devices 128 may be external and connect to the computing device 100 via an I/O device 130 that provides an external bus. Some storage device 128 may connect to the computing device 100 via the network interface 118 over a network 104, including, e.g., the Remote Disk for MACBOOK AIR by Apple. Some client devices 100 may not require a non-volatile storage device 128 and may be thin clients or zero clients 102. Some storage device 128 may also be used as an installation device 116, and may be suitable for installing software and programs.

Additionally, the operating system and the software can be run from a bootable medium, for example, a bootable CD, e.g. KNOPPIX, a bootable CD for GNU/Linux that is available as a GNU/Linux distribution from knoppix.net.

[0212] Client device 100 may also install software or application from an application distribution platform. Examples of application distribution platforms include the App Store for iOS provided by Apple, Inc., the Mac App Store provided by Apple, Inc., GOOGLE PLAY for Android OS provided by Google Inc., Chrome Webstore for CHROME OS provided by Google Inc., and Amazon Appstore for Android OS and KINDLE FIRE provided by Amazon.com, Inc. An application distribution platform may facilitate installation of software on a client device 102. An application distribution platform may include a repository of applications on a server 106 or a cloud 108, which the clients 102a- 102n may access over a network 104. An application distribution platform may include application developed and provided by various developers. A user of a client device 102 may select, purchase and/or download an application via the application distribution platform.

[0213] Furthermore, the computing device 100 may include a network interface 118 to interface to the network 104 through a variety of connections including, but not limited to, standard telephone lines LAN or WAN links (e.g., 802.11, Tl, T3, Gigabit Ethernet, Infiniband), broadband connections (e.g., ISDN, Frame Relay, ATM, Gigabit Ethernet, Ethernet-over-SONET, ADSL, VDSL, BPON, GPON, fiber optical including FiOS), wireless connections, or some combination of any or all of the above. Connections can be established using a variety of communication protocols (e.g., TCP/IP, Ethernet, ARCNET, SONET, SDH, Fiber Distributed Data Interface (FDDI), IEEE 802.1 la/b/g/n/ac CDMA, GSM, WiMax and direct asynchronous connections). In one embodiment, the computing device 100 communicates with other computing devices 100’ via any type and/or form of gateway or tunneling protocol e.g. Secure Socket Layer (SSL) or Transport Layer Security (TLS), or the Citrix Gateway Protocol manufactured by Citrix Systems, Inc. of Ft. Lauderdale, Florida. The network interface 118 may comprise a built-in network adapter, network interface card, PCMCIA network card, EXPRESSCARD network card, card bus network adapter, wireless network adapter, USB network adapter, modem or any other device suitable for interfacing the computing device 100 to any type of network capable of communication and performing the operations described herein.

[0214] A computing device 100 of the sort depicted in FIGs. 12B and 12C may operate under the control of an operating system, which controls scheduling of tasks and access to system resources. The computing device 100 can be running any operating system such as any of the versions of the MICROSOFT WINDOWS operating systems, the different releases of the Unix and Linux operating systems, any version of the MAC OS for Macintosh computers, any embedded operating system, any real-time operating system, any open source operating system, any proprietary operating system, any operating systems for mobile computing devices, or any other operating system capable of running on the computing device and performing the operations described herein. Typical operating systems include, but are not limited to: WINDOWS 2000, WINDOWS Server 2022, WINDOWS CE, WINDOWS Phone, WINDOWS XP, WINDOWS VISTA, and WINDOWS 7, WINDOWS RT, WINDOWS 8, and WINDOWS 10, all of which are manufactured by Microsoft Corporation of Redmond, Washington; MAC OS and iOS, manufactured by Apple, Inc. of Cupertino, California; and Linux, a freely-available operating system, e.g. Linux Mint distribution (“distro”) or Ubuntu, distributed by Canonical Ltd. of London, United Kingdom; or Unix or other Unix-like derivative operating systems; and Android, designed by Google, of Mountain View, California, among others. Some operating systems, including, e.g., the CHROME OS by Google, may be used on zero clients or thin clients, including, e.g., CHROMEBOOKS.

[0215] The computer system 100 can be any workstation, telephone, desktop computer, laptop or notebook computer, netbook, ULTRABOOK, tablet, server, handheld computer, mobile telephone, smartphone or other portable telecommunications device, media playing device, a gaming system, mobile computing device, or any other type and/or form of computing, telecommunications or media device that is capable of communication. The computer system 100 has sufficient processor power and memory capacity to perform the operations described herein. The computer system 100 can be of any suitable size, such as a standard desktop computer or a Raspberry Pi 4 manufactured by Raspberry Pi Foundation, of Cambridge, United Kingdom. In some embodiments, the computing device 100 may have different processors, operating systems, and input devices consistent with the device. The Samsung GALAXY smartphones, e.g., operate under the control of Android operating system developed by Google, Inc. GALAXY smartphones receive input via a touch interface.

[0216] In some embodiments, the computing device 100 is a gaming system. For example, the computer system 100 may comprise a PLAYSTATION 3, or PERSONAL PLAYSTATION PORTABLE (PSP), or a PLAYSTATION VITA device manufactured by the Sony Corporation of Tokyo, Japan, a NINTENDO DS, NINTENDO 3DS, NINTENDO WII, or a NINTENDO WII U device manufactured by Nintendo Co., Ltd., of Kyoto, Japan, an XBOX 360 device manufactured by the Microsoft Corporation of Redmond, Washington.

[0217] In some embodiments, the computing device 100 is a digital audio player such as the Apple IPOD, IPOD Touch, and IPOD NANO lines of devices, manufactured by Apple Computer of Cupertino, California. Some digital audio players may have other functionality, including, e.g., a gaming system or any functionality made available by an application from a digital application distribution platform. For example, the IPOD Touch may access the Apple App Store. In some embodiments, the computing device 100 is a portable media player or digital audio player supporting file formats including, but not limited to, MP3, WAV, M4A/AAC, WMA Protected AAC, AIFF, Audible audiobook, Apple Lossless audio file formats and .mov, ,m4v, and .mp4 MPEG-4 (H.264/MPEG-4 AVC) video file formats.

[0218] In some embodiments, the computing device 100 is a tablet e.g. the IPAD line of devices by Apple; GALAXY TAB family of devices by Samsung; or KINDLE FIRE, by Amazon.com, Inc. of Seattle, Washington. In other embodiments, the computing device 100 is an eBook reader, e.g. the KINDLE family of devices by Amazon.com, or NOOK family of devices by Barnes & Noble, Inc. of New York City, New York.

[0219] In some embodiments, the communications device 102 includes a combination of devices, e.g. a smartphone combined with a digital audio player or portable media player. For example, one of these embodiments is a smartphone, e.g. the IPHONE family of smartphones manufactured by Apple, Inc.; a Samsung GALAXY family of smartphones manufactured by Samsung, Inc.; or a Motorola DROID family of smartphones. In yet another embodiment, the communications device 102 is a laptop or desktop computer equipped with a web browser and a microphone and speaker system, e.g. a telephony headset. In these embodiments, the communications devices 102 are web-enabled and can receive and initiate phone calls. In some embodiments, a laptop or desktop computer is also equipped with a webcam or other video capture device that enables video chat and video call.

