PREDICTIVE BIOMARKER IN AVASTIN IN COLON CANCER

This application claims the benefit of US Provisional Application No. 63/395,801, filed on August 6, 2022, which is incorporated herein by reference in its entirety.

I. BACKGROUND

1. Colorectal cancer (CRC) accounts for 8% (n=149,500) of all new cancer cases and is the second most common cause of cancer-related death (9%; n=52,980) in the United States. Unfortunately, 22% of patients diagnosed with colon cancer have metastatic CRC (mCRC) with poor clinical outcome of a 15% 5-year survival rate, highlighting significant need of effective treatment strategy to improve prognosis. Systemic chemotherapy is the primary treatment for mCRC. The first-line conventional chemotherapy for mCRC includes fluoropyrimidine monotherapy (e.g., fluorouracil and capecitabine) and combination with a fluoropyrimidine (e.g., FOLFOX (intravenous fluorouracil, leucovorin, and oxaliplatin) and FOLFIRI (fluorouracil, leucovorin and irinotecan)). The resulting median OS ranges 17-23 months. Meanwhile, targeted therapy has been considered as an add-in option with conventional chemotherapy for first-line treatment of mCRC. One extensively characterized agent is Bevacizumab (AVASTIN®), a monoclonal antibody targeting the vascular endothelial growth factor (VEGF). Various clinical trials demonstrated its efficacy in improving progression-free survival (PFS), but not in OS with a modest response rate of 10-15%. What is needed are new ways to more effectively predict AVASTIN® treatment effect.

II. SUMMARY

2. Disclosed are methods and kits related to the detection of subjects who should and should not receive administration of bevacizumab (AVASTIN®) for the treatment of cancer.

3. In one aspect, disclosed herein are kits used for of the treatment of a cancer (such as, for example colorectal cancer, including, but not limited to metastatic colorectal cancers (mCRC) such as, for example, stage 4 mCRC) comprising one or more probe sets comprising merck2_AA101946_x_at, merck2_AA490328_at, merck2_AF129457_at, merck2_AF289590_at, merck2_AI091276_at, merck2_AI223270_at, merck2_AI962276_at, merck2 AK092910 at, merck2 AK093149 at, merck2 AK131291 at, merck2 AL359561 at, merck2_AL832223_at, merck2_AL834299_at, merck2_AL834442_at, merck2_AM392650_at, merck2_AW007481_at, merck2_AX721105_at, merck2_BC001038_at, merck2_BC033091_at, merck2_BC035840_at, merck2_BC039861_at, merck2_BE249972_x_at, merck2_BE349054_x_at, merck2_BF248252_at, merck2_BF591243_at, merck2_BF692777_at, merck2_BG896934_at, merck2_BI047264_at, merck2_BM545067_s_at, merck2_BM681401_at, merck2_BU618242_at, merck2_BX115227_at, merck2_BX647415_at, merck2_BX647735_at, merck2_BX648311_at, merck2_BY799718_at merck2_CMV_UL43_at, merck2_CR749241_s_at, merck2_CX783886_a_at, merck2_DB492896_at, merck2_DQ891843_at, merck2_ENST00000355104_x_at, merck2_ENST00000371290_s_at. merck2_F25718_at, merck2_HSV l_ORF_UL46_at, merck2_HS V 2_0RF_UL 18_at, merck2_JC_vir_smTAg_at, merck2_NM_001005224_s_at, merck2_NM_001037866_s_at, merck2_NM_001080537_at, merck2_NM_005570_at, merck2_NM_006485_at, merck2_NM_006594_at, merck2_NM_022079_at, merck2_NM_022747_at, merck2_NM_025214_at, merck2_NM_030813_at, merck2_NM_032260_s_at, merck2_NM_032639_at, merck2_NM_052996_a_at, merck2_NM_205833_at, merck2_VZV_OKA_O32_up_at, merck2_VZV_OKA_O47_up_at, merck2_XM_938193_at, merck_AB058756_a_at, merck_AF038451_a_at, merck_AF085981_at, merck_AF118083_a_at, merck_AF143326_al, merck_AF147412_al, merck_AF 14743 l_at, merck_AF161340_at, merck_AF169158_a_at, merck_AF311308_at, merck_AT204893_at, merck_AJ406951 _s_at, merck_AJ45983 _at, rnerck_AK000932_at, merck_AK021682_at, merck_AK022168_at, merck_AK022347_at, merck_AK022443_at, merck_AK023601_at, merck_AK024198_at, merck_AK024231_at, merck_AK024810_a_at, merck_AK025202_a_at, merck_AK025621_at, merck_AK026808_at, merck_AK054931_at, merck_AK055172_a_at, merck_AK055584_at, merck_AK.091999_at, merck_AK093735_s_at, merck_AK095449_at, merck_AK096712_at, merck_AK097571_s_at, merck_AK097840_a_at, merck_AK123535_at, merck_AK123655_s_at, merck_AK123888_at, merck_AK125149_at, merck_AK127206_s_at, merck_AK130508_at, merck_AK222828_a_at, merck_AL044815_at, merck_AL133569_at, merck_AL162044_at, merck_AL353936_at, merck_AL563761_at, merck_AV762307_at, merck_AW370282_at, merck_AW665698_at, merck_AW771625_a_at, merck_AW809224_at, merck_AW843987_at, merck_AW977003_at, merck_AY054391_at, merck_AY147849_a_at, merck_BC001905_a_at, merck_BC007984_at, merck BC012447 a at. merck BC014119 at, merck BC015877 a at. merck BC019893 s at, merck_BC022892_at, merck_BC034596_at, merck_BC036594_at, merck_BC039321_at, merck_BC064385_at, merck_BC110326_at, merck_BCl 10867_s_at, merck_BE219852_at, merck_BE463518_at, merck_BE546828_at, merck_BF342524_at, merck_BF679703_at, merck_BF965720_at, merck_BG236239_a_at, merck_BG287007_at, merck_BG675291_at, merck_BG740109_a_at, merck_BG943385_at, merck_BG956704_x_at, merck_BI045425_at, merck_BI757398_at, merck_BM676784_at, merck_BM805663_at, merck_BQ380337_at, merck_BU145850_at, merck_BU935068_a_at, merck_BX095858_at, merck_BX096093_at, merck_BX097755_a_at, merck_BX102791_at, merck_BX102980_at, merck_BX116278_at, merck_BX119057_at, merck_BX329942_at, merck_CA309176_at, merck_CA942562_at, merck_CD102009_at, merck_CN388529_a_at, merck_CR742243_at, merck_CR994266_a_at, merck_CV392556_at, merck_CX785712_at, merck_DA214150_a_at, merck_DA234289_at, merck_DB351522_at, merck_DB546490_at, merck_DN831737_at, merck_DV080080_at, merck_ENST00000248668_at, merck_ENST00000316506_a_at, merck_ENST00000323496_x_at, merck_ENST00000327196_at, merck_ENST00000331146_at, merck_ENST00000341244_a_at, merck_ENST00000359421_at, merck_ENST00000366485_at, merck_ENST00000376325_at, merck_ENST00000378999_s_at, merck_ENST00000381435_at, merck_G65625_at, merck_NC_001405_ORF_1045_s_at, merck_NM_000258_at, merck_NM_000273_at, merck_NM_000782_at, merck_NM_000873_at, merck_NM_001001706_at, merck_NM_OO 1002247_at, merck_NM_OO 1004434_s_al, merck_NM_OO 1004752_al, merck_NM_OO 1012505_a_at, merck_NM_001024599_s_at, merck_NM_001039753_s_at, merck_NM_001039_at, merck_NM_001294_at, merck_NM_001431_s_at. merck_NM_001494_at, merck_NM_001883_at, merck_NM_001993_at, merck_NM_002501_s_at, merck_NM_003920_s_at, merck_NM_003954_at, merck_NM_004318_at, merck_NM_004387_at, merck_NM_004422_at, merck_NM_004683_s_at, merck_NM_005184_s_at, merck_NM_006143_at, merck_NM_006268_at, merck_NM_007179_at, merck_NM_014184_s_at, merck_NM_014230_s_at, merck_NM_014553_at, merck_NM_015058_at, merck_NM_015832_a_at, merck_NM_016593_at, merck_NM_017916_at, merck_NM_018055_at, merck_NM_018219_at, merck_NM_020457_at, merck_NM_020651_at, merck_NM_020677_s_at, merck_NM_020774_at. merck_NM_021912_at, merck_NM_021946_s_at, merck_NM_021983_x_at, merck_NM_022358_at, merck_NM_025214_at, merck_NM_030944_at, merck_NM_032143_a_at, merck_NM_032594_at, merck_NM_052910_at, merck_NM_058165_at, merck_NM_058219_at, merck_NM_133262_at, merck_NM_133492_at, merck_NM_138447_a_at, merck_NM_139174_at, merck_NM_139315_s_at, merck_NM_145270_at, merck_NM_152730_s_at, merck_NM_153274_at, merck_NM_173798_at, merck_NM_174962_x_at, merck_NM_176889_at, merck_NM_178012_at, merck_NM_181608_x_at, merck_NM_182505_at, merck_NM_182800_at, merck_NM_l 82905_s_at, merck_NM_198994_at, merck_NM_199180_at, merck_VZV_OKA_ORF41_s_at, merck_VZV_0KA_0RF9_s_at, merck_X85629_at, merck_X98206_at, merck_XM_063314_at, merck_XM_210303_at, merck_XM_373233_x_at, merck_XM_378090_at, merck_XM_926011_at, merck_XM_928173_s_at, merck_XM_928586_x_at, merck_XM_929767_at, merck_XM_933463_at, merck_XM_937104_at, merck_XM_940419_at, merck_XM_943662_at, merck_XM_945363_at, merck_hCTl 651346_at, merck_hCTl 651838_3_at, merck_hCTl 812405_2_at, merck_hCT1846664_l_at, merck_hCT2307348_at, or merck_hsa_mir_153_l_x_at

4. Also disclosed herein are kits of any preceding aspect, wherein the one or more probe sets bind to one or more genes comprising TIMM8A, PRDM15, LOC100130744, LANCL2, LOC101929529, NPHP3 NPHP3-ACAD11, MY05B, ZSCAN30, ZNF462, CDON. ZNF689, NC0A7, ZNF280D, NFIX, ZNF467, EPN3, SLC25A27, GJC2, NODAL, RPL17 RPL17- C18orf32, TDRKH, FAM149B1, PPIE, FIP1L1, MRPL38, GABPB1-AS1, GALNT1, ERICH1, CEP126, AP3S1, AHI1, MRPL1, FRMPD2, UBE3A, ZNF365, ICAM2, PRR21, CT47A1 CT47A10 CT47A11 CT47A12 CT47A2 CT47A3 CT47A4 CT47A5 CT47A6 CT47A7 CT47A8 CT47A9, LINC01405, OR4F16 OR4F21 OR4F29 OR4F3, RGPD5 RGPD6, SNTN, LMAN1, FBLNlm AP4B1, HERC4, CCDC85C, CCDC68, CLPB, RGPD5 RGPD6, PLEKHA8, PRDM7, IGSF1, SH2D1A STAG2 HSPA8P20 NPM1P34 TEX13D ZIK1P1 LOC101928402, SRRM4, AGR2, ENTPD4, EXOC5, FOXP1 FOXP1-AS1 MIR1284, ARID1B MIR4466, DIS3L, CABP5, MGAT1, KRTAP9-9, 0R2H1, COL9A2, CSTF2T MIR605 PRKG1 RSU1P3 LOC102724719, CSTF2T MIR605 PRKG1 RSU1P3, LOC102724719, FOXP1 FOXP1-AS1 MIR1284, EFR3A, PRPF40A, LARGE1, LOC101927365, HERC4, MIR9-3HG, DLG5, STT3B, LOC101929713, CEP83, CRK, USP46, LOC105378730, LOC105379589 LQC107984097 LOC107987409 LQC107987410, FBXL18, UCHL5, ZNF555, CD99P1, LONRF2, LOC100507281, LMAN2L, MTMR6, LOC107987180, PCDH9 PCDH9-AS4, PSD3, USP3-AS1, MAP3K6, CSNK1G1, GTPBP1, BDNF-AS, MIB1, PCSK2, BFSP2-AS1, SP11O, LINC00824, CDH19, CD99P1, IWS1, LINC01725, TISP43 LOC646743, TRIQK, CDH24, LOC101927472, LINC02004, SIRPD, CLYBL, THUMPD3-AS1, KLRA1P, LINC01971, SOGA1, RIMBP2, TJP2, NFATC3 RPS12P27, GDAP2, MSN, ELFN1-AS1, PNPO, LOCI 01929371, LAMB1, JAK1, NDFIP1, UHRF2, RIN2, SLC25A48, PHF2P2, LRFN1, OR52B1P, BCAS4, LOC107985946, RPS17P5, TAF4B, FAM92A, OR14A2, SHISA7, REXO1L2P, MCHR1, MYL3, GPR143, CYP24A1, ICAM2, AK9, ANAPC11, SLC30A2, OR51F1, FOXP1, HIST2H2BF, EML6, SCNN1G, CLPTM1, EPB41L2, GDI2, CRHR2, F3, NFIX, TIMELESS, MAP3K14, ASPH, NKX2-5, DVL2, RGN, CALM3, GPR19, DPF2, INSL6, CNIH4, SRP68, TFCP2L1, VWA8, MBD2, CYP39A1, PIH1D1, NODAL, CCDC87, THAP11, PEL11, NMRAL1, M1B1, GABRB3, BC0RL1, HLA-DRB4, KCNK15, CCDC68, LINC00597, ZRANB3, INSM2, SLITRK1, M0GAT1, EXOSC6, ATP6V1G3, ACER1, ZNF689, ADAD2, TAF6, PRR35, TBC1D32, BEST4, ZCCHC12, SSX9, TAS2R20, TUBB2B, KRTAP19-2, C9orf85, SRRT, WASHCI, TGM6, KIRREL2, ARID1B MIR4466, OR11H5P, LOC642515, PPIAL4A PPIAL4C PPIAL4D PPIAL4E PPIAL4F PPIAL4G, FAM207BP FAM207CP, SLC9B1P1, RPS28P1, LOC100288437, ELOCP31, or MIR153-E In one aspect, the probes bind to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 of the genes selected from the group consisting of AGR2, BEST4, CRHR2, CRK, CYP24A1, DVL2, ELFN1-AS1, F3, FIP1L1, FOXP1, ICAM2, JAK1, MAP3K14, MBD2, MIB1, MSN, NKX2-5, NODAL, THUMPD3-AS1, TIMELESS, TJP2, and/or USP46. In one aspect, the probes bind to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 of the genes selected from the group consisting of BFSP2-AS1, ERICH1, HERC4, HIST2H2BF, IWS1, LINC01405, MCHR1, MTMR6, SLC30A2, SLITRK1, SRP68, SRRM4, TFCP2L1, and/or ZNF462. In one aspect, the probes bind to at least 1, 2, 3, 4, 5, 6, 7, or 8 of the genes selected from the group consisting of ER1CH1, HERC4, HIST2H2BF, IWS1 , MTMR6, SRP68, TFCP2L1 , ZNF462 (such as, for example, HERC4, HIST2H2BF, IWS1, SRP68, and/or ZNF462). In one aspect, the probes bind to at least 1, 2, 3, 4, 5, 6, or 7 of the genes selected from the group consisting of HERC4, HIST2H2BF, IWS1, MCHR1, SLC30A2, SRP68, ZNF462. It is understood and herein contemplated that low expression of some genes can be associated with an increase in death (i.e., low survivability and thus high expression is good) including, but not limited to CLPTM1, GTPBP1, IWS1, MAP3K14, MBD2, PIH1D1, SLC25A27, TJP2

5. In one aspect, disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating, and/or preventing a cancer and/or metastasis (such as, for example colorectal cancer, including, but not limited to metastatic colorectal cancers (mCRC) in a subject comprising: a) obtaining a cancerous tissue sample from the subject; b) contacting the tissue sample with one or more probe sets in the kit of claim 1 or 2; c) assaying the expression of one or more genes from the sample to create a gene signature, wherein principle component analysis is applied to the gene signature to create a probability score for the subject; and d) treating the subject with chemotherapy and bevacizumab (AV AS TIN®) when the probability score is high; and treating the subject with chemotherapy and not bevacizumab (AVASTIN®) when the probability score is low. In one aspect, the administration of bevacizumab (AVASTIN®) toa subject with a low probability score has a deleterious effect on the subject. For example, disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating, and/or preventing a cancer and/or metastasis (such as, for example colorectal cancer, including, but not limited to metastatic colorectal cancers (mCRC) in a subject compnsmg: a) obtaining a cancerous tissue sample from the subject; b) contacting the tissue sample with one or more probe sets that binds to one or more genes that are differentially expressed in the cancer; c) assaying the expression of one or more genes from the sample to create a gene signature, wherein principle component analysis is applied to the gene signature to create a probability score for the subject; and d) treating the subject with chemotherapy and bevacizumab (AVASTIN®) when the probability score is high; and treating the subject with chemotherapy and not bevacizumab (AVASTIN®) when the probability score is low. In one aspect, wherein the subject has a low probability score and is already receiving chemotherapy; bevacizumab is not administered. In one aspect, wherein the subject has a high probability score and is already receiving chemotherapy; bevacizumab is not administered.