[0220] In some embodiments, the status of one or more machines 102, 106 in the network 104 are monitored, generally as part of network management. In one of these embodiments, the status of a machine may include an identification of load information (e.g., the number of processes on the machine, CPU and memory utilization), of port information (e.g., the number of available communication ports and the port addresses), or of session status (e.g., the duration and type of processes, and whether a process is active or idle). In another of these embodiments, this information may be identified by a plurality of metrics, and the plurality of metrics can be applied at least in part towards decisions in load distribution, network traffic management, and network failure recovery as well as any aspects of operations of the present solution described herein. Aspects of the operating environments and components described above will become apparent in the context of the systems and methods disclosed herein. [0221] Referring to FIG. 13, in various embodiments, a system 2400 may include a computing device 2410 (or multiple computing devices, co-located or remote to each other), a sample processing system 2480, and an electronic health record (EHR) system 2490. In various embodiments, computing device 2410 (or components thereof) may be integrated with the sample processing system 2480 (or components thereof) and/or EHR system 2490 (or components thereof). In various embodiments, the sample processing system 2480 may include, may be, or may employ, in situ hybridization, PCR, Next-generation sequencing, Northern blotting, microarray, dot or slot blots, FISH, Western blotting, ELISA, colorimetric dye binding assays, complete blood count (CBC) panels, FACs, electrophoresis, chromatography, and/or mass spectroscopy on such biological sample as blood, plasma, serum, and/or tissue and/or Whole-body MRI and PET-CT scans of a subject. For example, in certain embodiments, the sample processing system 2490 may be or may include a Next-generation sequencer. In various embodiments, the EHR system 2490 may include, may be, or may employ, various computing devices that include health records of patients and study subjects (including devices of hospitals, clinics, healthcare practitioners, etc.), obtained from various sources, such as entries by healthcare practitioners, sample processing system 2480, university and hospital systems, government agency systems, etc.

[0222] In various embodiments, the computing device 2410 (or multiple computing devices) may be used to control, and receive signals acquired via, components of sample processing system 2480. The computing device 2410 may include one or more processors and one or more volatile and non-volatile memories for storing computing code and data that are captured, acquired, recorded, and/or generated. The computing device 2410 may include a control unit 2415 that in certain embodiments may be configured to exchange control signals with sample processing system 2480, allowing the computing device 2410 to be used to control, for example, processing of samples and/or scans and/or delivery of data generated and/or acquired through processing of samples and/or scans.

[0223] In various embodiments, computing device 2410 may include a data acquisition unit 2420 that may be configured to exchange control signals, or otherwise communicate, with sample processing system 2480 (or components thereof) and/or EHR system 2490, allowing the computing device 2410 to be used to control the capture of physiological data and/or signals via sensors of the sample processing system 2480, retrieve data or signals (e.g., from sample processing system 2480, EHR system 2490, and/or memory devices where data is stored), and direct transfer of data or signals (e.g., to sample processing system 2490 as feedback thereto, to EHR system 2490, to memory for storage, and/or to other systems or devices).

[0224] In various embodiment, a data analyzer 2425 may direct analysis of the data and signals, and output analysis results. Data analyzer 2425 may be used, for example, to transform raw data captured or obtained via sample processing system 2480 and/or EHR system 2490, and may employ pre-processing procedures involved in generating a training dataset. For example, in some implementations, data may be generated as a multidimensional array or vector with values representing, and to prevent the machine learning system from overemphasizing certain readings, values may be normalized to a predetermined range (e.g. 0-1, 0-100, or any other such range). The normalization may comprise linear rescaling, or may be a more complex function. In some implementations, dimension reduction may be performed to reduce large and sparse arrays or vectors. In some implementations, feature recognition may be performed to select a subset of features for further analysis, such as principal component analysis.

[0225] In various embodiments, a machine learning system 2430 may be used to implement various machine learning functionality discussed herein. Machine learning system 2430 may include a training engine 2435 configured to train predictive models using, for example, data obtained from or via data acquisition unit 2420 and/or processed data obtained from or via data analyzer 2425. The training engine 2435 may, for example, generate or obtain training datasets from or via data analyzer 2425 and may perform validation of datasets. The training engine 2435 may comprise a feature analyzer used to evaluate features by, for example, quantifying the impact of each feature on the developed model. Such a feature analyzer may, for example, uncover clinically important features that were globally predictive of the outcome, and may determine, for example, contributions of all features, or the top features (e.g., the top 2, top 5, top 10, top 15, top 20, top 25, top 30, etc.) on individual predictions. Features may be selected based on a threshold, such a percent contribution to predicting a medical condition, such as 0.5%, 1%, 2%, 5%, 10%, etc. A testing and application engine 2440 may be configured to test and apply models trained via training engine 2435 to, for example, study subject and/or patient data from data acquisition unit 2420 and/or data analyzer 2425. [0226] In various embodiments, a transceiver 2445 allows the computing device 2410 to exchange readings, control commands, and/or other data with sample processing system 2480 (or components thereof) and/or EHR system 2490 (or components thereof). The transceiver 2445 may additionally or alternatively include a network interface permitting the computing device 2410 to communicate with other remote devices and systems via, for example, a telecommunications network such as the internet. One or more user interfaces 2450 allow the computing device 2410 to receive user inputs (e.g., via a keyboard, touchscreen, microphone, camera, etc.) and provide outputs (e.g., via a touchscreen or other display screen, audio speakers, haptic devices, etc.). A display screen may be employed, for example, to provide real time or near real time waveforms or other readings or measurements obtained via sensors being used to capture physiological data from subjects and patients. The computing device 2410 may additionally include one or more databases 2455 (stored in, e.g., one or more computer-readable non-volatile memory devices) for storing, for example, data and analyses obtained from or via data acquisition unit 2420, data analyzer 2425, machine learning system 2430 (e.g., training engine 2435 and/or testing and application engine 2440), sample processing system 2480, and/or EHR system 2490. In some implementations, database 2455 (or portions thereof) may alternatively or additionally be part of another computing device that is co-located or remote and in communication with computing device 2410, sample processing system 2480 (or components thereof), and/or EHR system 2490.

[0227] In one aspect, the present disclosure provides a method of training a machine learning classifier for estimating risk of cancer-associated venous thromboembolism (VTE) in cancer patients comprising: (a) receiving data on a cohort of subjects, the subjects in the cohort having a plurality of cancer types; (b) generating a training dataset based on the received data, wherein the training dataset comprises a plurality of features for each subject in the cohort, wherein the plurality of features comprises (i) cell free DNA concentration, (ii) maximum ctDNA VAF, (iii) ctDNA alterations in at least one cancer associated gene, and (iv) cancer type; and (c) applying a machine learning method to the training dataset to develop the machine learning classifier for estimating risk of cancer-associated VTE in cancer patients, wherein applying the machine learning method comprises: applying a machine learning technique to the training dataset; performing hyperparameter optimization to identify one or more machine learning models with an accuracy that exceeds an accuracy threshold for the classifier; and determining an optimal operating-point threshold based on optimization of sensitivity and specificity of the receiver operating characteristic (ROC) curves for the training dataset; wherein the classifier is configured to receive the plurality of features for cancer patients and generate predictors for risk of cancer-associated VTE in cancer patients. The subjects in the cohort may be chemotherapy -naive or may have received systemic chemotherapy. Additionally or alternatively, in certain embodiments, the plurality of cancer types are selected from the group consisting of non-small cell lung cancer, breast cancer, pancreatic cancer, melanoma, retinoblastoma, prostate cancer, esophagogastric cancer, histiocytosis, germ cell tumor, endometrial cancer, small cell lung cancer, soft tissue sarcoma, Gastrointestinal Stromal Tumor, ovarian cancer, mature B-Cell neoplasms, small bowel cancer, renal cell carcinoma, thyroid cancer, ampullary cancer, appendiceal cancer, sellar tumor, uterine sarcoma, bone cancer, non-melanoma skin cancer, cervical cancer, mesothelioma, glioma, thymic tumor, gastrointestinal neuroendocrine tumor, salivary gland cancer, sex cord stromal tumor, anal cancer, mature T and NK neoplasms, peritoneal cancer, Head and neck cancer, choroid plexus tumor, leukemia, primary CNS melanocytic tumors, Myelodysplastic Syndromes, Peripheral Nervous System, mastocytosis, Wilms tumor, lymphatic cancer, vaginal cancer, Hodgkin lymphoma, adrenocortical carcinoma, brain tumors, embryonal tumors and Non-Hodgkin lymphoma.

[0228] The machine learning technique may model survival outcomes with competing risks. In some embodiments, the machine learning technique is a random forest technique, and the one or more machine learning models are random forest models. Additionally or alternatively, in certain embodiments, the machine learning classifier is an ensemble learning random forest classifier. Additionally or alternatively, in some embodiments, performing the hyperparameter optimization comprises performing an exhaustive grid search technique.

[0229] Additionally or alternatively, in some embodiments of the methods disclosed herein, the at least one cancer associated gene is selected from the group consisting of AKT1, ALK, APC, AR, ARAF, ARID1 A, ARID2, ATM, B2M, BCL2, BCOR, BRAF, BRCA1, BRCA2, CARD11, CBFB, CCND1, CDH1, CDK4, CDKN2A, CIC, CREBBP, CTCF, CTNNB1, DICER1, DIS3, DNMT3A, EGFR, EIF1AX, EP300, ERBB2, ERBB3, ERCC2, ESRI, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, FOXA1, FOXL2, FOXO1, FUBP1, GATA3, GNA11, GNAQ, GNAS, H3F3A, HIST1H3B, HRAS, IDH1, IDH2, IKZF1, INPPL1, JAK1, KDM6A, KEAP1, KIT, KNSTRN, KRAS, MAP2K1, MAPK1, MAX, MED12, MET, MLH1, MSH2, MSH3, MSH6, MTOR, MYC, MYCN, MYD88, MYODI, NF1, NFE2L2, NOTCH1, NRAS, NTRK1, NTRK2, NTRK3, NUP93, PAK7, PDGFRA, PIK3CA, PIK3CB, PIK3R1, PIK3R2, PMS2, POLE, PPP2R1A, PPP6C, PRKCI, PTCHI, PTEN, PTPN11, RAC1, RAFI, RBI, RET, RHOA, RIT1, ROS1, RRAS2, RXRA, SETD2, SF3B1, SMAD3, SMAD4, SMARCA4, SMARCB1, SOS1, SPOP, STAT3, STK11, STK19, TCF7L2, TGFBR1, TGFBR2, TP53, TP63, TSC1, TSC2, U2AF1, VHL, XPO1, and TERT.

[0230] Additionally or alternatively, in some embodiments of the methods disclosed herein, the plurality of features further comprises platelet count, hemoglobin levels, leukocyte counts, body mass index (BMI), administration of chemotherapy, age, time from cancer diagnosis, race, and metastatic sites of disease. In certain embodiments, the metastatic sites of disease comprise one or more of adrenal gland, bone, brain, liver, lung, lymph, and pleura.

[0231] In any of the preceding embodiments, the method further comprises applying the classifier to data on a cancer patient to generate a predictor, and determining whether the cancer patient is at risk for cancer-associated VTE based on the predictor and the operatingpoint threshold. In some embodiments, the predictor comprises a cumulative incidence function (CIF) for cancer-associated VTE.

[0232] In any of the foregoing embodiments, the method further comprises administering an effective amount of anticoagulant therapy to the cancer patient predicted to be at risk for cancer-associated VTE based on the predictor and the operating-point threshold. Examples of anticoagulant therapy include, but are not limited to, apixaban, betrixaban, dabigatran, edoxaban, fondaparinux, heparin, rivaroxaban, warfarin, Xa inhibitors, statins, and enoxaparin. Examples of statins include, but are not limited to atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0233] In some embodiments, the cancer patient is chemotherapy-naive or has received/is receiving systemic chemotherapy.

[0234] In one aspect, the present disclosure provides a method of estimating risk of cancer-associated venous thromboembolism (VTE) in a cancer patient using a machine learning classifier, the method comprising: receiving patient data corresponding to a plurality of features for the cancer patient; applying the machine learning classifier to the patient data to generate a predictor; and determining whether the cancer patient is at risk for cancer-associated VTE based on the predictor and an operating-point threshold, wherein the machine learning classifier is trained by: (a) receiving cohort data on a cohort of subjects, the subjects in the cohort having a plurality of cancer types; (b) generating a training dataset based on the received cohort data, wherein the training dataset comprises the plurality of features for each subject in the cohort, wherein the plurality of features comprises (i) cell free DNA concentration, (ii) maximum ctDNA VAF, (iii) ctDNA alterations in at least one cancer associated gene, and (iv) cancer type; and (c) applying a machine learning method to the training dataset to develop the machine learning classifier for estimating risk of cancer- associated VTE, wherein applying the machine learning method comprises: applying a machine learning technique to the training dataset; performing hyperparameter optimization to identify one or more machine learning models with an accuracy that exceeds an accuracy threshold for the machine learning classifier; and determining the optimal operating-point threshold based on optimization of sensitivity and specificity of the receiver operating characteristic (ROC) curves for the training dataset; wherein the machine learning classifier is configured to receive the plurality of features for cancer patients and generate predictors for risk of cancer-associated VTE in cancer patients. In some embodiments, the method further comprises administering an effective amount of anticoagulant therapy to the cancer patient predicted to be at risk for cancer-associated VTE based on the predictor and the operating-point threshold. Examples of anticoagulant therapy include, but are not limited to, apixaban, betrixaban, dabigatran, edoxaban, fondaparinux, heparin, rivaroxaban, warfarin, Xa inhibitors, statins, and enoxaparin. Examples of statins include, but are not limited to atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. Additionally or alternatively, in some embodiments, the predictor comprises a cumulative incidence function (CIF) for cancer-associated VTE. The subjects in the cohort may be chemotherapy-naive or may have received systemic chemotherapy. In any of the preceding embodiments of the methods disclosed herein, one or more of the plurality of features for the cancer patient are determined by assaying blood and/or sequencing tumor DNA.