6. Also disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating, and/or preventing a cancer and/or metastasis of any preceding aspect wherein the one or more probe sets comprise merck2_AA101946_x_at, merck2_AA490328_at, merck2_AF129457_at, merck2_AF289590_at, merck2_AI091276_at, merck2_AI223270_at, merck2_AI962276_at, merck2_AK092910_at, merck2_AK093149_at, merck2_AK131291_at, merck2_AL359561_at, merck2_AL832223_at, merck2_AL834299_at, merck2_AL834442_at, merck2_AM392650_at, merck2_AW007481_at, merck2_AX721105_at, merck2_BC001038_at, merck2_BC033091_at, merck2_BC035840_at, merck2_BC039861_at, merck2_BE249972_x_at, merck2_BE349054_x_at, merck2_BF248252_at, merck2_BF591243_at, merck2_BF692777_at, merck2_BG896934_at, merck2_BI047264_at, merck2_BM545067_s_at, merck2_BM681401_at, merck2_BU618242_at, merck2_BX115227_at, merck2_BX647415_at, merck2_BX647735_at, merck2_BX648311_at, merck2_BY799718_at, merck2_CMV_UL43_at, merck2_CR749241_s_at, merck2_CX783886_a_at, merck2_DB492896_at, merck2_DQ891843_at, merck2_ENST00000355104_x_at, merck2_ENST00000371290_s_at, merck2_F25718_at, merck2 HSV 1 ORF UL46 at, merck2 HSV2 ORF ULI 8 at, merck2 JC vir smTAg at, merck2_NM_001005224_s_at, merck2_NM_001037866_s_at, merck2_NM_001080537_at, merck2_NM_005570_at, merck2_NM_006485_at, merck2_NM_006594_at, merck2_NM_022079_at, merck2_NM_022747_at, merck2_NM_025214_at, merck2_NM_030813_at, merck2_NM_032260_s_at, merck2_NM_032639_at, merck2_NM_052996_a_at, merck2_NM_205833_at, merck2_V Z V_OKA_O32_up_at, merck2_VZV_OKA_O47_up_at, merck2_XM_938193_at, merck_AB058756_a_at, merck_AF038451_a_at, merck_AF085981_at, merck_AF118083_a_at, merck_AF143326_at, merck_AF147412_at, merck_AF147431_at, merck_AF161340_at, merck_AF169158_a_at, merck_AF311308_at, merck_AI204893_at, merck_AJ406951_s_at, merck_AJ459838_at, merck_AK000932_at, merck_AK021682_at, merck_AK022168_at, merck_AK022347_at, merck_AK022443_at, merck_AK023601_at, merck_AK024198_at, merck_AK024231_at, merck_AK024810_a_at, merck_AK025202_a_at, merck_AK025621_at, merck_AK026808_at, merck_AK054931_at, merck_AK055172_a_at, merck_AK055584_at, merck_AK091999_at, merck_AK093735_s_at, merck_AK095449_at, merck_AK096712_at, merck_AK097571_s_at, merck_AK097840_a_at, merck_AK123535_at, merck_AK423655_s_at, merck_AK123888_at, merck_AK125149_at, merck_AK127206_s_at, merck_AK130508_at, merck_AK222828_a_at, merck_AL044815_at, merck_AL133569_at, merck_AL162044_at, merck_AL353936_at, merck_AL563761_at, merck_AV762307_at, merck_AW370282_at, merck_AW665698_at, merck_AW771625_a_at, merck_AW809224_at, merck_AW843987_at, merck_AW977003_at, merck_AY054391_al, merck_AY147849_a_al, merck_BC001905_a_al, merck_BC007984_at, merck_BC012447_a_at, merck_BC014119_at, merck_BC015877_a_at, merck_BC019893_s_at, merck_BC022892_at, merck_BC034596_at, merck_BC036594_at, merck_BC039321_at, merck_BC064385_at, merck_BC110326_at, merck_BCl 10867_s_at, merck_BE219852_at, merck_BE463518_at, merck_BE546828_at, merck_BF342524_at, merck_BF679703_at, merck_BF965720_at, merck_BG236239_a_at, merck_BG287007_at, merck_BG675291_at, merck_BG740109_a_at, merck_BG943385_at, merck_BG956704_x_at, merck_BI045425_at, merck_BI757398_at, merck_BM676784_at, merck_BM805663_at, merck_BQ380337_at, merck_BU145850_at, merck_BU935068_a_at, merck_BX095858_at, merck_BX096093_at, merck_BX097755_a_at, merck_BX102791_at, merck_BX102980_at, merck_BX116278_at, merck_BX119057_at, merck_BX329942_at, merck_CA309176_at, merck_CA942562_at, merck_CD102009_at, merck_CN388529_a_at, merck_CR742243_at, merck_CR994266_a_at, merck_CV392556_at, merck_CX785712_at, merck_DA214150_a_at, merck_DA234289_at, merck_DB351522_at, merck_DB546490_at, merck_DN831737_at, merck_DV080080_at, merck ENST00000248668 at, merck ENST00000316506 a at, merck_ENST00000323496_x_at, merck_ENST00000327196_at, merck_ENST00000331146_at, merck_ENST00000341244_a_at, merck_ENST00000359421_at, merck_ENST00000366485_at, merck_ENST00000376325_at, merck_ENST00000378999_s_at, merck_ENST00000381435_at, merck_G65625_at, merck_NC_001405_ORF_1045_s_at, merck_NM_000258_at, merck_NM_000273_at, merck_NM_000782_at, merck_NM_000873_at, merck_NM_001001706_at, merck_NM_001002247_at, merck_NM_001004434_s_at, merck_NM_001004752_at, merck_NM_001012505_a_at, merck_NM_001024599_s_at, merck_NM_001039753_s_at, merck_NM_001039_at, merck_NM_001294_at, merck_NM_001431_s_at, merck_NM_001494_at, merck_NM_001883_at, merck_NM_001993_at, merck_NM_002501_s_at, merck_NM_003920_s_at, merck_NM_003954_at, merck_NM_004318_at, merck_NM_004387_at, merck_NM_004422_at, merck_NM_004683_s_at, merck_NM_005184_s_at, merck_NM_006143_at, merck_NM_006268_at, merck_NM_007179_at, merck_NM_014184_s_at, merck_NM_014230_s_at, merck_NM_014553_at, merck_NM_015058_at, merck_NM_015832_a_at, merck_NM_016593_at, merck_NM_017916_at, merck_NM_018055_at, merck_NM_018219_at, merck_NM_020457_at, merck_NM_020651_at, merck_NM_020677_s_at, merck_NM_020774_at, merck_NM_021912_at, merck_NM_021946_s_at, merck_NM_021983_x_at, merck_NM_022358_al, merck_NM_025214_al, merck_NM_030944_al, merck_NM_032143_a_at, merck_NM_032594_at, merck_NM_052910_at, merck_NM_0 8165_at, merck_NM_058219_at, merck_NM_133262_at, merck_NM_133492_at, merck_NM_138447_a_at, merck_NM_139174_at, merck_NM_139315_s_at, merck_NM_145270_at, merck_NM_152730_s_at, merck_NM_153274_at, merck_NM_173798_at, merck_NM_174962_x_at, merck_NM_176889_at, merck_NM_178012_at, merck_NM_181608_x_at, merck_NM_182505_at, merck_NM_182800_at, merck_NM_l 82905_s_at, merck_NM_198994_at, merck_NM_199180_at, merck_VZV_0KA_0RF41_s_at, merck_VZV_0KA_0RF9_s_at, merck_X85629_at, merck_X98206_at, merck_XM_063314_at, merck_XM_210303_at, merck_XM_373233_x_at, merck_XM_378090_at, merck_XM_92601 l_at, merck_XM_928173_s_at, merck_XM_928586_x_at, merck_XM_929767_at, merck_XM_933463_at, merck_XM_937104_at, merck_XM_940419_at, merck_XM_943662_at, merck_XM_945363_at, merck hCTl 651346 at, merck hCTl 651838 3 at, merck hCTl 812405 2 at, merck_hCT1846664_l_at, merck_hCT2307348_at, or merck_hsa_mir_153_l_x_at

7. In one aspect, disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating, and/or preventing a cancer and/or metastasis of any preceding aspect, wherein the one or more genes comprise TIMM8A, PRDM15, LOC100130744, LANCL2, LOC101929529, NPHP3 NPHP3-ACAD11, MYO5B, ZSCAN30, ZNF462, CDON. ZNF689, NCOA7, ZNF280D, NFIX, ZNF467, EPN3, SLC25A27, GJC2, NODAL, RPL17 RPL17- C18orf32, TDRKH, FAM149B1, PPIE, FIP1L1, MRPL38, GABPB1-AS1, GALNT1, ERICH1, CEP126, AP3S1, AH11, MRPL1, FRMPD2, UBE3A, ZNF365, 1CAM2, PRR21, CT47A1 CT47A10 CT47A11 CT47A12 CT47A2 CT47A3 CT47A4 CT47A5 CT47A6 CT47A7 CT47A8 CT47A9, LINC01405, OR4F16 OR4F21 OR4F29 OR4F3, RGPD5 RGPD6, SNTN, LMAN1, FBLNlm AP4B1, HERC4, CCDC85C, CCDC68, CLPB, RGPD5 RGPD6, PLEKHA8, PRDM7, IGSF1, SH2D1A STAG2 HSPA8P20 NPM1P34 TEX13D ZIK1P1 LOC101928402, SRRM4, AGR2, ENTPD4, EX0C5, F0XP1 FOXP1-AS1 MIR1284, ARID1B MIR4466, DIS3L, CABP5, MGAT1, KRTAP9-9, 0R2H1, COL9A2, CSTF2T MIR605 PRKG1 RSU1P3 LOC102724719, CSTF2T MIR605 PRKG1 RSU1P3, LOC102724719, FOXP1 FOXP1-AS1 MIR1284, EFR3A, PRPF40A, LARGE1, LOC101927365, HERC4, MIR9-3HG, DLG5, STT3B, LOC101929713, CEP83, CRK, USP46, LOC105378730, LOC105379589 LOC107984097 LOC107987409 LOC107987410, FBXL18, UCHL5, ZNF555, CD99P1, LONRF2, LOC100507281, LMAN2L, MTMR6, LOC107987180, PCDH9 PCDH9-AS4, PSD3, USP3-AS1, MAP3K6, CSNK1G1, GTPBP1, BDNF-AS, MIB1, PCSK2, BFSP2-AS1, SP11O, LINC00824, CDH19, CD99P1, IWS1, LINC01725, TISP43 LOC646743, TRIQK, CDH24, LOCI 01927472, LTNC02004, STRPD, CLYBL, THUMPD3-AS1 , KLRA1 P, L1NC01971 , SOGA1, RIMBP2, TJP2, NFATC3 RPS12P27, GDAP2, MSN, ELFN1-AS1, PNPO, LOCI 01929371, LAMB1, JAK1, NDFIP1, UHRF2, RIN2, SLC25A48, PHF2P2, LRFN1, OR52B1P, BCAS4, LOC107985946, RPS17P5, TAF4B, FAM92A, OR14A2, SHISA7, REXO1L2P, MCHR1, MYL3, GPR143, CYP24A1, ICAM2, AK9, ANAPC11, SLC30A2, OR51F1, FOXP1, HIST2H2BF, EML6, SCNN1G, CLPTM1, EPB41L2, GDI2, CRHR2, F3, NFIX, TIMELESS, MAP3K14, ASPH, NKX2-5, DVL2, RGN, CALM3, GPR19, DPF2, INSL6, CNIH4, SRP68, TFCP2L1, VWA8, MBD2, CYP39A1, PIH1D1, NODAL, CCDC87, THAP11, PEL11, NMRAL1, M1B1, GABRB3, BCORL1, HLA-DRB4, KCNK15, CCDC68, LINC00597, ZRANB3, INSM2, SLITRK1, MOGAT1, EXOSC6, ATP6V1G3, ACER1, ZNF689, ADAD2, TAF6, PRR35, TBC1D32, BEST4, ZCCHC12, SSX9, TAS2R20, TUBB2B, KRTAP19-2, C9orf85, SRRT, WASHCI, TGM6, KIRREL2, ARID1B MIR4466, OR11H5P, LOC642515, PPIAL4A PPIAL4C PPIAL4D PPIAL4E PPIAL4F PPIAL4G, FAM207BP FAM207CP, SLC9B1P1, RPS28P1, LOC100288437, ELOCP31, or MIR153-1. In one aspect, the probes bind to at least I, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 of the genes selected from the group consisting of AGR2, BEST4, CRHR2, CRK, CYP24A1, DVL2, ELFN1-ASL F3, FIP1L1, FOXP1, ICAM2, JAK1, MAP3K14, MBD2, MIB1, MSN, NKX2-5, NODAL, THUMPD3-AS1, TIMELESS, TJP2, and/or USP46. In one aspect, the probes bind to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 of the genes selected from the group consisting of BFSP2-AS1, ERICH1, HERC4, HIST2H2BF, IWSL LINC01405, MCHR1, MTMR6, SLC30A2, SL1TRK1, SRP68, SRRM4, TFCP2L1, and/or ZNF462. In one aspect, the probes bind to at least 1, 2, 3, 4, 5, 6, 7, or 8 of the genes selected from the group consisting of ERICH1, HERC4, HIST2H2BF, IWS1, MTMR6, SRP68, TFCP2L1, ZNF462 (such as, for example, HERC4, HIST2H2BF, IWS1, SRP68, and/or ZNF462). In one aspect, the probes bind to at least 1, 2, 3, 4, 5, 6, or 7 of the genes selected from the group consisting of HERC4, HIST2H2BF, IWS1, MCHR1, SLC30A2, SRP68, ZNF462. It is understood and herein contemplated that low expression of some genes can be associated with an increase in death (i.e., low survivability and thus high expression is good) including, but not limited to CLPTM1, GTPBP1, IWS1, MAP3K14, MBD2, PIH1D1, SLC25A27, TJP2

III. BRIEF DESCRIPTION OF THE DRAWINGS

8. The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments and together with the description illustrate the disclosed compositions and methods.

9. Figure 1 shows the survival probability for chemotherapy compared to chemotherapy and AVASTIN®.

10. Figures 2A, 2B, 2C, 2D, and 2E show a AVASTIN® efficacy signature by significant Moffitt genes: Moffitt Consortium Cohort: Interaction Model. Figure 2 shows the overall survival and progression free survival for the AVASTIN® efficacy signature. Figure 2B and 2C show signature refined by significant Moffitt genes: Moffitt Cohort: High PCI for overall survival (2B) and progression free survival (2C). Figure 2C shows signature by significant Moffitt genes: Moffitt Cohort: Low PCI for overall survival (2D) and progression free survival (2E).

11. Figures 3 A and 3B show validation in the Moffitt consortium cohort. Figure 3 A shows the survival probability for chemotherapy compared to chemotherapy and AVASTIN®. Figure 3B shows the survival probability for the PCI high group.

12. Figures 4A, 4B, 4C, and 4D show validation in the Moffitt avatar cohort. Figure 4A shows the survival probability for chemotherapy compared to chemotherapy and AVASTIN® in the Moffitt avatar cohort. Figure 4B shows the optimal PCI Optimal Cutoff Distribution for the avatar cohort. Figure 4C shows the PCI Optimal Cutoff (Overall). Figure 4C shows the PCI Optimal Cutoff (AVASTIN®).

13. Figures 5A, SB, and SC show refined signature based on significant consortium genes for the Moffitt Cohort. Figure 5A shows the signature refined by significant consortium genes overall. Figure 5B shows the signature refined by significant consortium genes for High PCI. Figure 5C shows the signature refined by significant consortium genes for Low PCI.