[0235] Additionally or alternatively, in certain embodiments, the plurality of cancer types are selected from the group consisting of non-small cell lung cancer, breast cancer, pancreatic cancer, melanoma, retinoblastoma, prostate cancer, esophagogastric cancer, histiocytosis, germ cell tumor, endometrial cancer, small cell lung cancer, soft tissue sarcoma, Gastrointestinal Stromal Tumor, ovarian cancer, mature B-Cell neoplasms, small bowel cancer, renal cell carcinoma, thyroid cancer, ampullary cancer, appendiceal cancer, sellar tumor, uterine sarcoma, bone cancer, non-melanoma skin cancer, cervical cancer, mesothelioma, glioma, thymic tumor, gastrointestinal neuroendocrine tumor, salivary gland cancer, sex cord stromal tumor, anal cancer, mature T and NK neoplasms, peritoneal cancer, Head and neck cancer, choroid plexus tumor, leukemia, primary CNS melanocytic tumors, Myelodysplastic Syndromes, Peripheral Nervous System, mastocytosis, Wilms tumor, lymphatic cancer, vaginal cancer, Hodgkin lymphoma, adrenocortical carcinoma, brain tumors, embryonal tumors and Non-Hodgkin lymphoma.

[0236] The machine learning technique may model survival outcomes with competing risks. In some embodiments, the machine learning technique is a random forest technique, and the one or more machine learning models are random forest models. Additionally or alternatively, in certain embodiments, the machine learning classifier is an ensemble learning random forest classifier. Additionally or alternatively, in some embodiments, performing the hyperparameter optimization comprises performing an exhaustive grid search technique.

[0237] Additionally or alternatively, in some embodiments of the methods disclosed herein, the plurality of features further comprises platelet count, hemoglobin levels, leukocyte counts, body mass index (BMI), administration of chemotherapy, age, time from cancer diagnosis, race, and metastatic sites of disease.

[0238] Additionally or alternatively, in some embodiments of the methods disclosed herein, the at least one cancer associated gene is selected from the group consisting of AKT1, ALK, APC, AR, ARAF, ARID1 A, ARID2, ATM, B2M, BCL2, BCOR, BRAF, BRCA1, BRCA2, CARD11, CBFB, CCND1, CDH1, CDK4, CDKN2A, CIC, CREBBP, CTCF, CTNNB1, DICER1, DIS3, DNMT3A, EGFR, EIF1AX, EP300, ERBB2, ERBB3, ERCC2, ESRI, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, FOXA1, FOXL2, FOXO1, FUBP1, GATA3, GNA11, GNAQ, GNAS, H3F3A, HIST1H3B, HRAS, IDH1, IDH2, IKZF1, INPPL1, JAK1, KDM6A, KEAP1, KIT, KNSTRN, KRAS,

MAP2K1, MAPK1, MAX, MED12, MET, MLH1, MSH2, MSH3, MSH6, MTOR, MYC,

MYCN, MYD88, MYODI, NF1, NFE2L2, NOTCH1, NRAS, NTRK1, NTRK2, NTRK3, NUP93, PAK7, PDGFRA, PIK3CA, PIK3CB, PIK3R1, PIK3R2, PMS2, POLE, PPP2R1A, PPP6C, PRKCI, PTCHI, PTEN, PTPN11, RAC1, RAFI, RBI, RET, RHOA, RIT1, ROS1, RRAS2, RXRA, SETD2, SF3B1, SMAD3, SMAD4, SMARCA4, SMARCB1, S0S1, SPOP, STAT3, STK11, STK19, TCF7L2, TGFBR1, TGFBR2, TP53, TP63, TSC1, TSC2, U2AF1, VHL, XPO1, and TERT.

[0239] In some embodiments, the cancer patient is chemotherapy -naive or has received/is receiving systemic chemotherapy.

[0240] In any and all embodiments of the methods disclosed herein, one or more of the plurality of features for each subject in the cohort are determined by assaying blood and/or sequencing tumor DNA.

[0241] In any and all embodiments of the methods disclosed herein, the cancer- associated VTE is pulmonary embolism or lower extremity deep vein thrombosis (DVT), optionally wherein lower extremity DVT includes thrombi involving a common iliac vein, an external iliac vein, a common femoral vein, a superficial femoral vein, a deep femoral vein, a popliteal vein, a peroneal vein, an anterior tibial vein, a posterior tibial vein, or a deep calf vein.

[0242] In another aspect, the present disclosure provides a machine learning system for training a machine learning classifier for estimating risk of cancer-associated venous thromboembolism (VTE) in cancer patients, the system comprising a processor and a memory with instructions which, when executed by the processor, cause the processor to: (a) receive data on a cohort of subjects, the subjects in the cohort having a plurality of cancer types; (b) generate a training dataset based on the received data, wherein the training dataset comprises a plurality of features for each subject in the cohort, wherein the plurality of features comprises (i) cell free DNA concentration, (ii) maximum ctDNA VAF, (iii) ctDNA alterations in at least one cancer associated gene, and (iv) cancer type; and (c) apply a machine learning method to the training dataset to develop the machine learning classifier for estimating risk of cancer-associated VTE in cancer patients; wherein applying the machine learning method comprises: applying a machine learning technique to the training dataset; performing hyperparameter optimization to identify one or more machine learning models with an accuracy that exceeds an accuracy threshold for the machine learning classifier; and determining an optimal operating-point threshold based on optimization of sensitivity and specificity of the receiver operating characteristic (ROC) curves for the training dataset; wherein the machine learning classifier is configured to receive the plurality of features for cancer patients and generate predictors for risk of cancer-associated VTE in cancer patients. The subjects in the cohort may be chemotherapy-naive or may have received systemic chemotherapy.

[0243] The machine learning technique may model survival outcomes with competing risks. In some embodiments, the machine learning technique is a random forest technique, and the one or more machine learning models are random forest models. Additionally or alternatively, in certain embodiments, the machine learning classifier is an ensemble learning random forest classifier.

[0244] Additionally or alternatively, in some embodiments, performing the hyperparameter optimization comprises performing an exhaustive grid search technique.

[0245] Additionally or alternatively, in some embodiments of the systems disclosed herein, the at least one cancer associated gene is selected from the group consisting of AKT1, ALK, APC, AR, ARAF, ARID1 A, ARID2, ATM, B2M, BCL2, BCOR, BRAF, BRCA1, BRCA2, CARD11, CBFB, CCND1, CDH1, CDK4, CDKN2A, CIC, CREBBP, CTCF, CTNNB1, DICER1, DIS3, DNMT3A, EGFR, EIF1AX, EP300, ERBB2, ERBB3, ERCC2, ESRI, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, FOXA1, FOXL2, FOXO1, FUBP1, GATA3, GNA11, GNAQ, GNAS, H3F3A, HIST1H3B, HRAS, IDH1, IDH2, IKZF1, INPPL1, JAK1, KDM6A, KEAP1, KIT, KNSTRN, KRAS, MAP2K1, MAPK1, MAX, MED12, MET, MLH1, MSH2, MSH3, MSH6, MTOR, MYC, MYCN, MYD88, MYODI, NF1, NFE2L2, NOTCH1, NRAS, NTRK1, NTRK2, NTRK3, NUP93, PAK7, PDGFRA, PIK3CA, PIK3CB, PIK3R1, PIK3R2, PMS2, POLE, PPP2R1A, PPP6C, PRKCI, PTCHI, PTEN, PTPN11, RAC1, RAFI, RBI, RET, RHOA, RIT1, ROS1, RRAS2, RXRA, SETD2, SF3B1, SMAD3, SMAD4, SMARCA4, SMARCB1, S0S1, SPOP, STAT3, STK11, STK19, TCF7L2, TGFBR1, TGFBR2, TP53, TP63, TSC1, TSC2, U2AF1, VHL, XPO1, and TERT.

[0246] Additionally or alternatively, in some embodiments of the systems disclosed herein, the plurality of features further comprises platelet count, hemoglobin levels, leukocyte counts, body mass index (BMI), administration of chemotherapy, age, time from cancer diagnosis, race, and metastatic sites of disease. Metastatic sites of disease may comprise one or more of adrenal gland, bone, brain, liver, lung, lymph, and pleura.

[0247] Additionally or alternatively, in certain embodiments of the systems disclosed herein, the plurality of cancer types are selected from the group consisting of non-small cell lung cancer, breast cancer, pancreatic cancer, melanoma, retinoblastoma, prostate cancer, esophagogastric cancer, histiocytosis, germ cell tumor, endometrial cancer, small cell lung cancer, soft tissue sarcoma, Gastrointestinal Stromal Tumor, ovarian cancer, mature B-Cell neoplasms, small bowel cancer, renal cell carcinoma, thyroid cancer, ampullary cancer, appendiceal cancer, sellar tumor, uterine sarcoma, bone cancer, non-melanoma skin cancer, cervical cancer, mesothelioma, glioma, thymic tumor, gastrointestinal neuroendocrine tumor, salivary gland cancer, sex cord stromal tumor, anal cancer, mature T and NK neoplasms, peritoneal cancer, Head and neck cancer, choroid plexus tumor, leukemia, primary CNS melanocytic tumors, Myelodysplastic Syndromes, Peripheral Nervous System, mastocytosis, Wilms tumor, lymphatic cancer, vaginal cancer, Hodgkin lymphoma, adrenocortical carcinoma, brain tumors, embryonal tumors and Non-Hodgkin lymphoma.

[0248] In any of the preceding embodiments of the systems described herein, the instructions further cause the processor to apply the machine learning classifier to data on a cancer patient to generate a predictor, and determine whether the cancer patient is at risk for cancer-associated VTE based on the predictor and the operating-point threshold. In some embodiments, the predictor comprises a cumulative incidence function (CIF) for cancer- associated VTE.

[0249] In any of the foregoing embodiments of the systems described herein, the instructions further cause the processor to recommend an anticoagulant therapy to the cancer patient predicted to be at risk for cancer-associated VTE based on the predictor and the operating-point threshold. Examples of anticoagulant therapy include, but are not limited to, apixaban, betrixaban, dabigatran, edoxaban, fondaparinux, heparin, rivaroxaban, warfarin, Xa inhibitors, statins, and enoxaparin. Examples of statins include, but are not limited to atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0250] In some embodiments, the cancer patient is chemotherapy -naive or has received/is receiving systemic chemotherapy. [0251] In yet another aspect, the present disclosure provides a computing system for estimating risk of cancer-associated venous thromboembolism (VTE) in a cancer patient, the computing system comprising a processor and a memory with instructions which, when executed by the processor, cause the processor to: receive patient data corresponding to a plurality of features for the cancer patient; apply a machine learning classifier to the patient data to generate a predictor; and determine whether the cancer patient is at risk for cancer- associated VTE based on the predictor and an operating-point threshold, wherein the classifier is trained by: (a) receiving cohort data on a cohort of subjects, the subjects in the cohort having a plurality of cancer types; (b) generating a training dataset based on the received cohort data, wherein the training dataset comprises the plurality of features for each subject in the cohort, wherein the plurality of features comprises (i) cell free DNA concentration, (ii) maximum ctDNA VAF, (iii) ctDNA alterations in at least one cancer associated gene, and (iv) cancer type; and (c) applying a machine learning method to the training dataset to develop the machine learning classifier for estimating risk of cancer- associated VTE, wherein applying the machine learning method comprises: applying a machine learning technique to the training dataset; performing hyperparameter optimization to identify one or more machine learning models with an accuracy that exceeds an accuracy threshold for the machine learning classifier; and determining the optimal operating-point threshold based on optimization of sensitivity and specificity of the receiver operating characteristic (ROC) curves for the training dataset; wherein the machine learning classifier is configured to receive the plurality of features for cancer patients and generate predictors for risk of cancer-associated VTE in cancer patients.

[0252] The machine learning technique may model survival outcomes with competing risks. In some embodiments, the machine learning technique is a random forest technique, and the one or more machine learning models are random forest models. Additionally or alternatively, in certain embodiments, the machine learning classifier is an ensemble learning random forest classifier.

[0253] Additionally or alternatively, in some embodiments, performing the hyperparameter optimization comprises performing an exhaustive grid search technique.

[0254] Additionally or alternatively, in some embodiments of the systems disclosed herein, the plurality of features further comprises platelet count, hemoglobin levels, leukocyte counts, body mass index (BMI), administration of chemotherapy, age, time from cancer diagnosis, race, and metastatic sites of disease.

[0255] In certain embodiments, the at least one cancer associated gene is selected from the group consisting of AKT1, ALK, APC, AR, ARAF, ARID1A, ARID2, ATM, B2M, BCL2, BCOR, BRAF, BRCA1, BRCA2, CARD11, CBFB, CCND1, CDH1, CDK4, CDKN2A, CIC, CREBBP, CTCF, CTNNB1, DICER1, DIS3, DNMT3A, EGFR, EIF1AX, EP300, ERBB2, ERBB3, ERCC2, ESRI, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, FOXA1, FOXL2, FOXO1, FUBP1, GATA3, GNA11, GNAQ, GNAS, H3F3A, HIST1H3B, HRAS, IDH1, IDH2, IKZF1, INPPL1, JAK1, KDM6A, KEAP1, KIT, KNSTRN, KRAS, MAP2K1, MAPK1, MAX, MED12, MET, MLH1, MSH2, MSH3, MSH6, MTOR, MYC, MYCN, MYD88, MYODI, NF1, NFE2L2, NOTCH1, NRAS, NTRK1, NTRK2, NTRK3, NUP93, PAK7, PDGFRA, PIK3CA, PIK3CB, PIK3R1, PIK3R2, PMS2, POLE, PPP2R1 A, PPP6C, PRKCI, PTCHI, PTEN, PTPN11, RAC1, RAFI, RBI, RET, RHOA, RIT1, ROS1, RRAS2, RXRA, SETD2, SF3B1, SMAD3, SMAD4, SMARCA4, SMARCB1, S0S1, SPOP, STAT3, STK11, STK19, TCF7L2, TGFBR1, TGFBR2, TP53, TP63, TSC1, TSC2, U2AF1, VHL, XPO1, and TERT