14. Figures 6A, and 6B show refined signature based on significant consortium genes for the Moffitt Consortium Cohort. Figure 6A shows the signature refined by significant consortium genes overall. Figure 6B shows the signature refined by significant consortium genes for High PCI.

15. Figures 7A, and 7B show refined signature based on significant consortium genes for the Moffitt Avatar Cohort. Figure 7A shows the signature refined by significant consortium genes with a 33% cutoff. Figure 7B shows the signature refined by significant consortium genes with an optimal PCI cutoff.

16. Figures 8A, 8B, and 8C show refined signature based on significant avatar genes for the Moffitt Cohort. Figure 8A shows the signature refined by significant avatar genes overall. Figure 8B shows the signature refined by significant avatar genes for High

PCI. Figure 8C shows the signature refined by significant avatar genes for Low PCI.

17. Figures 9 A, and 9B show refined signature based on significant avatar genes for the Moffitt Consortium Cohort. Figure 9A shows the signature refined by significant avatar genes overall. Figure 9B shows the signature refined by significant avatar genes for High PCI.

18. Figures 10A, and 10B show refined signature based on significant avatar genes for the Moffitt Avatar Cohort. Figure 10A shows the signature refined by significant avatar genes for 39% cutoff. Figure 10B shows the signature refined by significant avatar genes for Optimal PCI cutoff.

IV. DETAILED DESCRIPTION

19. Before the present compounds, compositions, articles, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods or specific recombinant biotechnology methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, 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.

A. Definitions

20. As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like. 21. Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that when a value is disclosed that “less than or equal to” the value, “greater than or equal to the value” and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “10” is disclosed the “less than or equal to 10”as well as “greater than or equal to 10” is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data, represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point 15 are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

22. In this specification and in the claims which follow, reference will be made to a number of terms which shall be defined to have the following meanings:

23. “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

24. An "increase" can refer to any change that results in a greater amount of a symptom, disease, composition, condition or activity. An increase can be any individual, median, or average increase in a condition, symptom, activity , composition in a statistically significant amount. Thus, the increase can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% increase so long as the increase is statistically significant.

25. A "decrease" can refer to any change that results in a smaller amount of a symptom, disease, composition, condition, or activity. A substance is also understood to decrease the genetic output of a gene when the genetic output of the gene product with the substance is less relative to the output of the gene product without the substance. Also for example, a decrease can be a change in the symptoms of a disorder such that the symptoms are less than previously observed A decrease can be any individual, median, or average decrease in a condition, symptom, activity, composition in a statistically significant amount. Thus, the decrease can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% decrease so long as the decrease is statistically significant.

26. "Inhibit," "inhibiting," and "inhibition" mean to decrease an activity, response, condition, disease, or other biological parameter. This can include but is not limited to the complete ablation of the activity, response, condition, or disease. This may also include, for example, a 10% reduction in the activity, response, condition, or disease as compared to the native or control level. Thus, the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to native or control levels.

27. By “reduce” or other forms of the word, such as “reducing” or “reduction,” is meant lowering of an event or characteristic (e.g, tumor growth). It is understood that this is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to For example, “reduces tumor growth” means reducing the rate of growth of a tumor relative to a standard or a control.

28. By “prevent” or other forms of the word, such as “preventing” or “prevention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce. As used herein, something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed.

29. The term “subject” refers to any individual who is the target of administration or treatment. The subject can be a vertebrate, for example, a mammal. In one aspect, the subject can be human, non-human primate, bovine, equine, porcine, canine, or feline. The subject can also be a guinea pig, rat, hamster, rabbit, mouse, or mole. Thus, the subject can be a human or veterinary patient. The term “patient” refers to a subject under the treatment of a clinician, e.g., physician.

30. The term “therapeutically effective” refers to the amount of the composition used is of sufficient quantity to ameliorate one or more causes or symptoms of a disease or disorder. Such amelioration only requires a reduction or alteration, not necessarily elimination. 31. The term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.

32. "Biocompatible" generally refers to a material and any metabolites or degradation products thereof that are generally non-toxic to the recipient and do not cause significant adverse effects to the subject.

33. "Comprising" is intended to mean that the compositions, methods, etc. include the recited elements, but do not exclude others. "Consisting essentially of when used to define compositions and methods, shall mean including the recited elements, but excluding other elements of any essential significance to the combination. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. "Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions provided and/or claimed in this disclosure. Embodiments defined by each of these transition terms are within the scope of this disclosure.

34. A “control” is an alternative subject or sample used in an experiment for comparison purposes. A control can be "positive" or "negative."

35. “Effective amount” of an agent refers to a sufficient amount of an agent to provide a desired effect. The amount of agent that is “effective” will vary from subject to subject, depending on many factors such as the age and general condition of the subject, the particular agent or agents, and the like. Thus, it is not alway s possible to specify a quantified “effective amount.” However, an appropriate “effective amount” in any subject case may be determined by one of ordinary skill in the art using routine experimentation. Also, as used herein, and unless specifically stated otherwise, an “effective amount” of an agent can also refer to an amount covering both therapeutically effective amounts and prophylactically effective amounts. An “effective amount” of an agent necessary to achieve a therapeutic effect may vary according to factors such as the age, sex, and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.

36. A "pharmaceutically acceptable" component can refer to a component that is not biologically or otherwise undesirable, i.e., the component may be incorporated into a pharmaceutical formulation provided by the disclosure and administered to a subject as described herein without causing significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained. When used in reference to administration to a human, the term generally implies the component has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

37. "Pharmaceutically acceptable carrier" (sometimes referred to as a “carrier”) means a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic and includes a carrier that is acceptable for veterinary and/or human pharmaceutical or therapeutic use. The terms "carrier" or "pharmaceutically acceptable carrier" can include, but are not limited to, phosphate buffered saline solution, water, emulsions (such as an oil/water or water/oil emulsion) and/or various types of wetting agents. As used herein, the term "carrier" encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations and as described further herein.

38. “Pharmacologically active” (or simply “active”), as in a “pharmacologically active” derivative or analog, can refer to a derivative or analog (e.g., a salt, ester, amide, conjugate, metabolite, isomer, fragment, etc.) having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.

39. “Therapeutic agent” refers to any composition that has a beneficial biological effect. Beneficial biological effects include both therapeutic effects, e.g., treatment of a disorder or other undesirable physiological condition, and prophylactic effects, e.g., prevention of a disorder or other undesirable physiological condition (e.g., a non-immunogenic cancer). The terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of beneficial agents specifically mentioned herein, including, but not limited to, salts, esters, amides, proagents, active metabolites, isomers, fragments, analogs, and the like. When the terms “therapeutic agent” is used, then, or when a particular agent is specifically identified, it is to be understood that the term includes the agent per se as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, proagents, conjugates, active metabolites, isomers, fragments, analogs, etc.

40. “Therapeutically effective amount” or “therapeutically effective dose” of a composition (e.g. a composition comprising an agent) refers to an amount that is effective to achieve a desired therapeutic result. In some embodiments, a desired therapeutic result is the control of type I diabetes. In some embodiments, a desired therapeutic result is the control of obesity. Therapeutically effective amounts of a given therapeutic agent will typically vary with respect to factors such as the type and severity of the disorder or disease being treated and the age, gender, and weight of the subject. The term can also refer to an amount of a therapeutic agent, or a rate of delivery of a therapeutic agent (e.g., amount over time), effective to facilitate a desired therapeutic effect, such as pain relief. The precise desired therapeutic effect will vary according to the condition to be treated, the tolerance of the subject, the agent and/or agent formulation to be administered (e.g., the potency of the therapeutic agent, the concentration of agent in the formulation, and the like), and a variety of other factors that are appreciated by those of ordinary skill in the art. In some instances, a desired biological or medical response is achieved following administration of multiple dosages of the composition to the subject over a period of days, weeks, or years.

41. “Probes” are molecules capable of interacting with a target nucleic acid, typically in a sequence specific manner, for example through hybridization. The hybridization of nucleic acids is well understood in the art and discussed herein. Typically a probe can be made from any combination of nucleotides or nucleotide derivatives or analogs available in the art.

42. Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon.

B. Compositions

43. Disclosed are the components to be used to prepare the disclosed compositions as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular kit, probe, gene, or gene signature is disclosed and discussed and a number of modifications that can be made to a number of molecules including the kit, probe, gene, or gene signature are discussed, specifically contemplated is each and every combination and permutation of kit, probe, gene, or gene signature and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods.

1. Hybridization/selective hybridization

44. The term hybridization ty pically means a sequence driven interaction between at least two nucleic acid molecules, such as a primer or a probe and a gene. Sequence driven interaction means an interaction that occurs between two nucleotides or nucleotide analogs or nucleotide derivatives in a nucleotide specific manner. For example, G interacting with C or A interacting with T are sequence driven interactions. Typically sequence driven interactions occur on the Watson-Crick face or Hoogsteen face of the nucleotide. The hybridization of two nucleic acids is affected by a number of conditions and parameters known to those of skill in the art. For example, the salt concentrations, pH, and temperature of the reaction all affect whether two nucleic acid molecules will hybridize.

45. Parameters for selective hybridization between two nucleic acid molecules are well known to those of skill in the art. For example, in some embodiments selective hybridization conditions can be defined as stringent hybridization conditions. For example, stringency of hybridization is controlled by both temperature and salt concentration of either or both of the hybridization and washing steps. For example, the conditions of hybridization to achieve selective hybridization may involve hybridization in high ionic strength solution (6X SSC or 6X SSPE) at a temperature that is about 12-25°C below the Tm (the melting temperature at which half of the molecules dissociate from their hybridization partners) followed by washing at a combination of temperature and salt concentration chosen so that the washing temperature is about 5°C to 20°C below the Tm. The temperature and salt conditions are readily determined empirically in preliminary experiments in which samples of reference DNA immobilized on filters are hybridized to a labeled nucleic acid of interest and then washed under conditions of different stringencies. Hybridization temperatures are typically higher for DNA-RNA and RNA-RNA hybridizations. The conditions can be used as described above to achieve stringency, or as is known in the art. A preferable stringent hybridization condition for a DNA:DNA hybridization can be at about 68°C (in aqueous solution) in 6X SSC or 6X SSPE followed by washing at 68°C. Stringency of hybridization and washing, if desired, can be reduced accordingly as the degree of complementarity desired is decreased, and further, depending upon the G-C or A-T richness of any area wherein variability is searched for. Likewise, stringency of hybridization and washing, if desired, can be increased accordingly as homology desired is increased, and further, depending upon the G-C or A-T richness of any area wherein high homology is desired, all as known in the art.

46. Another way to define selective hybridization is by looking at the amount (percentage) of one of the nucleic acids bound to the other nucleic acid. For example, in some embodiments selective hybridization conditions would be when at least about, 60, 65, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 percent of the limiting nucleic acid is bound to the non-limiting nucleic acid. Typically, the non-limiting primer is in for example, 10 or 100 or 1000 fold excess. This type of assay can be performed at under conditions where both the limiting and non-limiting primer are for example, 10 fold or 100 fold or 1000 fold below their ka, or where only one of the nucleic acid molecules is 10 fold or 100 fold or 1000 fold or where one or both nucleic acid molecules are above their ka.

47. Another way to define selective hybridization is by looking at the percentage of primer that gets enzymatically manipulated under conditions where hybridization is required to promote the desired enzymatic manipulation. For example, in some embodiments selective hybridization conditions would be when at least about, 60, 65, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 percent of the primer is enzymatically manipulated under conditions which promote the enzymatic manipulation, for example if the enzymatic manipulation is DNA extension, then selective hybridization conditions would be when at least about 60, 65, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 percent of the primer molecules are extended. Preferred conditions also include those suggested by the manufacturer or indicated in the art as being appropriate for the enzyme performing the manipulation. 48. Just as with homology, it is understood that there are a vanety of methods herein disclosed for determining the level of hybridization between two nucleic acid molecules. It is understood that these methods and conditions may provide different percentages of hybridization between two nucleic acid molecules, but unless otherwise indicated meeting the parameters of any of the methods would be sufficient. For example if 80% hybridization was required and as long as hybridization occurs within the required parameters in any one of these methods it is considered disclosed herein.

49. It is understood that those of skill in the art understand that if a composition or method meets any one of these criteria for determining hy bridization either collectively or singly it is a composition or method that is disclosed herein.

2. Nucleic acids

50. There are a variety of molecules disclosed herein that are nucleic acid based. The disclosed nucleic acids are made up of for example, nucleotides, nucleotide analogs, or nucleotide substitutes. Non-limiting examples of these and other molecules are discussed herein. It is understood that for example, when a vector is expressed in a cell, that the expressed mRNA will typically be made up of A, C, G, and U. Likewise, it is understood that if, for example, an antisense molecule is introduced into a cell or cell environment through for example exogenous delivery, it is advantagous that the antisense molecule be made up of nucleotide analogs that reduce the degradation of the antisense molecule in the cellular environment. a) Nucleotides and related molecules

51. A nucleotide is a molecule that contains a base moiety, a sugar moiety and a phosphate moiety. Nucleotides can be linked together through their phosphate moieties and sugar moieties creating an intemucleoside linkage. The base moiety of a nucleotide can be adenin-9-yl (A), cytosin-l-yl (C), guanin-9-yl (G), uracil-l-yl (U), and thymin-l-yl (T). The sugar moiety of a nucleotide is a ribose or a deoxyribose. The phosphate moiety of a nucleotide is pentavalent phosphate. An non-limiting example of a nucleotide would be 3'-AMP (3 - adenosine monophosphate) or 5'-GMP (5'-guanosine monophosphate). There are many varieties of these types of molecules available in the art and available herein.

52. A nucleotide analog is a nucleotide which contains some type of modification to either the base, sugar, or phosphate moieties. Modifications to nucleotides are well known in the art and would include for example, 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, and 2-ammoadenme as well as modifications at the sugar or phosphate moieties. There are many varieties of these types of molecules available in the art and available herein. 53. Nucleotide substitutes are molecules having similar functional properties to nucleotides, but which do not contain a phosphate moiety, such as peptide nucleic acid (PNA). Nucleotide substitutes are molecules that will recognize nucleic acids in a Watson-Crick or Hoogsteen manner, but which are linked together through a moiety other than a phosphate moiety. Nucleotide substitutes are able to conform to a double helix type structure when interacting with the appropriate target nucleic acid. There are many varieties of these types of molecules available in the art and available herein.

54. It is also possible to link other types of molecules (conjugates) to nucleotides or nucleotide analogs to enhance for example, cellular uptake. Conjugates can be chemically linked to the nucleotide or nucleotide analogs. Such conjugates include but are not limited to lipid moieties such as a cholesterol moiety. (Letsinger et al., Proc. Natl. Acad. Set. USA, 1989, 86, 6553-6556). There are many varieties of these types of molecules available in the art and available herein.

55. A Watson-Crick interaction is at least one interaction with the Watson-Crick face of a nucleotide, nucleotide analog, or nucleotide substitute. The Watson-Crick face of a nucleotide, nucleotide analog, or nucleotide substitute includes the C2, Nl, and C6 positions of a purine based nucleotide, nucleotide analog, or nucleotide substitute and the C2, N3, C4 positions of a pyrimidine based nucleotide, nucleotide analog, or nucleotide substitute.

56. A Hoogsteen interaction is the interaction that takes place on the Hoogsteen face of a nucleotide or nucleotide analog, which is exposed in the major groove of duplex DNA. The Hoogsteen face includes the N7 position and reactive groups (NH2 or O) at the C6 position of purine nucleotides. b) Primers and probes

57. Disclosed in Table 24 are compositions including primers and probes. In certain embodiments the primers are used to support DNA amplification reactions. Typically the primers will be capable of being extended in a sequence specific manner. Extension of a primer in a sequence specific manner includes any methods wherein the sequence and/or composition of the nucleic acid molecule to which the primer is hybridized or otherwise associated directs or influences the composition or sequence of the product produced by the extension of the primer. Extension of the primer in a sequence specific manner therefore includes, but is not limited to, PCR, DNA sequencing, DNA extension, DNA polymerization, RNA transcription, or reverse transcription. Techniques and conditions that amplify the primer in a sequence specific manner are preferred. In certain embodiments the primers are used for the DNA amplification reactions, such as PCR or direct sequencing. It is understood that in certain embodiments the primers can also be extended using non-enzymatic techniques, where for example, the nucleotides or oligonucleotides used to extend the primer are modified such that they will chemically react to extend the primer in a sequence specific manner. Typically the disclosed primers hybridize with the disclosed nucleic acids or region of the nucleic acids or they hybridize with the complement of the nucleic acids or complement of a region of the nucleic acids.