[0256] In any of the preceding embodiments of the systems described herein, the instructions further cause the processor to recommend an anticoagulant therapy to the cancer patient predicted to be at risk for cancer-associated VTE based on the predictor and the operating-point threshold. In some embodiments, the predictor comprises a cumulative incidence function (CIF) for cancer-associated VTE. Examples of anticoagulant therapy include, but are not limited to, apixaban, betrixaban, dabigatran, edoxaban, fondaparinux, heparin, rivaroxaban, warfarin, Xa inhibitors, statins, and enoxaparin. Examples of statins include, but are not limited to atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0257] Additionally or alternatively, in certain embodiments of the systems disclosed herein, the plurality of cancer types are selected from the group consisting of non-small cell lung cancer, breast cancer, pancreatic cancer, melanoma, retinoblastoma, prostate cancer, esophagogastric cancer, histiocytosis, germ cell tumor, endometrial cancer, small cell lung cancer, soft tissue sarcoma, Gastrointestinal Stromal Tumor, ovarian cancer, mature B-Cell neoplasms, small bowel cancer, renal cell carcinoma, thyroid cancer, ampullary cancer, appendiceal cancer, sellar tumor, uterine sarcoma, bone cancer, non-melanoma skin cancer, cervical cancer, mesothelioma, glioma, thymic tumor, gastrointestinal neuroendocrine tumor, salivary gland cancer, sex cord stromal tumor, anal cancer, mature T and NK neoplasms, peritoneal cancer, Head and neck cancer, choroid plexus tumor, leukemia, primary CNS melanocytic tumors, Myelodysplastic Syndromes, Peripheral Nervous System, mastocytosis, Wilms tumor, lymphatic cancer, vaginal cancer, Hodgkin lymphoma, adrenocortical carcinoma, brain tumors, embryonal tumors and Non-Hodgkin lymphoma.

[0258] In some embodiments, the cancer patient is chemotherapy -naive or has received/is receiving systemic chemotherapy.

[0259] In any and all embodiments of the systems disclosed herein, one or more of the plurality of features for each subject in the cohort are determined by assaying blood and/or sequencing tumor DNA.

[0260] In one aspect, the present disclosure provides a non-transitory computer-readable storage medium comprising instructions which, when executed by a processor of a machine learning system, configure the machine learning system to train a machine learning classifier to estimate risk of cancer-associated venous thromboembolism (VTE) in cancer patients, wherein the instructions are configured to cause the processor to: (a) receive data on a cohort of subjects, the subjects in the cohort having a plurality of cancer types; (b) generate a training dataset based on the received data, wherein the training dataset comprises a plurality of features for each subject in the cohort, the plurality of features comprising (i) cell free DNA concentration, (ii) maximum ctDNA VAF, (iii) ctDNA alterations in at least one cancer associated gene, and (iv) cancer type; and (c) apply a machine learning method to the training dataset to develop the machine learning classifier for estimating risk of cancer-associated VTE in cancer patients; wherein applying the machine learning method comprises: applying a machine learning technique to the training dataset; performing hyperparameter optimization to identify one or more machine learning models with an accuracy that exceeds an accuracy threshold for the machine learning classifier; and determining an optimal operating-point threshold based on optimization of sensitivity and specificity of the receiver operating characteristic (ROC) curves for the training dataset; wherein the machine learning classifier is configured to receive the plurality of features for cancer patients and generate predictors for risk of cancer-associated VTE in cancer patients. The subjects in the cohort may be chemotherapy-naive or may have received systemic chemotherapy. [0261] The machine learning technique may model survival outcomes with competing risks. In some embodiments, the machine learning technique is a random forest technique, and the one or more machine learning models are random forest models. Additionally or alternatively, in certain embodiments, the machine learning classifier is an ensemble learning random forest classifier.

[0262] Additionally or alternatively, in some embodiments, performing the hyperparameter optimization comprises performing an exhaustive grid search technique.

[0263] Additionally or alternatively, in some embodiments of the computer-readable storage medium disclosed herein, the at least one cancer associated gene is selected from the group consisting of AKT1, ALK, APC, AR, ARAF, ARID1A, ARID2, ATM, B2M, BCL2, BCOR, BRAF, BRCA1, BRCA2, CARD11, CBFB, CCND1, CDH1, CDK4, CDKN2A, CIC, CREBBP, CTCF, CTNNB1, DICER1, DIS3, DNMT3A, EGFR, EIF1AX, EP300, ERBB2, ERBB3, ERCC2, ESRI, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, FOXA1, FOXL2, FOXO1, FUBP1, GATA3, GNA11, GNAQ, GNAS, H3F3A, HIST1H3B, HRAS, IDH1, IDH2, IKZF1, INPPL1, JAK1, KDM6A, KEAP1, KIT, KNSTRN, KRAS, MAP2K1, MAPK1, MAX, MED12, MET, MLH1, MSH2, MSH3, MSH6, MTOR, MYC, MYCN, MYD88, MYODI, NF1, NFE2L2, NOTCH1, NRAS, NTRK1, NTRK2, NTRK3, NUP93, PAK7, PDGFRA, PIK3CA, PIK3CB, PIK3R1, PIK3R2, PMS2, POLE, PPP2R1 A, PPP6C, PRKCI, PTCHI, PTEN, PTPN11, RAC1, RAFI, RBI, RET, RHOA, RIT1, ROS1, RRAS2, RXRA, SETD2, SF3B1, SMAD3, SMAD4, SMARCA4, SMARCB1, S0S1, SPOP, STAT3, STK11, STK19, TCF7L2, TGFBR1, TGFBR2, TP53, TP63, TSC1, TSC2, U2AF1, VHL, XPO1, and TERT.

[0264] Additionally or alternatively, in some embodiments of the computer-readable storage medium disclosed herein, the plurality of features further comprises platelet count, hemoglobin levels, leukocyte counts, body mass index (BMI), administration of chemotherapy, age, time from cancer diagnosis, race, and metastatic sites of disease. Metastatic sites of disease may comprise one or more of adrenal gland, bone, brain, liver, lung, lymph, and pleura.

[0265] In any of the preceding embodiments of the computer-readable storage medium described herein, the instructions further cause the processor to apply the machine learning classifier to data on a cancer patient to generate a predictor, and determine whether the cancer patient is at risk for cancer-associated VTE based on the predictor and the operatingpoint threshold. In some embodiments, the predictor comprises a cumulative incidence function (CIF) for cancer-associated VTE.

[0266] Additionally or alternatively, in certain embodiments of the computer-readable storage medium disclosed herein, the plurality of cancer types are selected from the group consisting of non-small cell lung cancer, breast cancer, pancreatic cancer, melanoma, retinoblastoma, prostate cancer, esophagogastric cancer, histiocytosis, germ cell tumor, endometrial cancer, small cell lung cancer, soft tissue sarcoma, Gastrointestinal Stromal Tumor, ovarian cancer, mature B-Cell neoplasms, small bowel cancer, renal cell carcinoma, thyroid cancer, ampullary cancer, appendiceal cancer, sellar tumor, uterine sarcoma, bone cancer, non-melanoma skin cancer, cervical cancer, mesothelioma, glioma, thymic tumor, gastrointestinal neuroendocrine tumor, salivary gland cancer, sex cord stromal tumor, anal cancer, mature T and NK neoplasms, peritoneal cancer, Head and neck cancer, choroid plexus tumor, leukemia, primary CNS melanocytic tumors, Myelodysplastic Syndromes, Peripheral Nervous System, mastocytosis, Wilms tumor, lymphatic cancer, vaginal cancer, Hodgkin lymphoma, adrenocortical carcinoma, brain tumors, embryonal tumors and NonHodgkin lymphoma.

[0267] In any of the preceding embodiments of the computer-readable storage medium described herein, the instructions further cause the processor to recommend an anticoagulant therapy to the cancer patient predicted to be at risk for cancer-associated VTE based on the predictor and the operating-point threshold. Examples of anticoagulant therapy include, but are not limited to, apixaban, betrixaban, dabigatran, edoxaban, fondaparinux, heparin, rivaroxaban, warfarin, Xa inhibitors, statins, and enoxaparin. Examples of statins include, but are not limited to atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0268] In some embodiments, the cancer patient is chemotherapy -naive or has received/is receiving systemic chemotherapy.

[0269] In another aspect, the present disclosure provides a non-transitory computer- readable storage medium comprising instructions which, when executed by a processor of a computing system, configure the computing system to estimate risk of cancer-associated venous thromboembolism (VTE) in a cancer patient, wherein the instructions are configured to cause the processor to: receive patient data corresponding to a plurality of features for the cancer patient; apply a machine learning classifier to the patient data to generate a predictor; and determine whether the cancer patient is at risk for cancer-associated VTE based on the predictor and an operating-point threshold, wherein the classifier is trained by: (a) receiving cohort data on a cohort of subjects, the subjects in the cohort having a plurality of cancer types; (b) generating a training dataset based on the received cohort data, wherein the training dataset comprises the plurality of features for each subject in the cohort, wherein the plurality of features comprises (i) cell free DNA concentration, (ii) maximum ctDNA VAF, (iii) ctDNA alterations in at least one cancer associated gene, and (iv) cancer type; and (c) applying a machine learning method to the training dataset to develop the machine learning classifier for estimating risk of cancer-associated VTE, wherein applying the machine learning method comprises: applying a machine learning technique to the training dataset; performing hyperparameter optimization to identify one or more machine learning models with an accuracy that exceeds an accuracy threshold for the machine learning classifier; and determining the optimal operating-point threshold based on optimization of sensitivity and specificity of the receiver operating characteristic (ROC) curves for the training dataset; wherein the machine learning classifier is configured to receive the plurality of features for cancer patients and generate predictors for risk of cancer-associated VTE in cancer patients.

[0270] The machine learning technique may model survival outcomes with competing risks. In some embodiments, the machine learning technique is a random forest technique, and the one or more machine learning models are random forest models. Additionally or alternatively, in certain embodiments, the machine learning classifier is an ensemble learning random forest classifier.

[0271] Additionally or alternatively, in some embodiments, performing the hyperparameter optimization comprises performing an exhaustive grid search technique.

[0272] Additionally or alternatively, in some embodiments of the computer-readable storage medium disclosed herein, the at least one cancer associated gene is selected from the group consisting of AKT1, ALK, APC, AR, ARAF, ARID1A, ARID2, ATM, B2M, BCL2, BCOR, BRAF, BRCA1, BRCA2, CARD11, CBFB, CCND1, CDH1, CDK4, CDKN2A, CIC, CREBBP, CTCF, CTNNB1, DICER1, DIS3, DNMT3A, EGFR, EIF1AX, EP300, ERBB2, ERBB3, ERCC2, ESRI, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, F0XA1, FOXL2, FOXO1, FUBP1, GATA3, GNA11, GNAQ, GNAS, H3F3A, HIST1H3B, HRAS, IDH1, IDH2, IKZF1, INPPL1, JAK1, KDM6A, KEAP1, KIT, KNSTRN, KRAS, MAP2K1, MAPK1, MAX, MED12, MET, MLH1, MSH2, MSH3, MSH6, MTOR, MYC, MYCN, MYD88, MYODI, NF1, NFE2L2, NOTCH1, NRAS, NTRK1, NTRK2, NTRK3, NUP93, PAK7, PDGFRA, PIK3CA, PIK3CB, PIK3R1, PIK3R2, PMS2, POLE, PPP2R1 A, PPP6C, PRKCI, PTCHI, PTEN, PTPN11, RAC1, RAFI, RBI, RET, RHOA, RIT1, ROS1, RRAS2, RXRA, SETD2, SF3B1, SMAD3, SMAD4, SMARCA4, SMARCB1, SOS1, SPOP, STAT3, STK11, STK19, TCF7L2, TGFBR1, TGFBR2, TP53, TP63, TSC1, TSC2, U2AF1, VHL, XPO1, and TERT.

[0273] Additionally or alternatively, in some embodiments of the computer-readable storage medium disclosed herein, the plurality of features further comprises platelet count, hemoglobin levels, leukocyte counts, body mass index (BMI), administration of chemotherapy, age, time from cancer diagnosis, race, and metastatic sites of disease.

[0274] In any of the preceding embodiments of the computer-readable storage medium described herein, the instructions further cause the processor to recommend an anticoagulant therapy to the cancer patient predicted to be at risk for cancer-associated VTE based on the predictor and the operating-point threshold. In some embodiments, the predictor comprises a cumulative incidence function (CIF) for cancer-associated VTE. Examples of anticoagulant therapy include, but are not limited to, apixaban, betrixaban, dabigatran, edoxaban, fondaparinux, heparin, rivaroxaban, warfarin, Xa inhibitors, statins, and enoxaparin. Examples of statins include, but are not limited to atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0275] Additionally or alternatively, in certain embodiments of the computer-readable storage medium disclosed herein, the plurality of cancer types are selected from the group consisting of non-small cell lung cancer, breast cancer, pancreatic cancer, melanoma, retinoblastoma, prostate cancer, esophagogastric cancer, histiocytosis, germ cell tumor, endometrial cancer, small cell lung cancer, soft tissue sarcoma, Gastrointestinal Stromal Tumor, ovarian cancer, mature B-Cell neoplasms, small bowel cancer, renal cell carcinoma, thyroid cancer, ampullary cancer, appendiceal cancer, sellar tumor, uterine sarcoma, bone cancer, non-melanoma skin cancer, cervical cancer, mesothelioma, glioma, thymic tumor, gastrointestinal neuroendocrine tumor, salivary gland cancer, sex cord stromal tumor, anal cancer, mature T and NK neoplasms, peritoneal cancer, Head and neck cancer, choroid plexus tumor, leukemia, primary CNS melanocytic tumors, Myelodysplastic Syndromes, Peripheral Nervous System, mastocytosis, Wilms tumor, lymphatic cancer, vaginal cancer, Hodgkin lymphoma, adrenocortical carcinoma, brain tumors, embryonal tumors and NonHodgkin lymphoma.

[0276] In some embodiments, the cancer patient is chemotherapy -naive or has received/is receiving systemic chemotherapy.

[0277] In any of the preceding embodiments of the computer-readable storage medium disclosed herein, one or more of the plurality of features for the cancer patient are determined by assaying blood and/or sequencing tumor DNA.

EXAMPLES

[0278] The present technology is further illustrated by the following Examples, which should not be construed as limiting in any way.