58. The size of the primers or probes for interaction with the nucleic acids in certain embodiments can be any size that supports the desired enzymatic manipulation of the primer, such as DNA amplification or the simple hybridization of the probe or primer. A typical primer or probe would be at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,

52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77,

78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 125, 150,

175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700, 750,

800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, 3000, 3500, or 4000 nucleotides long.

59. In other embodiments a primer or probe can be less than or equal to 6, 7, 8, 9, 10, 11,

12 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,

38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,

64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,

90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375,

400, 425, 450, 475, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, 3000, 3500, or 4000 nucleotides long.

3. Immunoassays and fluorochromes

60. The steps of various useful immunodetection methods have been described in the scientific literature, such as, e.g., Maggio et al., Enzyme-Immunoassay, (1987) and Nakamura, et al., Enzyme Immunoassays: Heterogeneous and Homogeneous Systems, Handbook of Experimental Immunology , Vol. 1: Immunochemistry , 27.1-27.20 (1986), each of which is incorporated herein by reference in its entirety and specifically for its teaching regarding immunodetection methods. Immunoassays, in their most simple and direct sense, are binding assays involving binding between antibodies and antigen. Many types and formats of immunoassays are known and all are suitable for detecting the disclosed biomarkers. Examples of immunoassays are enzyme linked immunosorbent assays (ELISAs), radioimmunoassays (RIA), radioimmune precipitation assays (RIP A), immunobead capture assays, Western blotting, dot blotting, gel-shift assays, Flow cytometry, protein arrays, multiplexed bead arrays, magnetic capture, in vivo imaging, fluorescence resonance energy transfer (FRET), and fluorescence recovery /localization after photobleaching (FRAP/ FLAP).

61. In general, immunoassays involve contacting a sample suspected of containing a molecule of interest (such as the disclosed biomarkers) with an antibody to the molecule of interest or contacting an antibody to a molecule of interest (such as antibodies to the disclosed biomarkers) with a molecule that can be bound by the antibody, as the case may be, under conditions effective to allow the formation of immunocomplexes. Contacting a sample with the antibody to the molecule of interest or with the molecule that can be bound by an antibody to the molecule of interest under conditions effective and for a period of time sufficient to allow the formation of immune complexes (pnmary immune complexes) is generally a matter of simply bringing into contact the molecule or antibody and the sample and incubating the mixture for a period of time long enough for the antibodies to form immune complexes with, i.e., to bind to, any molecules (e.g., antigens) present to which the antibodies can bind. In many forms of immunoassay, the sample-antibody composition, such as a tissue section, ELISA plate, dot blot or Western blot, can then be washed to remove any non-specifically bound antibody species, allowing only those antibodies specifically bound within the primary immune complexes to be detected.

62. Immunoassays can include methods for detecting or quantifying the amount of a molecule of interest (such as the disclosed biomarkers or their antibodies) in a sample, which methods generally involve the detection or quantitation of any immune complexes formed during the binding process. In general, the detection of immunocomplex formation is well known in the art and can be achieved through the application of numerous approaches. These methods are generally based upon the detection of a label or marker, such as any radioactive, fluorescent, biological or enzymatic tags or any other known label.

63. As used herein, a label can include a fluorescent dye, a member of a binding pair, such as biotin/streptavidin, a metal (e.g., gold), or an epitope tag that can specifically interact with a molecule that can be detected, such as by producing a colored substrate or fluorescence. Substances suitable for detectably labeling proteins include fluorescent dyes (also known herein as fluorochromes and fluorophores) and enzymes that react with colorometric substrates (e.g., horseradish peroxidase). The use of fluorescent dyes is generally preferred in the practice of the invention as they can be detected at very low amounts. Furthermore, in the case where multiple antigens are reacted with a single array, each antigen can be labeled with a distinct fluorescent compound for simultaneous detection. Labeled spots on the array are detected using a fluorimeter, the presence of a signal indicating an antigen bound to a specific antibody. 64. Fluorophores are compounds or molecules that luminesce. Typically fluorophores absorb electromagnetic energy at one wavelength and emit electromagnetic energy at a second wavelength. Representative fluorophores include, but are not limited to, 1,5 IAEDANS; 1,8- ANS; 4- Methylumbelliferone; 5-carboxy-2,7-dichlorofluorescein; 5-Carboxyfluorescein (5- FAM); 5-Carboxynapthofluorescein; 5-Carboxytetramethylrhodamine (5-TAMRA); 5-Hydroxy Tryptamine (5-HAT); 5-ROX (carboxy-X-rhodamine); 6-Carboxyrhodamine 6G; 6-CR 6G; 6- JOE; 7-Amino-4-methylcoumarin; 7-Aminoactinomycin D (7-AAD); 7-Hydroxy-4- 1 methylcoumarin; 9-Amino-6-chloro-2-methoxyacridine (ACMA); ABQ; Acid Fuchsin; Acridine Orange; Acridine Red; Acridine Yellow; Acriflavin; Acriflavin Feulgen SITS A; Aequorin (Photoprotein); AFPs - AutoFluorescent Protein - (Quantum Biotechnologies) see sgGFP, sgBFP; Alexa Fluor 350™; Alexa Fluor 430™; Alexa Fluor 488™; Alexa Fluor 532™; Alexa Fluor 546™; Alexa Fluor 568™; Alexa Fluor 594™; Alexa Fluor 633™; Alexa Fluor 647™; Alexa Fluor 660™; Alexa Fluor 680™; Alizarin Complexon; Alizarin Red; Allophycocyanin (APC); AMC, AMCA-S; Aminomethylcoumarin (AMCA); AMCA-X; Aminoactinomycin D; Aminocoumarin; Anilin Blue; Anthrocyl stearate; APC-Cy7; APTRA-BTC; APTS; Astrazon Brilliant Red 4G; Astrazon Orange R; Astrazon Red 6B; Astrazon Yellow 7 GLL; Atabrine; ATTO- TAG™ CBQCA; ATTO-TAG™ FQ; Auramine; Aurophosphine G; Aurophosphine; BAO 9 (Bisaminophenyloxadiazole); BCECF (high pH); BCECF (low pH); Berberine Sulphate; Beta Lactamase; BFP blue shifted GFP (Y66H); Blue Fluorescent Protein; BFP/GFP FRET; Bimane; Bisbenzemide; Bisbenzimide (Hoechst); bis- BTC; Blancophor FFG; Blancophor SV; BOBO™ -1; BOBO™-3; Bodipy 492/515; Bodipy493/503; Bodipy 500/510; Bodipy; 505/515; Bodipy 530/550; Bodipy 542/563; Bodipy 558/568; Bodipy 564/570; Bodipy 576/589; Bodipy 581/591; Bodipy 630/650-X, Bodipy 650/665-X; Bodipy 665/676; Bodipy Fl; Bodipy FL ATP; Bodipy Fl-Ceramide; Bodipy R6G SE; Bodipy TMR; Bodipy TMR-X conjugate; Bodipy TMR- X, SE; Bodipy TR; Bodipy TR ATP; Bodipy TR-X SE; BO-PRO™ -1; BO-PRO™ -3; Brilliant Sulphoflavin FF; BTC; BTC-5N; Calcein; Calcein Blue; Calcium Crimson - ; Calcium Green; Calcium Green-1 Ca ²⁺ Dye; Calcium Green-2 Ca ²⁺ ; Calcium Green-5N Ca ²⁺ ; Calcium Green- C18 Ca ²⁺ ; Calcium Orange; Calcofluor White; Carboxy-X-rhodamine (5-ROX); Cascade Blue™; Cascade Yellow; Catecholamine; CCF2 (GeneBlazer); CFDA; CFP (Cyan Fluorescent Protein); CFP/YFP FRET; Chlorophyll; Chromomycin A; Chromomycin A; CL-NERF; CMFDA; Coelenterazine; Coelenterazine cp; Coelenterazine f; Coelenterazine fcp; Coelenterazine h; Coelenterazine hep; Coelenterazine ip; Coelenterazine n; Coelenterazine O; Coumarin Phalloidin; C-phycocyanine; CPM I Methylcoumarin; CTC; CTC Formazan; Cy2™; Cy3.1 8; Cy3.5™; Cy3™; Cy5.1 8; Cy5.5™; Cy5™; Cy7™; Cyan GFP; cyclic AMP Fluorosensor (FiCRhR); Dabcyl; Dansyl; Dansyl Amine; Dansyl Cadaverine; Dansyl Chloride; Dansyl DHPE; Dansyl fluoride; DAPI; Dapoxyl; Dapoxyl 2; Dapoxyl 3’DCFDA; DCFH (Dichlorodihydrofluorescein Diacetate); DDAO; DHR (Dihydorhodamine 123); Di-4-ANEPPS; Di-8-ANEPPS (non-ratio); Di A (4-Di 16-ASP); Dichlorodihydrofluorescein Diacetate (DCFH); DiD- Lipophilic Tracer; DiD (DilC18(5)); DIDS; Dihydorhodamine 123 (DHR); Dil (DilC18(3)); I Dinitrophenol; DiO (DiOC18(3)); DiR; DiR (DilC18(7)); DM-NERF (high pH); DNP; Dopamine; DsRed; DTAF; DY-630-NHS; DY-635-NHS; EBFP; ECFP; EGFP; ELF 97; Eosin; Erythrosin; Erythrosin ITC; Ethidium Bromide; Ethidium homodimer-1 (EthD-1);

Euchrysin; EukoLight; Europium (111) chloride; EYFP; Fast Blue; FDA; Feulgen (Pararosaniline); FIF (Formaldehyd Induced Fluorescence); FITC; Flazo Orange; Fluo-3; Fluo- 4; Fluorescein (FITC); Fluorescein Diacetate; Fluoro-Emerald; Fluoro-Gold (Hydroxystilbamidine); Fluor-Ruby; FluorX; FM 1-43™; FM 4-46; Fura Red™ (high pH); Fura Red™/Fluo-3; Fura-2; Fura-2/BCECF; Genacryl Brilliant Red B; Genacryl Brilliant Yellow 10GF; Genacry l Pink 3G; Genacry l Yellow 5GF; GeneBlazer; (CCF2); GFP (S65T); GFP red shifted (rsGFP); GFP wild type’ non-UV excitation (wtGFP); GFP wild type, UV excitation (wtGFP); GFPuv; Gloxalic Acid; Granular blue; Haematoporphyrin; Hoechst 33258; Hoechst 33342; Hoechst 34580; HPTS; Hydroxy coumarin; Hydroxystilbamidine (FluoroGold);

Hydroxytryptamine; Indo-1, high calcium; Indo-1 low calcium; Indodi carbocyanine (DiD); Indotricarbocyanine (DiR); Intrawhite Cf; JC-1; JO JO-1; JO-PRO-1; LaserPro; Laurodan; LDS 751 (DNA); LDS 751 (RNA); Leucophor PAF; Leucophor SF; Leucophor WS; Lissamine Rhodamine; Lissamine Rhodamine B; Calcein/Ethidium homodimer; LOLO-1; LO-PRO-1; ; Lucifer Yellow; Lyso Tracker Blue; Lyso Tracker Blue- White; Lyso Tracker Green; Lyso Tracker Red; Lyso Tracker Yellow; LysoSensor Blue; LysoSensor Green; LysoSensor Yellow/Blue; Mag Green; Magdala Red (Phloxin B); Mag-Fura Red; Mag-Fura-2; Mag-Fura-5; Mag-lndo-1; Magnesium Green; Magnesium Orange; Malachite Green; Marina Blue; I Maxiion Brilliant Flavin 10 GFF; Maxiion Brilliant Flavin 8 GFF; Merocyanin; Methoxy coumarin;

Mitotracker Green FM; Mitotracker Orange; Mitotracker Red; Mitramycin; Monobromobimane; Monobromobimane (mBBr-GSH); Monochlorobimane; MPS (Methyl Green Pyronine Stilbene); NBD; NBD Amine; Nile Red; Nitrobenzoxedidole; Noradrenaline; Nuclear Fast Red; i Nuclear Yellow; Nylosan Brilliant lavin E8G; Oregon Green™; Oregon Green™ 488; Oregon Green™ 500; Oregon Green™ 514; Pacific Blue; Pararosaniline (Feulgen); PBFI; PE-Cy5; PE-Cy7; PerCP; PerCP-Cy5.5; PE-TexasRed (Red 613); Phloxin B (Magdala Red); Phorwite AR; Phorwite BKL; Phorwite Rev; Phorwite RPA; Phosphine 3R; PhotoResist; Phycoerythrin B [PE]; Phycoerythrin R [PE]; PKH26 (Sigma); PKH67; PMIA; Pontochrome Blue Black; POPO- 1; POPO-3; PO-PRO-1; PO- 1 PRO-3; Primuline; Procion Yellow; Propidium lodid (Pl); PyMPO; Pyrene; Pyronine; Pyronine B; Pyrozal Brilliant Flavin 7GF; QSY 7; Quinacrine Mustard; Resorufin; RH 414; Rhod-2; Rhodamine; Rhodamine 110; Rhodamine 123; Rhodamine 5 GLD; Rhodamine 6G; Rhodamine B; Rhodamine B 200; Rhodamine B extra; Rhodamine BB; Rhodamine BG; Rhodamine Green; Rhodamine Phallicidine; Rhodamine: Phalloidine; Rhodamine Red; Rhodamine WT; Rose Bengal; R-phy cocyanine; R-phycoerythrin (PE); rsGFP; S65A; S65C; S65L; S65T; Sapphire GFP; SBFI; Serotonin; Sevron Brilliant Red 2B; Sevron Brilliant Red 4G; Sevron I Brilliant Red B; Sevron Orange; Sevron Yellow L; sgBFP™ (super glow BFP); sgGFP™ (super glow GFP); SITS (Primuline; Stilbene Isothiosulphonic Acid); SNAFL calcein; SNAFL-1; SNAFL-2; SNARF calcein; SNARF1; Sodium Green; SpectrumAqua; SpectrumGreen; SpectrumOrange; Spectrum Red; SPQ (6- methoxy- N-(3 sulfopropyl) quinolinium); Stilbene; Sulphorhodamine B and C;

Sulphorhodamine Extra; SYTO 11; SYTO 12; SYTO 13; SYTO 14; SYTO 15; SYTO 16; SYTO 17; SYTO 18; SYTO 20; SYTO 21; SYTO 22; SYTO 23; SYTO 24; SYTO 25; SYTO 40; SYTO 41; SYTO 42; SYTO 43; SYTO 44; SYTO 45; SYTO 59; SYTO 60; SYTO 61; SYTO 62; SYTO 63; SYTO 64; SYTO 80; SYTO 81; SYTO 82; SYTO 83; SYTO 84; SYTO 85; SYTOX Blue; SYTOX Green; SYTOX Orange; Tetracycline; Tetramethylrhodamine (TRITC); Texas Red™; Texas Red-X™ conjugate; Thiadicarbocyanine (DiSC3); Thiazine Red R; Thiazole Orange; Thioflavin 5; Thioflavin S; Thioflavin TON; Thiolyte; Thiozole Orange; Tinopol CBS (Calcofluor White); TIER; TO-PRO-1; TO-PRO-3; TO-PRO-5; TOTO-1; TOTO- 3; TriColor (PE-Cy5); TRITC TetramethylRodaminelsoThioCyanate; True Blue; Tru Red; Ultralite; Uranine B; Uvitex SFC; wt GFP; WW 781; X-Rhodamine; XRITC; Xylene Orange; Y66F; Y66H; Y66W; Yellow GFP; YFP; YO-PRO-1; YO- PRO 3; YOYO- 1; YOYO-3; Svbr Green; Thiazole orange (interchelating dyes); semiconductor nanoparticles such as quantum dots; or caged fluorophore (which can be activated with light or other electromagnetic energy source), or a combination thereof.

65. A modifier unit such as a radionuclide can be incorporated into or attached directly to any of the compounds described herein by halogenation. Examples of radionuclides useful in this embodiment include, but are not limited to, tritium, iodine-125, iodine-131, iodine-123, iodine-124, astatine-210, carbon-11, carbon-14, nitrogen-13, fluorine-18. In another aspect, the radionuclide can be attached to a linking group or bound by a chelating group, which is then attached to the compound directly or by means of a linker. Examples of radionuclides useful in the apset include, but are not limited to, Tc-99m, Re-186, Ga-68, Re-188, Y-90, Sm-153, Bi- 212, Cu-67, Cu-64, and Cu-62. Radiolabeling techniques such as these are routinely used in the radiopharmaceutical industry.

66. The radiolabeled compounds are useful as imaging agents to diagnose neurological disease (e.g., a neurodegenerative disease) or a mental condition or to follow the progression or treatment of such a disease or condition in a mammal (e.g., a human). The radiolabeled compounds described herein can be conveniently used in conjunction with imaging techniques such as positron emission tomography (PET) or single photon emission computerized tomography (SPECT).

67. Labeling can be either direct or indirect. In direct labeling, the detecting antibody (the antibody for the molecule of interest) or detecting molecule (the molecule that can be bound by an antibody to the molecule of interest) include a label. Detection of the label indicates the presence of the detecting antibody or detecting molecule, which in turn indicates the presence of the molecule of interest or of an antibody to the molecule of interest, respectively. In indirect labeling, an additional molecule or moiety is brought into contact with, or generated at the site of, the immunocomplex. For example, a signal-generating molecule or moiety such as an enzyme can be attached to or associated with the detecting antibody or detecting molecule. The signal-generating molecule can then generate a detectable signal at the site of the immunocomplex. For example, an enzyme, when supplied with suitable substrate, can produce a visible or detectable product at the site of the immunocomplex. ELISAs use this type of indirect labeling.

68. As another example of indirect labeling, an additional molecule (which can be referred to as a binding agent) that can bind to either the molecule of interest or to the antibody (primary antibody) to the molecule of interest, such as a second antibody to the primary antibody, can be contacted with the immunocomplex. The additional molecule can have a label or signal-generating molecule or moiety. The additional molecule can be an antibody, which can thus be termed a secondary antibody. Binding of a secondary antibody to the primary antibody can form a so-called sandwich with the first (or primary) antibody and the molecule of interest. The immune complexes can be contacted with the labeled, secondary antibody under conditions effective and for a period of time sufficient to allow the formation of secondary immune complexes. The secondary immune complexes can then be generally washed to remove any non-specifically bound labeled secondary antibodies, and the remaining label in the secondary immune complexes can then be detected. The additional molecule can also be or include one of a pair of molecules or moieties that can bind to each other, such as the biotin/avadin pair. In this mode, the detecting antibody or detecting molecule should include the other member of the pair.

69. Other modes of indirect labeling include the detection of primary immune complexes by a two step approach. For example, a molecule (which can be referred to as a first binding agent), such as an antibody, that has binding affinity for the molecule of interest or corresponding antibody can be used to form secondary immune complexes, as described above. After washing, the secondary immune complexes can be contacted with another molecule (which can be referred to as a second binding agent) that has binding affinity for the first binding agent, again under conditions effective and for a period of time sufficient to allow the formation of immune complexes (thus forming tertiary immune complexes). The second binding agent can be linked to a detectable label or signal-genrating molecule or moiety, allowing detection of the tertiary immune complexes thus formed. This system can provide for signal amplification.

4. Kits

70. Disclosed herein are kits that are drawn to reagents that can be used in practicing the methods disclosed herein. The kits can include any reagent or combination of reagent discussed herein or that would be understood to be required or beneficial in the practice of the disclosed methods. For example, the kits could include primers to perform the amplification reactions discussed in certain embodiments of the methods, as well as the buffers and enzymes required to use the primers as intended. For example, disclosed herein are kits used for of the treatment of a cancer (such as, for example colorectal cancer, including, but not limited to metastatic colorectal cancers (mCRC) such as, for example, stage 4 mCRC) comprising one or more probe sets comprising merck2_AA101946_x_at, merck2_AA490328_at, merck2_AF129457_at, merck2_AF289590_at, merck2_A1091276_at, merck2_A1223270_at, merck2_A1962276_at, merck2_AK092910_at, merck2_AK093149_at, merck2_AK131291_at, merck2_AL359561_at, merck2_AL832223_at, merck2_AL834299_at, merck2_AL834442_at, merck2_AM392650_at, merck2_AW007481_at, merck2_AX721105_at, merck2_BC001038_at, merck2_BC033091_at, merck2 BC035840 at, merck2 BC039861 at, merck2 BE249972 x at, merck2_BE349054_x_at, merck2_BF248252_at, merck2_BF591243_at, merck2_BF692777_at, merck2_BG896934_at, merck2_BI047264_at, merck2_BM545067_s_at, merck2_BM681401_at, merck2_BU618242_at, merck2_BXl 15227_at, merck2_BX647415_at, merck2_BX647735_at, merck2_BX648311_at, merck2_BY799718_at, merck2_CMV_UL43_at, merck2_CR749241_s_at, merck2_CX783886_a_at, merck2_DB492896_at, merck2_DQ891843_at, merck2_ENST00000355104_x_at, merck2_ENST00000371290_s_at, merck2_F25718_at, merck2_HSV l_ORF_UL46_at, merck2_HSV2_ORF_UL18_at, merck2_JC_vir_smTAg_at, merck2_NM_001005224_s_at, merck2_NM_001037866_s_at, merck2_NM_001080537_at, merck2_NM_005570_at, merck2_NM_006485_at, merck2_NM_006594_at, merck2_NM_022079_at, merck2_NM_022747_at, merck2_NM_025214_at, merck2_NM_030813_at, merck2_NM_032260_s_at, merck2_NM_032639_at, merck2_NM_052996_a_at, merck2_NM_205833_at, merck2_VZV_OKA_O32_up_at, merck2_VZV_OKA_O47_up_at, merck2_XM_938193_at, merck_AB058756_a_at, merck_AF038451_a_at, merck_AF085981_at, merck_AF118083_a_at, merck_AF143326_at, merck_AF147412_at, merck_AF147431_at, merck_AF161340_at, merck_AF169158_a_at, merck_AF311308_at, merck_AI204893_at, merck_AJ406951_s_at, merck_AJ459838_at, merck_AK000932_at, merck_AK021682_at, merck_AK022168_at, merck_AK022347_at, merck_AK022443_at, merck_AK023601_at, merck_AK024198_at, merck_AK024231_at, merck_AK024810_a_at, merck_AK025202_a_al, merck_AK025621_al, merck_AK026808_at, merck_AK054931_at, merck_AK055172_a_at, merck_AK055584_at, merck_AK091999_at, merck_AK093735_s_at, merck_AK095449_at, merck_AK096712_at, merck_AK097571_s_at, merck_AK097840_a_at, merck_AK123535_at, merck_AK123655_s_at, merck_AK123888_at, merck_AK125149_at, merck_AK127206_s_at, merck_AK130508_at, merck_AK222828_a_at, merck_AL044815_at, merck_AL133569_at, merck_AL162044_at, merck_AL353936_at, merck_AL563761_at, merck_AV762307_at, merck_AW370282_at, merck_AW665698_at, merck_AW771625_a_at, merck_AW809224_at, merck_AW843987_at, merck_AW977003_at, merck_AY054391_at, merck_AY147849_a_at, merck_BC001905_a_at, merck_BC007984_at, merck_BC012447_a_at, merck_BC014119_at, merck_BC015877_a_at, merck_BC019893_s_at, merck_BC022892_at, merck_BC034596_at, merck_BC036594_at, merck_BC039321_at, merck_BC064385_at, merck_BC110326_at, merck_BCl 10867_s_at, merck_BE219852_at, merck_BE463518_at, merck_BE546828_at, merck_BF342524_at, merck_BF679703_at, merck_BF965720_at, merck_BG236239_a_at, merck_BG287007_at, merck_BG675291_at, merck BG740109 a at, merck BG943385 at, merck BG956704 x at, merck BI045425 at, merck_BI757398_at, merck_BM676784_at, merck_BM805663_at, merck_BQ380337_at, merck_BU145850_at, merck_BU935068_a_at, merck_BX095858_at, merck_BX096093_at, merck_BX097755_a_at, merck_BX102791_at, merck_BX102980_at, merck_BX116278_at, merck_BX119057_at, merck_BX329942_at, merck_CA309176_at, merck_CA942562_at, merck_CD102009_at, merck_CN388529_a_at, merck_CR742243_at, merck_CR994266_a_at, merck_CV392556_at, merck_CX785712_at, merck_DA214150_a_at, merck_DA234289_at, merck_DB351522_at, merck_DB546490_at, merck_DN831737_at, merck_DV080080_at, merck_EN ST00000248668_at, merck_EN ST00000316506_a_at, merck_ENST00000323496_x_at, merck_ENST00000327196_at, merck_ENST00000331146_at, merck_ENST00000341244_a_at, merck_ENST00000359421_at, merck_ENST00000366485_at, merck_ENST00000376325_at, merck_ENST00000378999_s_at, merck_ENST00000381435_at, merck_G65625_at, merck_NC_001405_ORF_1045_s_at, merck_NM_000258_at, merck_NM_000273_at, merck_NM_000782_at, merck_NM_000873_at, merck_NM_001001706_at, merck_NM_OO 1002247_at, merck_NM_OO 1004434_s_at, merck_NM_OO 1004752_at, merck_NM_OO 1012505_a_at, merck_NM_001024599_s_at, merck_NM_001039753_s_at, merck_NM_001039_at, merck_NM_001294_at, merck_NM_001431_s_at, merck_NM_001494_at, merck_NM_001883_at, merck_NM_001993_at, merck_NM_002501_s_at, merck_NM_003920_s_at, merck_NM_003954_at, merck_NM_004318_al, merck_NM_004387_al, merck_NM_004422_al, merck_NM_004683_s_at, merck_NM_005184_s_at, merck_NM_006143_at, merck_NM_006268_at, merck_NM_007179_at, merck_NM_014184_s_at, merck_NM_014230_s_at, merck_NM_014553_at, merck_NM_015058_at, merck_NM_015832_a_at, merck_NM_016593_at, merck_NM_017916_at, merck_NM_018055_at, merck_NM_018219_at, merck_NM_020457_at, merck_NM_020651_at, merck_NM_020677_s_at, merck_NM_020774_at, merck_NM_021912_at, merck_NM_021946_s_at, merck_NM_021983_x_at, merck_NM_022358_at, merck_NM_025214_at, merck_NM_030944_at, merck_NM_032143_a_at, merck_NM_032594_at, merck_NM_052910_at, merck_NM_058165_at, merck_NM_058219_at, merck_NM_133262_at, merck_NM_133492_at, merck_NM_138447_a_at, merck_NM_139174_at, merck_NM_139315_s_at, merck_NM_145270_at, merck_NM_152730_s_at, merck_NM_153274_at, merck_NM_173798_at, merck_NM_174962_x_at, merck NM 176889 at, merck NM 178012 at, merck NM 181608 x at, merck_NM_182505_at, merck_NM_182800_at, merck_NM_l 82905_s_at, merck_NM_198994_at, merck_NM_199180_at, merck_VZV_OKA_ORF41_s_at, merck_VZV_OKA_ORF9_s_at, merck_X85629_at, merck_X98206_at, merck_XM_063314_at, merck_XM_210303_at, merck_XM_373233_x_at, merck_XM_378090_at, merck_XM_926011_at, merck_XM_928173_s_at, merck_XM_928586_x_at, merck_XM_929767_at, merck_XM_933463_at, merck_XM_937104_at, merck_XM_940419_at, merck_XM_943662_at, merck_XM_945363_at, merck_hCTl 651346_at, merck_hCTl 651838_3_at, merck_hCTl 812405_2_at, merck_hCT1846664_l_at, merck_hCT2307348_at, and/or merck_hsa_mir_153_l_x_at

71. Also disclosed herein are kits, wherein the one or more probe sets bind to one or more genes comprising TIMM8A, PRDM15, LOC100130744, LANCL2, LOC101929529, NPHP3 NPHP3-ACAD11, MY05B, ZSCAN30, ZNF462, CDON. ZNF689, NC0A7, ZNF280D, NFIX, ZNF467, EPN3, SLC25A27, GJC2, NODAL, RPL17 RPL17-C18orfi2, TDRKH, FAM149B1, PPIE, FIP1L1, MRPL38, GABPB1-AS1, GALNT1, ERICH 1, CEP 126, AP3S1, AHI1, MRPL1, FRMPD2, UBE3A, ZNF365, ICAM2, PRR21, CT47A1 CT47A10 CT47A11 CT47A12 CT47A2 CT47A3 CT47A4 CT47A5 CT47A6 CT47A7 CT47A8 CT47A9, LINC01405, OR4F16 OR4F21 OR4F29 OR4F3, RGPD5 RGPD6, SNTN, LMAN1, FBLNlm AP4B1, HERC4, CCDC85C, CCDC68, CLPB, RGPD5 RGPD6, PLEKHA8, PRDM7, IGSF1, SH2D1A STAG2 HSPA8P20 NPM1P34 TEX13D ZIK1P1 LOC101928402, SRRM4, AGR2, ENTPD4, EXOC5, FOXP1 FOXP1-AS1 MIR1284, ARID1B MIR4466, DIS3L, CABP5, MGAT1, KRTAP9-9, 0R2H1, COL9A2, CSTF2T MIR605 PRKG1 RSU1P3 LOC102724719, CSTF2T MIR605 PRKG1 RSU1P3, LOCI 02724719, FOXP1 FOXP1 -AS1 MIR1284, EFR3A, PRPF40A, LARGE1, LOC101927365, HERC4, MIR9-3HG, DLG5, STT3B, LOC101929713, CEP83, CRK, USP46, LOC105378730, LOC105379589 LOC107984097 LOC107987409 LOC107987410, FBXL18, UCHL5, ZNF555, CD99P1, LONRF2, LOC100507281, LMAN2L, MTMR6, LOC107987180, PCDH9 PCDH9-AS4, PSD3, USP3-AS1, MAP3K6, CSNK1G1, GTPBP1, BDNF-AS, MIB1, PCSK2, BFSP2-AS1, SP110, LINC00824, CDH19, CD99P1, IWS1, LINC01725, TISP43 LOC646743, TRIQK, CDH24, LOC101927472, LINC02004, SIRPD, CLYBL, THUMPD3-AS1, KLRA1P, LINC01971, SOGA1, RIMBP2, TJP2, NFATC3 RPS12P27, GDAP2, MSN, ELFN1-AS1, PNPO, LOC101929371, LAMB1, JAK1, NDF1P1, UHRF2, RIN2, SLC25A48, PHF2P2, LRFN1, OR52B1P, BCAS4, LOC107985946, RPS17P5, TAF4B, FAM92A, OR14A2, SHISA7, REXO1L2P, MCHR1, MYL3, GPR143, CYP24A1, ICAM2, AK9, ANAPC11, SLC30A2, OR51F1, FOXP1, HIST2H2BF, EML6, SCNN1G, CLPTM1, EPB41L2, GDI2, CRHR2, F3, NFIX, TIMELESS, MAP3K14, ASPH, NKX2-5, DVL2, RGN, CALM3, GPR19, DPF2, INSL6, CNIH4, SRP68, TFCP2L1, VWA8, MBD2, CYP39A1, PIH1D1, NODAL, CCDC87, THAP11, PELI1, NMRAL1, MIB1, GABRB3, BCORL1, HLA-DRB4, KCNK15, CCDC68, LINC00597, ZRANB3, INSM2, SLITRK1, MOGAT1, EXOSC6, ATP6V1G3, ACER1, ZNF689, ADAD2, TAF6, PRR35, TBC1D32, BEST4, ZCCHC12, SSX9, TAS2R20, TUBB2B, KRTAP19-2, C9orf85, SRRT, WASHCI, TGM6, KIRREL2, ARID1B MIR4466, OR11H5P, LOC642515, PPIAL4A PPIAL4C PPIAL4D PP1AL4E PP1AL4F PP1AL4G, FAM207BP FAM207CP, SLC9B1P1, RPS28P1, LOC100288437, EL0CP31, and/or MIR153-1.

72. In one aspect, the kit includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,

16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,

42, 4,3 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,

68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93,

94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133,

134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152,

153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171,

172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190,

191 ,192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209,

210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228,

229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247,

248, 249, 250, 251 , 252, 253, 254, 255, 256, 257, 258, 259, 260, 261 , 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, or 279 of the disclosed probe sets (see for example, Table 24 and those listed above). In one aspect the probe sets bind to at least

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,

30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 4,3 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,

56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81,

82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105,

106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124,

125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143,

144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162,

163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181,

182, 183, 184, 185, 186, 187, 188, 189, 190, 191 ,192, 193, 194, 195, 196, 197, or 198 genes (see for example table 24 and those listed above). In one aspect, the probes bind to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 of the genes selected from the group consisting of AGR2, BEST4, CRHR2, CRK, CYP24A1, DVL2, ELFN1-AS1, F3, FIP1L1, FOXP1, ICAM2, JAK1, MAP3K14, MBD2, MIB1, MSN, NKX2-5, NODAL, THUMPD3-AS1, TIMELESS, TJP2, and/or USP46. In one aspect, the probes bind to at least 1,

2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 of the genes selected from the group consisting of BFSP2-AS1, ERICH1, HERC4, HIST2H2BF, IWS1, LINC01405, MCHR1, MTMR6, SLC30A2, SLITRK1, SRP68, SRRM4, TFCP2L1, and/or ZNF462. In one aspect, the probes bind to at least 1, 2, 3, 4, 5, 6, 7, or 8 of the genes selected from the group consisting of ERICH1, HERC4, HIST2H2BF, IWS1, MTMR6, SRP68, TFCP2L1, ZNF462 (such as, for example, HERC4, HIST2H2BF, IWS1, SRP68, and/or ZNF462). In one aspect, the probes bind to at least 1, 2, 3, 4, 5, 6, or 7 of the genes selected from the group consisting of HERC4, HIST2H2BF, IWS1, MCHR1, SLC30A2, SRP68, ZNF462. It is understood and herein contemplated that low expression of some genes can be associated with an increase in death (i.e., low survivability and thus high expression is good) including, but not limited to CLPTM1, GTPBP1, IWS1, MAP3K14, MBD2, PIH1D1, SLC25A27, TJP2

73. While various embodiments of the present disclosure have been described above, it should be understood that they have been presented by way of example only, and not of limitation. Likewise, the various diagrams may depict an example architectural or other configuration for the invention, which is provided to aid in understanding the features and functionality that can be included in the invention. The invention is not restricted to the illustrated example architectures or configurations, but the desired features can be implemented using a variety of alternative architectures and configurations.

74. Indeed, it will be apparent to one of skill in the art how alternative functional configurations can be implemented to implement the desired features of the present disclosure. Additionally, with regard to flow diagrams, operational descriptions and method claims, the order in which the steps are presented herein shall not mandate that various embodiments be implemented to perform the recited functionality in the same order unless the context dictates otherwise.

75. Although the disclosure is described above in terms of various exemplary embodiments and implementations, it should be understood that the various features, aspects and functionality described in one or more of the individual embodiments are not limited in their applicability to the particular embodiment with which they are described, but instead can be applied, alone or in various combinations, to one or more of the other embodiments of the disclosure, whether or not such embodiments are described and whether or not such features are presented as being a part of a described embodiment. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments.

C. Method of treating cancer

76. The disclosed compositions can be used to treat any disease where uncontrolled cellular proliferation occurs such as cancers. A representative but non-limiting list of cancers that the disclosed compositions can be used to treat is the following: lymphomas such as B cell lymphoma and T cell lymphoma; mycosis fungoides; Hodgkin’s Disease; myeloid leukemia (including, but not limited to acute myeloid leukemia (AML) and/or chronic myeloid leukemia (CML)); bladder cancer; brain cancer; nervous system cancer; head and neck cancer; squamous cell carcinoma of head and neck; renal cancer; lung cancers such as small cell lung cancer, nonsmall cell lung carcinoma (NSCLC), lung squamous cell carcinoma (LUSC), and Lung Adenocarcinomas (LUAD); neuroblastoma/glioblastoma; ovarian cancer; pancreatic cancer; prostate cancer; skin cancer; hepatic cancer; melanoma; squamous cell carcinomas of the mouth, throat, larynx, and lung; cervical cancer; cervical carcinoma; breast cancer including, but not limited to triple negative breast cancer; genitourinary cancer; pulmonary cancer; esophageal carcinoma; head and neck carcinoma; large bowel cancer; hematopoietic cancers; testicular cancer; and colon and rectal cancers. In one aspect, the cancer is metastatic colorectal cancer including, but not limited to late term or stage 4 colorectal cancer.

77. In one aspect, disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating, and/or preventing a cancer and/or metastasis (such as, for example colorectal cancer, including, but not limited to metastatic colorectal cancers (mCRC) in a subject comprising: a) obtaining a cancerous tissue sample from the subject; b) contacting the tissue sample with one or more probesets in the kit of claim 1 or 2; c) assaying the expression of one or more genes from the sample to create a gene signature, wherein principle component analy sis is applied to the gene signature to create a probability score for the subject; and d) treating the subject with chemotherapy and bevacizumab (AV AS TIN®) when the probability score is high; and treating the subject with chemotherapy and not bevacizumab (AVASTIN®) when the probability score is low. In one aspect, the administration of bevacizumab (AVASTIN®) toa subject with a low probability score has a deleterious effect on the subject. For example, disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating, and/or preventing a cancer and/or metastasis (such as, for example colorectal cancer, including, but not limited to metastatic colorectal cancers (mCRC) in a subject comprising: a) obtaining a cancerous tissue sample from the subject; b) contacting the tissue sample with one or more probesets that binds to one or more genes that are differentially expressed in the cancer; c) assaying the expression of one or more genes from the sample to create a gene signature, wherein principle component analysis is applied to the gene signature to create a probability score for the subject; and d) treating the subject with chemotherapy and bevacizumab (AVASTIN®) when the probability score is high; and treating the subject with chemotherapy and not bevacizumab (AVASTIN®) when the probability score is low. In one aspect, wherein the subject has a low probability score and is already receiving chemotherapy; bevacizumab is not administered. In one aspect, wherein the subject has a high probability score and is already receiving chemotherapy; bevacizumab is not administered.

78. Also disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating, and/or preventing a cancer and/or metastasis of any preceding aspect wherein the one or more probe sets comprise merck2_AA101946_x_at, merck2_AA490328_at, merck2_AF129457_at, merck2_AF289590_at, merck2_AI091276_at, merck2_AI223270_at, merck2_AI962276_at, merck2_AK092910_at, merck2_AK093149_at, merck2_AK131291_at, merck2_AL359561_at, merck2_AL832223_at, merck2_AL834299_at, merck2_AL834442_at, merck2_AM392650_at, merck2_AW007481_at, merck2_AX721105_at, merck2_BC001038_at, merck2_BC033091_at, merck2_BC035840_at, merck2_BC039861_at, merck2_BE249972_x_at, merck2_BE349054_x_at, merck2_BF248252_at, merck2_BF591243_at, merck2_BF692777_at, merck2_BG896934_at, merck2_BI047264_at, merck2_BM545067_s_at, merck2_BM681401_at, merck2_BU618242_at, merck2_BX115227_at, merck2_BX647415_at, merck2_BX647735_at, merck2_BX648311_at, merck2_BY799718_at, merck2_CMV_UL43_at, merck2_CR749241_s_at, merck2_CX783886_a_at, merck2_DB492896_at, merck2_DQ891843_at, merck2_ENST00000355104_x_at, merck2_ENST00000371290_s_at, merck2_F25718_at, merck2_HSV l_ORF_UL46_at, merck2_HSV2_ORF_ULl 8_at, merck2_JC_vir_smTAg_at, merck2_NM_001005224_s_at, merck2_NM_001037866_s_at, merck2_NM_001080537_at, merck2_NM_005570_at, merck2_NM_006485_at, merck2_NM_006594_at, merck2_NM_022079_at, merck2_NM_022747_at, merck2_NM_025214_at, merck2_NM_030813_at, merck2_NM_032260_s_at, merck2_NM_032639_at, merck2_NM_052996_a_at, merck2_NM_205833_at, merck2_VZV_OKA_O32_up_at, merck2_VZV_OKA_O47_up_at, merck2_XM_938193_at, merck_AB058756_a_at, merck_AF038451_a_at, merck_AF085981_at, merck_AF118083_a_at, merck_AF143326_at, merck_AF147412_at, merck_AF147431_at, merck_AF161340_at, merck_AF169158_a_at, merck AF311308 at, merck AI204893 at, merck AJ406951 s at, merck AJ459838 at, merck_AK000932_at, merck_AK021682_at, merck_AK022168_at, merck_AK022347_at, merck_AK022443_at, merck_AK023601_at, merck_AK024198_at, merck_AK024231_at, merck_AK024810_a_at, merck_AK025202_a_at, merck_AK025621_at, merck_AK026808_at, merck_AK054931_at, merck_AK055172_a_at, merck_AK055584_at, merck_AK091999_at, merck_AK093735_s_at, merck_AK095449_at, merck_AK096712_at, merck_AK097571_s_at, merck_AK097840_a_at, merck_AK123535_at, merck_AK123655_s_at, merck_AK123888_at, merck_AK125149_at, merck_AK127206_s_at, merck_AK130508_at, merck_AK222828_a_at, merck_AL044815_at, merck_AL133569_at, merck_AL162044_at, merck_AL353936_at, merck_AL563761_at, merck_AV762307_at, merck_AW370282_at, merck_AW665698_at, merck_AW771625_a_at, merck_AW809224_at, merck_AW843987_at, merck_AW977003_at, merck_AY054391_at, merck_AY147849_a_at, merck_BC001905_a_at, merck_BC007984_at, merck_BC012447_a_at, merck_BC014119_at, merck_BC015877_a_at, merck_BC019893_s_at, merck_BC022892_at, merck_BC034596_at, merck_BC036594_at, merck_BC039321_at, merck_BC064385_at, merck_BC110326_at, merck_BC110867_s_at, merck_BE219852_at, merck_BE463518_at, merck_BE546828_at, merck_BF342524_at, merck_BF679703_at, merck_BF965720_at, merck_BG236239_a_at, merck_BG287007_at, merck_BG675291_at, merck_BG740109_a_at, merck_BG943385_at, merck_BG956704_x_at, merck_BI045425_at, merck_BI757398_at, merck_BM676784_at, merck_BM805663_at. merck_BQ380337_at, merck_BU145850_at, merck_BU935068_a_at, merck_BX095858_at, merck_BX096093_at, merck_BX097755_a_al, merck_BX102791_al, merck_BX102980_at, merck_BX116278_al, merck_BX119057_at, merck_BX329942_at, merck_CA309176_at, merck_CA942562_at, merck_CD102009_at, merck_CN388529_a_at, merck_CR742243_at, merck_CR994266_a_at, merck_CV392556_at, merck_CX785712_at, merck_DA214150_a_at, merck_DA234289_at, merck_DB351522_at, merck_DB546490_at, merck_DN831737_at, merck_DV080080_at, merck_ENST00000248668_at, merck_ENST00000316506_a_at, merck_ENST00000323496_x_at, merck_ENST00000327196_at, merck_ENST00000331146_at, merck_ENST00000341244_a_at, merck_ENST00000359421_at, merck_ENST00000366485_at, merck_ENST00000376325_at, merck_ENST00000378999_s_at, merck_ENST00000381435_at, merck_G65625_at, merck_NC_001405_ORF_1045_s_at, merck_NM_000258_at, merck_NM_000273_at, merck_NM_000782_at, merck_NM_000873_at, merck_NM_001001706_at, merck_NM_OO 1002247_at, merck_NM_OO 1004434_s_at, merck_NM_OO 1004752_at, merck_NM_OO 1012505_a_at, merck_NM_001024599_s_at, merck_NM_001039753_s_at, merck_NM_001039_at, merck_NM_001294_at, merck_NM_001431_s_at, merck_NM_001494_at, merck_NM_001883_at, merck_NM_001993_at, merck_NM_002501_s_at, merck_NM_003920_s_at, merck_NM_003954_at, merck_NM_004318_at, merck_NM_004387_at, merck_NM_004422_at, merck_NM_004683_s_at, merck_NM_005184_s_at, merck_NM_006143_at, merck_NM_006268_at, merck_NM_007179_at, merck_NM_014184_s_at, merck_NM_014230_s_at, merck_NM_014553_at, merck_NM_015058_at, merck_NM_015832_a_at, merck_NM_016593_at, merck_NM_017916_at, merck_NM_018055_at, merck_NM_018219_at, merck_NM_020457_at, merck_NM_020651_at, merck_NM_020677_s_at, merck_NM_020774_at, merck_NM_021912_at, merck_NM_021946_s_at, merck_NM_021983_x_at, merck_NM_022358_at, merck_NM_025214_at, merck_NM_030944_at, merck_NM_032143_a_at, merck_NM_032594_at, merck_NM_052910_at, merck_NM_058165_at, merck_NM_058219_at, merck_NM_133262_at, merck_NM_133492_at, merck_NM_138447_a_at, merck_NM_139174_at, merck_NM_139315_s_at, merck_NM_145270_at, merck_NM_152730_s_at, merck_NM_153274_at, merck_NM_173798_at, merck_NM_174962_x_at, merck_NM_176889_at, merck_NM_178012_at, merck_NM_181608_x_at, merck_NM_182505_at, merck_NM_182800_at, merck_NM_l 82905_s_at, merck_NM_198994_at, merck_NM_199180_at, merck_VZV_0KA_0RF41_s_at, merck_VZV_0KA_0RF9_s_al, merck_X85629_al, merck_X98206_at, merck_XM_063314_al, merck_XM_210303_at, merck_XM_373233_x_at, merck_XM_378090_at, merck_XM_92601 l_at, merck_XM_928173_s_at, merck_XM_928586_x_at, merck_XM_929767_at, merck_XM_933463_at, merck_XM_937104_at, merck_XM_940419_at, merck_XM_943662_at, merck_XM_945363_at, merck_hCTl 651346_at, merck_hCTl 651838_3_at, merck_hCTl 812405_2_at, merck_hCT1846664_l_at, merck_hCT2307348_at, or merck_hsa_mir_153_l_x_at

79. In one aspect, disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating, and/or preventing a cancer and/or metastasis of any preceding aspect, wherein the one or more genes comprise TIMM8A, PRDM15, LOC100130744, LANCL2, LOC101929529, NPHP3 NPHP3-ACAD11, MY05B, ZSCAN30, ZNF462, CDON. ZNF689, NC0A7, ZNF280D, NFIX, ZNF467, EPN3, SLC25A27, GJC2, NODAL, RPL17 RPL17- C18orf32, TDRKH, FAM149B1, PPIE, FIP1L1, MRPL38, GABPB1-AS1, GALNT1, ERICH1, CEP126, AP3S1, AHI1, MRPL1, FRMPD2, UBE3A, ZNF365, ICAM2, PRR21, CT47A1 CT47A10 CT47A11 CT47A12 CT47A2 CT47A3 CT47A4 CT47A5 CT47A6 CT47A7 CT47A8 CT47A9, LINC01405, OR4F16 OR4F21 OR4F29 OR4F3, RGPD5 RGPD6, SNTN, LMAN1, FBLNlm AP4B1, HERC4, CCDC85C, CCDC68, CLPB, RGPD5 RGPD6, PLEKHA8, PRDM7, IGSF1, SH2D1A STAG2 HSPA8P20 NPM1P34 TEX13D ZIK1P1 LOC101928402, SRRM4, AGR2, ENTPD4, EXOC5, FOXP1 FOXP1-AS1 MIR1284, ARID1B MIR4466, DIS3L, CABP5, MGAT1, KRTAP9-9, 0R2H1, COL9A2, CSTF2T MIR605 PRKG1 RSU1P3 LOC102724719, CSTF2T MIR605 PRKG1 RSU1P3, LOC102724719, FOXP1 FOXP1-AS1 MIR1284, EFR3A, PRPF40A, LARGE1, LOC101927365, HERC4, MIR9-3HG, DLG5, STT3B, LOC101929713, CEP83, CRK, USP46, LOC105378730, LOC105379589 LOC107984097 LOC107987409 LOC107987410, FBXL18, UCHL5, ZNF555, CD99P1, L0NRF2, LOC100507281, LMAN2L, MTMR6, LOC107987180, PCDH9 PCDH9-AS4, PSD3, USP3-AS1, MAP3K6, CSNK1G1, GTPBP1, BDNF-AS, MIB1, PCSK2, BFSP2-AS1, SP110, LINC00824, CDH19, CD99P1, IWS1, LINC01725, TISP43 LOC646743, TRIQK, CDH24, LOC101927472, LINC02004, SIRPD, CLYBL, THUMPD3-AS1, KLRA1P, LINC01971, SOGA1, RIMBP2, TJP2, NFATC3 RPS12P27, GDAP2, MSN, ELFN1-AS1, PNPO, LOCI 01929371, LAMB1, JAK1, NDFIP1, UHRF2, RIN2, SLC25A48, PHF2P2, LRFN1, OR52B1P, BCAS4, LOC107985946, RPS17P5, TAF4B, FAM92A, OR14A2, SHISA7, REXO1L2P, MCHR1, MYL3, GPR143, CYP24A1, ICAM2, AK9, ANAPC11, SLC30A2, OR51F1, FOXP1, HIST2H2BF, EML6, SCNN1G, CLPTM1, EPB41L2, GDI2, CRHR2, F3, NFIX, TIMELESS, MAP3K14, ASPH, NKX2-5, DVL2, RGN, CALM3, GPR19, DPF2, INSL6, CNIH4, SRP68, TFCP2L1, VWA8, MBD2, CYP39A1, PIH1D1, NODAL, CCDC87, THAP11, PELI1, NMRAL1, MIB1, GABRB3, BCORL1, HLA-DRB4, KCNK15, CCDC68, LINC00597, ZRANB3, INSM2, SLITRK1 , MOGAT1 , EXOSC6, ATP6V1 G3, ACER1 , ZNF689, ADAD2, TAF6, PRR35, TBC1D32, BEST4, ZCCHC12, SSX9, TAS2R20, TUBB2B, KRTAP19-2, C9orf85, SRRT, WASHCI, TGM6, KIRREL2, ARID1B MIR4466, OR11H5P, LOC642515, PPIAL4A PPIAL4C PPIAL4D PPIAL4E PPIAL4F PPIAL4G, FAM207BP FAM207CP, SLC9B1P1, RPS28P1, LOC100288437, ELOCP31, or MIR153-1.

80. In one aspect, the method includes assaying with at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,

I I, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,

37, 38, 39, 40, 41, 42, 4,3 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,

63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,

89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110,

I I I, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129,

130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148,

149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167,

168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186,

187, 188, 189, 190, 191 ,192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205,

206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224,

225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243,

244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262,

263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, or 279 of the disclosed probe sets (see for example, Table 24 and those listed above). In one aspect the probe sets bind to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 4,3 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191 ,192, 193, 194, 195, 196, 197, or 198 genes (see for example table 24 and those listed above). In one aspect, the probes bind to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 of the genes selected from the group consisting of AGR2, BEST4, CRHR2, CRK, CYP24A1, DVL2, ELFN1-AS1, F3, FIP1L1, FOXP1, ICAM2, JAK1, MAP3K14, MBD2, MIB1, MSN, NKX2-5, NODAL, THUMPD3-AS 1, TIMELESS, TJP2, and/or USP46. In one aspect, the probes bind to at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, or 14 of the genes selected from the group consisting of BFSP2-AS1, ERICH1, HERC4, HIST2H2BF, IWSL LINC01405, MCHR1, MTMR6, SLC30A2, SLITRK1, SRP68, SRRM4, TFCP2L1, and/or ZNF462. In one aspect, the probes bind to at least 1, 2, 3, 4, 5, 6, 7, or 8 of the genes selected from the group consisting of ERICH1, HERC4, HIST2H2BF, IWS1, MTMR6, SRP68, TFCP2L1, ZNF462 (such as, for example, HERC4, HIST2H2BF, IWS1, SRP68, and/or ZNF462). In one aspect, the probes bind to at least 1, 2, 3, 4, 5, 6, or 7 of the genes selected from the group consisting of HERC4, HIST2H2BF, IWS1, MCHR1, SLC30A2, SRP68, ZNF462. It is understood and herein contemplated that low expression of some genes can be associated with an increase in death (i.e., low survivability and thus high expression is good) including, but not limited to CLPTM1, GTPBP1, IWS1, MAP3K14, MBD2, PIH1D1, SLC25A27, TJP2

81. It is understood and herein contemplated that the disclosed treatment regimens can used alone or in combination with any anti-cancer therapy known in the art including, but not limited to Abemaciclib, Abiraterone Acetate, Abitrexate (Methotrexate), Abraxane (Paclitaxel Albumin-stabilized Nanoparticle Formulation), ABVD, ABVE, ABVE-PC, AC, AC-T, Adcetris (Brentuximab Vedotin), ADE, Ado-Trastuzumab Emtansine, Adriamycin (Doxorubicin Hydrochloride), Afatinib Dimaleate, Afinitor (Everolimus), Akynzeo (Netupitant and Palonosetron Hydrochloride), Aldara (Imiquimod), Aldesleukin, Alecensa (Alectimb), Alectimb, Alemtuzumab, Alimta (Pemetrexed Disodium), Aliqopa (Copanlisib Hydrochloride), Alkeran for Injection (Melphalan Hydrochloride), Alkeran Tablets (Melphalan), Al oxi (Palonosetron Hydrochloride), Alunbrig (Brigatinib), Ambochlorin (Chlorambucil), Amboclorin Chlorambucil), Amifostine, Aminolevulinic Acid, Anastrozole, Aprepitant, Aredia (Pamidronate Disodium), Arimidex (Anastrozole), Aromasin (Exemestane),Arranon (Nelarabine), Arsenic Trioxide, Arzerra (Ofatumumab), Asparaginase Erwinia chrysanthemi, Atezolizumab, AVASTIN® (Bevacizumab), Avelumab, Axitinib, Azacitidine, Bavencio (Avelumab), BEACOPP, Becenum (Carmustine), Beleodaq (Belinostat), Belinostat, Bendamustine Hydrochloride, BEP, Besponsa (Inotuzumab Ozogamicin) , Bevacizumab, Bexarotene, Bexxar (Tositumomab and Iodine I 131 Tositumomab), Bicalutamide, BiCNU (Carmustine), Bleomycin, Blinatumomab, Blincyto (Blinatumomab), Bortezomib, Bosulif (Bosutinib), Bosutimb, Brentuximab Vedotin, Bngatinib, BuMel, Busulfan, Busulfex (Busulfan), Cabazitaxel, Cabometyx (Cabozantinib-S-Malate), Cabozantinib-S-Malate, CAF, Campath (Alemtuzumab), Camptosar , (Irinotecan Hydrochloride), Capecitabine, CAPOX, Carac (Fluorouracil— Topical), Carboplatin, CARBOPLATIN-TAXOL, Carfilzomib, Carmubris (Carmustine), Carmustine, Carmustine Implant, Casodex (Bicalutamide), CEM, Ceritinib, Cerubidine (Daunorubicin Hydrochloride), Cervarix (Recombinant HPV Bivalent Vaccine), Cetuximab, CEV, Chlorambucil, CHLORAMBUCIL-PREDNISONE, CHOP, Cisplatin, Cladribine, Clafen (Cyclophosphamide), Clofarabine, Clofarex (Clofarabine), Clolar (Clofarabine), CMF, Cobimetinib, Cometriq (Cabozantinib-S-Malate), Copanlisib Hydrochloride, COPDAC, COPP, COPP-ABV, Cosmegen (Dactinomycin), Cotellic (Cobimetinib), Crizotinib, CVP, Cyclophosphamide, Cyfos (Ifosfamide), Cyramza (Ramucirumab), Cytarabine, Cytarabine Liposome, Cytosar-U (Cytarabine), Cytoxan (Cyclophosphamide), Dabrafenib, Dacarbazine, Dacogen (Decitabine), Dactinomycin, Daratumumab, Darzalex (Daratumumab), Dasatmib, Daunorubicin Hydrochlonde, Daunorubicin Hydrochloride and Cytarabine Liposome, Decitabine, Defibrotide Sodium, Defitelio (Defibrotide Sodium), Degarelix, Denileukin Diftitox, Denosumab, DepoCyt (Cytarabine Liposome), Dexamethasone, Dexrazoxane Hydrochloride, Dinutuximab, Docetaxel, Doxil (Doxorubicin Hydrochloride Liposome), Doxorubicin Hydrochloride, Doxorubicin Hydrochloride Liposome, Dox-SL (Doxorubicin Hydrochloride Liposome), DTIC-Dome (Dacarbazine), Durvalumab, Efudex (Fluorouracil— Topical), Elitek (Rasburicase), Ellence (Epirubicin Hydrochloride), Elotuzumab, Eloxatin (Oxaliplatin), Eltrombopag Olamine, Emend (Aprepitant), Empliciti (Elotuzumab), Enasidenib Mesylate, Enzalutamide, Epirubicin Hydrochlonde , EPOCH, Erbitux (Cetuximab), Enbulm Mesylate, Envedge (Vismodegib), Erlotinib Hydrochloride, Erwinaze (Asparaginase Erwinia chrysanthemi) , Ethyol (Amifostine), Etopophos (Etoposide Phosphate), Etoposide, Etoposide Phosphate, Evacet (Doxorubicin Hydrochlonde Liposome), Everolimus, Evista , (Raloxifene Hydrochloride), Evomela (Melphalan Hydrochloride), Exemestane, 5-FU (Fluorouracil Injection), 5-FU (Fluorouracil- Topical), Fareston (Toremifene), Farydak (Panobinostat), Faslodex (Fulvestrant), FEC, Femara (Letrozole), Filgrastim, Fludara (Fludarabine Phosphate), Fludarabine Phosphate, Fluoroplex (Fluorouracil— Topical), Fluorouracil Injection, Fluorouracil-Topical, Flutamide, Fol ex (Methotrexate), Folex PFS (Methotrexate), FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI- CETUXIMAB, FOLFIRINOX, FOLFOX, Folotyn (Pralatrexate), FU-LV, Fulvestrant, Gardasil (Recombinant HPV Quadrivalent Vaccine), Gardasil 9 (Recombinant HPV Nonaval ent Vaccine), Gazyva (Obinutuzumab), Gefitinib, Gemcitabine Hydrochloride, GEMCITABINECISPLATIN, GEMCITABINE-OXALIPLATIN, Gemtuzumab Ozogamicin, Gemzar (Gemcitabine Hydrochloride), Gilotrif (Afatinib Dimaleate), Gleevec (Imatinib Mesylate), Gliadel (Carmustine Implant), Gliadel wafer (Carmustine Implant), Glucarpidase, Goserelin Acetate, Halaven (Eribulin Mesylate), Hemangeol (Propranolol Hydrochloride), Herceptin (Trastuzumab), HPV Bivalent Vaccine, Recombinant, HPV Nonavalent Vaccine, Recombinant, HPV Quadrivalent Vaccine, Recombinant, Hycamtin (Topotecan Hydrochloride), Hydrea (Hydroxyurea), Hydroxyurea, Hyper-CVAD, Ibrance (Palbociclib), Ibritumomab Tiuxetan, Ibrutinib, ICE, Iclusig (Ponatinib Hydrochloride), Idamycin (Idarubicin Hydrochloride), Idarubicin Hydrochloride, Idelalisib, Idhifa (Enasidenib Mesylate), Ifex (Ifosfamide), Ifosfamide, Ifosfamidum (Ifosfamide), IL-2 (Aldesleukin), Imatinib Mesylate, Imbruvica (Ibrutinib), Imfinzi (Durvalumab), Imiquimod, Imlygic (Talimogene Laherparepvec), Inlyta (Axitinib), Inotuzumab Ozogamicin, Interferon Alfa-2b, Recombinant, Interleukin-2 (Aldesleukin), Intron A (Recombinant Interferon Alfa-2b), Iodine 1 131 Tositumomab and Tositumomab, Ipihmumab, Iressa (Gefitinib), Irinotecan Hydrochloride, Irinotecan Hydrochloride Liposome, Istodax (Romidepsin), Ixabepilone, Ixazomib Citrate, Ixempra (Ixabepilone), Jakafi (Ruxolitinib Phosphate), JEB, Jevtana (Cabazitaxel), Kadcyla (Ado- Trastuzumab Emtansine), Keoxifene (Raloxifene Hydrochloride), Kepivance (Palifermin), Keytruda (Pembrolizumab), Kisqali (Ribociclib), Kymriah (Tisagenlecleucel), Kyprolis (Carfilzomib), Lanreotide Acetate, Lapatinib Ditosylate, Lartruvo (Olaratumab), Lenalidomide, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate), Letrozole, Leucovorin Calcium, Leukeran (Chlorambucil), Leuprolide Acetate, Leustatin (Cladribine), Levulan (Aminolevulinic Acid), Linfolizin (Chlorambucil), LipoDox (Doxorubicin Hydrochloride Liposome), Lomustine, Lonsurf (Tnfluridme and Tipiracil Hydrochloride), Lupron (Leuprolide Acetate), Lupron Depot (Leuprolide Acetate), Lupron Depot-Ped (Leuprolide Acetate), Lynparza (Olaparib), Marqibo (Vincristine Sulfate Liposome), Matulane (Procarbazine Hydrochloride), Mechlorethamine Hydrochloride, Megestrol Acetate, Mekimst (Trametimb), Melphalan, Melphalan Hydrochloride, Mercaptopurine, Mesna, Mesnex (Mesna), Methazolastone (Temozolomide), Methotrexate, Methotrexate LPF (Methotrexate), Methylnaltrexone Bromide, Mexate (Methotrexate), Mexate-AQ (Methotrexate), Midostaurin, Mitomycin C, Mitoxantrone Hydrochloride, Mitozytrex (Mitomycin C), MOPP, Mozobil (Plerixafor), Mustargen (Mechlorethamine Hydrochloride) , Mutamycin (Mitomycin C), Myleran (Busulfan), Mylosar (Azacitidine), Mylotarg (Gemtuzumab Ozogamicin), Nanoparticle Paclitaxel (Paclitaxel Albumin-stabilized Nanoparticle Formulation), Navelbine (Vinorelbine Tartrate), Necitumumab, Nelarabine, Neosar (Cyclophosphamide), Neratinib Maleate, Nerlynx (Neratinib Maleate), Netupitant and Palonosetron Hydrochloride, Neulasta (Pegfilgrastim), Neupogen (Filgrastim), Nexavar (Sorafenib Tosylate), Nilandron (Nilutamide), Nilotinib, Nilutamide, Ninlaro (Ixazomib Citrate), Niraparib Tosylate Monohydrate, Nivolumab, Nolvadex (Tamoxifen Citrate), Nplate (Romiplostim), Obinutuzumab, Odomzo (Sonidegib), OEPA, Ofatumumab, OFF, Olaparib, Olaratumab, Omacetaxine Mepesuccinate, Oncaspar (Pegaspargase), Ondansetron Hydrochloride, Onivyde (Irinotecan Hydrochloride Liposome), Ontak (Denileukin Diftitox), Opdivo (Nivolumab), OPP A, Osimertinib, Oxaliplatin, Paclitaxel, Paclitaxel Albumin- stabilized Nanoparticle Formulation, PAD, Palbociclib, Palifermin, Palonosetron Hydrochloride, Palonosetron Hydrochloride and Netupitant, Pamidronate Disodium, Panitumumab, Panobinostat, Paraplat (Carboplatin), Paraplatin (Carboplatin), Pazopanib Hydrochloride, PCV, PEB, Pegaspargase, Pegfilgrastim, Peginterferon Alfa-2b, PEG-Intron (Peginterferon Alfa-2b), Pembrolizumab, Pemetrexed Disodium, Perjeta (Pertuzumab), Pertuzumab, Platinol (Cisplatin), Platinol-AQ (Cisplatin), Plerixafor, Pomalidomide, Pomalyst (Pomalidomide), Ponatinib Hydrochlonde, Portrazza (Necitumumab), Pralatrexate, Prednisone, Procarbazine Hydrochloride , Proleukin (Aldesleukin), Prolia (Denosumab), Promacta (Eltrombopag Olamine), Propranolol Hydrochloride, Provenge (Sipuleucel-T), Purinethol (Mercaptopurine), Purixan (Mercaptopurine), Radium 223 Dichloride, Raloxifene Hydrochloride, Ramucirumab, Rasburicase, R-CHOP, R-CVP, Recombinant Human Papillomavirus (HPV) Bivalent Vaccine, Recombinant Human Papillomavirus (HPV) Nonaval ent Vaccine, Recombinant Human Papillomavirus (HPV) Quadrivalent Vaccine, Recombinant Interferon Alfa-2b, Regorafenib, Relistor (Methylnaltrexone Bromide), R-EPOCH, Revlimid (Lenalidomide), Rheumatrex (Methotrexate), Ribociclib, R-ICE, Rituxan (Rituximab), Rituxan Hycela (Rituximab and Hyaluronidase Human), Rituximab, Rituximab and , Hyaluronidase Human, ,Rolapitant Hydrochloride, Romidepsin, Romiplostim, Rubidomycin (Daunorubicin Hydrochloride), Rubraca (Rucaparib Camsylate), Rucaparib Camsylate, Ruxolitinib Phosphate, Rydapt (Midostaurin), Sclerosol Intrapleural Aerosol (Talc), Siltuximab, Sipuleucel-T, Somatuline Depot (Lanreotide Acetate), Sonidegib, Sorafenib Tosylate, Spry cel (Dasatinib), STANFORD V, Sterile Talc Powder (Talc), Steritalc (Talc), Stivarga (Regorafenib), Sunitinib Malate, Sutent (Sunitinib Malate), Sylatron (Peginterferon Alfa-2b), Sylvant (Siltuximab), Synribo (Omacetaxine Mepesuccinate), Tabloid (Thioguanine), TAC, Tafinlar (Dabrafenib), Tagrisso (Osimertinib), Talc, Talimogene Laherparepvec, Tamoxifen Citrate, Tarabine PFS (Cytarabine), Tarceva (Erlotinib Hydrochloride), Targretin (Bexarotene), Tasigna (Nilotinib), Taxol (Paclitaxel), Taxotere (Docetaxel), Tecentriq , (Atezolizumab), Temodar (Temozolomide), Temozolomide, Temsirolimus, Thalidomide, Thalomid (Thalidomide), Thioguanine, Thiotepa, Tisagenlecleucel, Tolak (Fluorouracil-Topical), Topotecan Hydrochloride, Toremifene, Tonsel (Temsirolimus), Tositumomab and Iodine 1 131 Tositumomab, Totect (Dexrazoxane Hydrochloride), TPF, Trabectedin, Trametinib, Trastuzumab, Treanda (Bendamustine Hydrochloride), Trifluridine and Tipiracil Hydrochloride, Trisenox (Arsenic Trioxide), Tykerb (Lapatinib Ditosylate), Unituxin (Dinutuximab), Uridine Triacetate, VAC, Vandetanib, VAMP, Varubi (Rolapitant Hydrochloride), Vectibix (Panitumumab), VelP, Velban (Vinblastine Sulfate), Velcade (Bortezomib), Velsar (Vinblastine Sulfate), Vemurafenib, Venclexta (Venetoclax), Venetoclax, Verzenio (Abemaciclib), Viadur (Leuprolide Acetate), Vidaza (Azacitidine), Vinblastine Sulfate, Vincasar PFS (Vincristine Sulfate), Vincristine Sulfate, Vincristine Sulfate Liposome, Vinorelbine Tartrate, VIP, Vismodegib, Vistogard (Uridine Triacetate), Voraxaze (Glucarpidase), Vorinostat, Votrient (Pazopanib Hydrochloride), Vyxeos (Daunorubicin Hydrochloride and Cytarabine Liposome), Wellcovorin (Leucovorin Calcium), Xalkori (Crizotinib), Xeloda (Capecitabine), XELIRI, XELOX, Xgeva (Denosumab), Xofigo (Radium 223 Diehl onde), Xtandi (Enzalutamide), Yervoy (Ipilimumab), Yondelis (Trabectedin), Zaltrap (Ziv-Aflibercept), Zarxio (Filgrastim), Zejula (Niraparib Tosylate Monohydrate), Zelboraf (Vemurafenib), Zevalin (Ibritumomab Tiuxetan), Zinecard (Dexrazoxane Hydrochloride), Ziv-Aflibercept, Zofran (Ondansetron Hydrochloride), Zoladex (Goserelin Acetate), Zoledronic Acid, Zolinza (Vorinostat), Zometa (Zoledronic Acid), Zydelig (Idelalisib), Zykadia (Ceritinib), and/or Zytiga (Abiraterone Acetate). The treatment methods can include or further include checkpoint inhibitors including, but are not limited to antibodies that block PD-1 (such as, for example, Nivolumab (BMS-936558 or MDX1106), pembrolizumab, CT-011, MK-3475), PD-L1 (such as, for example, atezolizumab, avelumab. durvalumab, MDX-1105 (BMS-936559), MPDL3280A, or MSB0010718C), PD-L2 (such as, for example, rHIgM12B7), CTLA-4 (such as, for example, Ipilimumab (MDX-010), Tremelimumab (CP-675,206)), IDO, B7-H3 (such as, for example, MGA271, MGD009, omburtamab), B7-H4, B7-H3, T cell immunoreceptor with 1g and IT1M domains (TlGlT)(such as, for example BMS-986207, OMP-313M32, MK-7684, AB- 154, ASP-8374, MTIG7192A, or PVSRIPO), CD96, B- and T-lymphocyte attenuator (BTLA), -domain Ig suppressor of T cell activation (VISTA)(such as, for example, JNJ-61610588, CA-170), TIM3 (such as, for example, TSR-022, MBG453, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, RO7121661), LAG-3 (such as, for example, BMS-986016, LAG525, MK-4280, REGN3767, TSR-033, BI754111, Sym022, FS118, MGD013, and Immutep)

D. Examples

82. The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and descnption of how the compounds, compositions, articles, devices and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary and are not intended to limit the disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

1. Example 1: Development of Predictive A VASTIN® Gene Signature in Colorectal Cancer

83. An important treatment option for patients diagnosed with metastatic (stage 4) colorectal cancer (mCRC) is an anti-angiogenesis strategy combining chemotherapy with the monoclonal antibody bevacizumab (AVASTIN®) targeting the vascular endothelial growth factor (VEGF). Here, we developed a gene signatures for the potential power in predicting AVASTIN® clinical benefit. a) Methods.

84. Three study cohorts were used to develop the AVASTIN® gene signature: Moffitt training cohort (n=78) for model building, Moffitt Consortium cohort (n=39) and Moffitt Avatar cohort (n=36) as two test sets. Data analysis: Cox proportional hazards method was used to identify predictive AVASTIN® gene signatures by utilizing a statistical interaction term of gene signature score and treatment in the model. Principal component analysis (PCA) was used for data reduction to derive a summary predictive score. b) Results.

85. Univariate Cox analysis of the interaction model yielded 279 probe sets (198 unique genes) associated with AVASTIN® effect. Analysis of the median cutoff of the first principal component of the 279 probe sets showed patients treated with AVASTIN® tended to improve survival for high PCI score group (p<0.001). On the other hand, a patient with a low PCI score seems to have better OS if treated with chemotherapy only (p<0.001).

In Consortium cohort, the signature showed numerically improved median OS if AVASTIN®+Chemo was given (p=0.1). For the Avatar cohort, the median OS was higher in high PCI compared to low PCI in the overall group (p = 0.04) and in the AVASTIN®+Chemo group (p=0.11). In the refinement analysis of AVASTIN® gene signature, the Consortium significant genes (14 genes) showed robust predictive effect in the three cohorts. The Avatar significant genes (8 genes) showed robust predictive effect (prediction of AVASTIN®) in Moffitt training cohort and also showed numerically improved OS for patients with high PCI in overall and in the AVASTIN® group.

(1) Moffit Training Cohort

86. To investigate the efficacy of AVASTIN® to treat metastatic colorectal cancer (mCRC) patients, we looked at gene expression within a population of 78 patients with mCRC. Among the cohort, the overall survival was incredibly low with 87% (68 patients) dying from CRC. In this population 56 patients (72%) received AVASTIN® and chemotherapy and the remaining 22 patients (28%) only received chemotherapy. Gene expression data were generated using HuRSTA-2a520709 Affymetrix arrays and normalized by the iterative rank order normalization method. As shown in the comparison of overall survival and progression free survival between the two treatment groups did not yield a significant AVASTIN® treatment effect (p = 0.79; Figure 1 and Table 1). While the median OS was 4.26 years in patients treated with AV ASTIN®+ chemotherapy versus 2.58 years in patients with chemotherapy only, the survival curves started to crossover at year 9 (Fig 1).

(2) Model building using interaction model to predict AVASTIN® effect

87. Wanting to find a way to distinguish patients that would respond favorably to AVASTIN®, we used an interaction model to predict AVASTIN® effect. Cox proportional hazards method was used to develop a predictive AVASTIN® gene signature. Specifically, a statistical interaction model for prediction of treatment benefit was built including two variables, treatment and a binary probe set expression, as main effects, and an interaction term of both variables. The binary probe set expression variable was constructed based on median cutoff of the probe set expression. Principal component analysis (PCA) was performed to summarize the significant genes.

(a) Univariate analysis

88. Results showed 279 probe sets with adjusted p value<0.05 in the interaction term. These probe sets were linked to 198 genes (See Table 24). Among these significant probe sets, there were 152 probe sets with main effect of HR>1 for patient with chemotherapy only (median HR=7.93; interquartile range: 6.82-9.95). In other words, higher expression of these probe sets increased death risk if patients were not treated with AVASTIN®. On the other hand, the HR in the interaction term became less than 1 for patients additionally treated with AVASTIN® (median HR= 0.09; interquartile range: 0.08-0. 1). This indicates that AVASTIN® could improve OS for patients with high expression of these probe sets. The other 127 probe sets had opposite trend with HR<1 in the main effect (median HR= 0.12; interquartile range: 0.1-0.14) and HR>1 in the interaction term (median HR= 10.63; interquartile range: 9.79-12.72), showing association of low expression with high risk for patients treated with chemotherapy only and with improved OS when AVASTIN® was received.

Probe

Treatmen set “Treat m

Probe set t ent adj_pvalu

ProbelD Symbol HR (95%) p_value e HR (95%) p_value adj_pvalue HR (95%) p_value adj_pvalue merck2_AAl

01946_x_at TIMM8A 0.09 (0.03-027) 1.51E-05 0.02735 0.26(0.13-0.53) 240E-04 0.049330742 10.46(3.07-35.59) 1.72E-04 0.043915 merck2 AF2 LOC10013

89590_at 0744 0.13 (0.05-036) 8.13E-05 0.03674 0.24(0.11-0.51) 197E-04 0.046260143 9.44(2.99-29.81) 1.29E-04 0.040085 merck2 AIO

91276_at LANCL2 0.08 (0.03 - 026) 2.33E-05 0.02905 0.24(0.11-0.49) 922E-05 0.037355406 16.15(4.34-60.04) 3.30E-05 0.031623 merck2 AI2 LOC10192

23270_at 9529 3.6(1.34-9.63) 0.010925 0.21429 2.38(1.13-5.01) 0.02234 0.288955919 0.11(0.03-0.35) 2.06E-04 0.046856 merck2_AI9 62276_at 10.26(293-3592) 2.71E-04 0.05071 5.38(1.63-17.78) 0.00583 0.165007322 0.05 (0.01-0.19) 1.51E-05 0.027346

NPHP3 merck2 AKO NPHP3-

92910 at ACAD11 8.55 (3.16-23.12) 2.38E-05 0.02905 2.22(0.95-5.19) 0.06629 0.442914315 0.1(0.03-0.32) 9.21E-05 0.037355 merck2_AK0

93149_at MYO5B 8.51 (3.02-23.95) 5.05E-05 0.03312 1.95(0.92-4.14) 0.08206 0.478296378 0.08(0.02-0.26) 2.97E-05 0.030943 merck2_AKl

31291_at ZSCAN30 6.61 (2.35- 18.55) 3.40E-04 0.05425 3.19(1.28-7.92) 0.01258 0.227301814 0.08(0.02-0.25) 2.75E-05 0.030721 merck2_AL3

59561_at ZNF462 6.19 (2.18-17.54) 6.08E-04 0.06881 2.93(1.12 - 7.65) 0.02815 0.318119551 0.1(0.03-0.34) 1.99E-04 0.046293 merck2_AL8

32223_at CDON 7.91 (2.82-22.17) 8.53E-05 0.03698 2.58(1.05-6.34) 0.03845 0.359052143 0.1(0.03-0.32) 1.11E-04 0.037864

merck2_AL8 34299_at ZNF689 0.14 (0.05-039) 1.13E-O4 0.03791 0.22(0.1-0.49) 162E-04 0.042632345 9.82(3.09-31.2) 1.08E-04 0.03757 merck2_AW

007481_at NFIX 0.1(0.03-0.34) 1.57E-04 0.04236 0.26(0.13-0.54) 282E-04 0.051044945 15.15(3.99-57.49) 6.46E-05 0.034824 merck2_AX7

21105_at ZNF467 9.82 (3.48-27.69) 1.58E-05 0.02735 2.04(0.88-4.75) 0.09651 0.507347422 0.11(0.03-0.35) 1.85E-04 0.045272 merck2_BC0

01038_at EPN3 7.53 (2.73-20.78) 9.79E-05 0.03736 1.83(0.87-3.86) 0.11237 0.535814749 0.1(0.03-0.31) 8.20E-05 0.036737 merck2_BC0

33091_at SLC25A27 7.4(2.49-2193) 3.08E-04 0.05243 3.15(1.2-8.29) 0.02008 0.277414194 0.09(0.03-0.3) 1.07E-04 0.03757 merck2_BC0

35840_at GJC2 0.13 (0.05-034) 3.67E-05 0.03162 0.2(0.09-0.44) 564E-05 0.033692775 10.97(3.47-34.71) 4.61E-05 0.033064 merck2_BC0

39861_at NODAL 0.12 (0.04-034) 6.27E-05 0.03482 0.24(0.11-0.49) 125E-04 0.039651341 11.69(3.55-38.46) 5.18E-05 0.033119 RPL17 merck2_BE2 RPL17-

49972_x_at C18orf32 4.19 (1.6-1098) 0.003494 0.13421 2.3(1.05-5.05) 0.03744 0.355433593 0.12(0.04-0.37) 2.44E-04 0.049436 merck2_BE3

49054_x_at TDRKH 6.26(2.31- 16.97) 3.12E-04 0.05259 2.52(1.08-5.91) 0.03313 0.338695291 0.1(0.03-0.32) 9.93E-05 0.037355 merck2_BF2 FAM149B

48252_at 1 7.56(2.54-22.52) 2.82E-04 0.05104 3.08(1.16-8.2) 0.02421 0.29951072 0.09(0.03-0.32) 1.87E-04 0.045541 merck2_BF5

91243_at PPIE 0.12 (0.04-032) 4.02E-05 0.03191 0.13(0.05-0.32) 120E-05 0.027345536 16.14(4.89-53.32) 5.08E-06 0.027253 merck2_BF6

92777_at 0.14 (0.05-037) 1.02E-04 0.03736 0.19(0.08-0.44) 142E-04 0.040831643 9.22 (2.88-29.51) 1.81E-04 0.044798 merck2_BG8

96934 at FIP1L1 0.13 (0.04-035) 9.16E-05 0.03736 0.2(0.09-0.43) 312E-05 0.031476456 17.67(5.2-60.11) 4.25E-06 0.027253

merck2 BIO 47264_at 0.14 (0.05-036) 6.54E-05 0.03482 0.22(0.1-0.48) 128E-04 0.040085056 9.54 (3.04 - 29.94) 1.10E-04 0.037864 merck2_BM

545067_s_at MRPL38 0.17 (0.06-047) 5.96E-04 0.06831 0.27(0.13-0.57) 632E-04 0.069813311 9.01(2.83-28.72) 2.02E-04 0.046589 merck2_BM GABPB1-

681401_at AS1 6.83 (2.4-19.47) 3.23E-04 0.05346 1.58(0.78-3.22) 0.20789 0.657976999 0.11(0.03-0.35) 2.40E-04 0.049331 merck2_BU6

18242_at GALNT1 10.19 (359-2897) 1.33E-05 0.02735 2.56(1.03-6.31) 0.04196 0.371529111 0.09 (0.03-0.29) 6.51E-05 0.034824 merck2_BXl

15227_at ERICH1 0.18 (0.06-052) 0.001404 0.09482 0.3(0.15-0.61) 884E-04 0.07968467 10.48(3.16-34.74) 1.22E-04 0.039022 merck2_BX6

47415_at CEP126 8.69 (2.95-25.66) 8.97E-05 0.03736 2.97(1.13-7.8) 0.02721 0.314222724 0.09(0.03-0.31) 1.19E-04 0.038671 merck2_BX6

47735_at AP3S1 9.91 (3.33-29.52) 3.79E-05 0.03163 2.86(1.09-7.56) 0.03353 0.340363806 0.09(0.03-0.31) 1.51E-04 0.041766 merck2_BX6

48311_at AHI1 8.53 (3.11-23.4) 3.08E-05 0.03148 2.56(1.09-6.01) 0.03106 0.330098208 0.08(0.02-0.26) 2.26E-05 0.029051 merck2_BY7

99718_at MRPL1 7.72 (2.39-24.96) 6.37E-04 0.06996 4.09(1.39-12.05) 0.01061 0.211292893 0.07 (0.02-0.27) 9.05E-05 0.037355 merck2_CM

V_UL43_at 0.13 (0.04-036) 9.16E-05 0.03736 0.26(0.13-0.55) 419E-04 0.058762307 9.49 (