Example 1: Materials and Experimental Methods

[0279] Patients. Adults with stage IV or recurrent NSCLC and either no known driver mutation pre-enrollment or progression of disease following targeted therapy were eligible for ctDNA sequencing at the provider’s discretion. Patients also required clinical annotation based on previous cohort requirements (Mantha et al Blood 2021).

[0280] ctDNA Sequencing. Blood samples were sent for plasma sequencing by the ctDx Lung Assay (Resolution Bioscience, Agilent Technologies), a hybrid capture nextgeneration sequencing assay with a variant allele fraction (VAF) detection limit of 0.1%- 0.5%. Detection of any copy number alteration or mutation that passed a standard germline filtering protocol (Jee et al ASCO 2021) resulted in a label of ctDNA being detected in that plasma sample. Genes/alterations included in the panel are the following:

[0281] Clinical annotation. CAT events were abstracted from the clinical chart using a previously validated process (Mantha et al, Blood 137(15):2103-2113 (2021)). Khorana score parameters were obtained from pre-chemotherapy laboratory and BMI values as previously described (Khorana et al., Blood 111(10):4902-7 (2008)).

[0282] Statistical analysis. Time-to-event analyses were performed from time of ctDNA blood draw to time of CAT event or last follow-up (right censorship). Risk of CAT between cohorts were compared using Cox proportional hazards models.

[0283] Machine learning model details. We implemented random survival forest (RSF; Ishwaran et al The Annals of Applied Statistics 2008) models to predict time to CAT. Models were implemented in python using the sksurv library. We implemented two versions of the RSF model. In the first, input variables included cancer type (i.e. the cancer types in Fig. 11 as one-hot encoded variables) as well as liquid biopsy-related parameters (i.e. logwcfDNA concentration and max VAF as continuous variables, and presence or absence of any of the listed MSK -ACCESS genes as one-hot encoded variables). In the second, the aforementioned variables were included as well as Khorana score components (platelet count, hemoglobin level, leukocyte count, BMI, and receipt of chemotherapy), demographics (age and time since diagnosis as a continuous variable as well as White, Black, Asian, or Other race as one-hot encoded variables), and metastatic sites of disease (adrenal, bone, brain, liver, lung, lymph, pleura, and other as one-hot encoded variables).

I l l Models were trained and validated using 5-fold cross validation. The primary metric of success was the c-index. The first model achieved a c-index of 0.73 (95%CI 0.70-0.76) and the second achieved a c-index of 0.75 (0.72-0.78). These models outperformed those based on Khorana score, metastatic sites, or demographics alone including within cancer subtypes (FIG. 8B, "Liquid Biopsy" = model 1, "All" = model 2) and successfully risk-stratified patients CAT (FIG 8D).

Example 2: ctDNA Biomarker Accurately Predicts Cancer-associated Thromboembolism in Lung Cancer Patients

[0284] A total of 480 patients were analyzed. Of these 480 patients, 157 had no detectable ctDNA (i.e. no ctDNA alterations). Among patients with detectable ctDNA, most patients had only one ctDNA alteration (FIG. 1).

[0285] FIG. 2 demonstrates that patients with ctDNA alterations had higher risk of CAT than those without (HR 2.9, 95%CI 1.8-4.9). In subgroup analyses in which only alterations in specific, individual genes are considered (with at least 8 patients with ctDNA mutations in that gene), trends toward higher CAT rates were observed for all genes considered relative to the ctDNA(-) group, supporting the notion that a diverse gene panel increases the sensitivity of the assay for patients at risk for CAT. See FIG. 3.

[0286] As shown in FIG. 4, there was a trend toward higher rates of CAT with higher ctDNA VAF, although any above the limit of detection (LOD) with this assay resulted in higher rates of CAT than the ctDNA(-) group.

[0287] Surprisingly, ctDNA levels did not correlate with Khorana Score (R=0.18, p<0.001) or its individual components. See FIG. 5. Moreover, ctDNA predicts CAT risk in a manner that is orthogonal to the Khorana Score (FIG. 6). These results demonstrate a means for risk-stratifying patients for CAT based on the results of ctDNA panel sequencing using a prespecified gene panel and a LOD of 0. l%-0.5%.

Example 3: ctDNA Biomarker Accurately Predicts Cancer-associated Thromboembolism in Additional Cancer Types

[0288] Patients and Methods

[0289] A single-center, pan-cancer observational study including patients who underwent ctDNA sequencing with MSK-ACCESS, a NY State-approved, 129-gene assay (N=4,659, breakdown by cancer type included in FIG. 11) was conducted. It was hypothesized that ctDNA detection would be associated with higher rates of CAT while controlling for cancer type and genomic content. It was further hypothesized that the inclusion of data from ctDNA sequencing assays in multivariable machine learning models including cell-free (cf)DNA concentrations, Khorana score components, and other features would improve CAT prediction. The ability of ctDNA as a predictive biomarker for prophylactic anti coagulation using nonrandomized, real-world evidence was assessed.

[0290] Results

[0291] ctDNA detection was associated with CAT (HR 2.88, 95%CI 2.32-3.58) in a dose-dependent manner (FIGs. 7A-7B). This association was observed across multiple cancer types and regardless of detected gene alterations (FIGs. 7C-7D). ctDNA and cfDNA concentration were predictive of CAT independent of each other and other CAT- related variables including Khorana score and number of organ sites of metastasis (FIGs. 8A-8B) Patients receiving pre-existing anticoagulant agents had lower rates of CAT if ctDNA was detected (HR 0.60 95%CI 0.38-0.92) but not if ctDNA was undetected (FIGs. 9A-9B) Patients receiving pre-existing statins also had lower rates of CAT if ctDNA was detected but not if ctDNA was undetected (FIGs. 10A-10B).

[0292] Random survival forests (python, sksurv) from time of plasma draw (for ctDNA) to CAT or last follow-up were 5-fold trained and cross validated across all patients with MSK-ACCESS (N=4,659). The probability of CAT at 6 months was computed for all patients in the respective validation sets. Patients in the validation set who either had CAT within 6 months of plasma draw or were confirmed CAT-free for at least 6 months were used as labels to generate the receiver operating curve (shown in FIG. 12) and to compute the area under the curve (AUC) as well as sensitivity and specificity for optimal cut points.

[0293] The sensitivity/specificity metrics for the three models Khorana Score, Liquid biopsy and combined are shown below:

[0294] Khorana Score (Sensitivity : 0.658, Specificity : 0.585)

[0295] Liquid Biopsy (Sensitivity : 0.698, Specificity : 0.697)

[0296] All (Sensitivity : 0.705, Specificity : 0.703)

[0297] The AUCs of the three models are reported in FIG. 14. [0298] Conclusion

[0299] ctDNA is an independent prognostic biomarker for CAT and may help identify patients who may benefit from prophylactic anticoagulation in a pan-cancer setting.

EQUIVALENTS

[0300] The present technology is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the present technology. It is to be understood that this present technology is not limited to particular methods, reagents, compounds compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0301] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0302] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a nonlimiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 cells refers to groups having 1, 2, or 3 cells. Similarly, a group having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so forth.

[0303] All patents, patent applications, provisional applications, and publications referred to or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification.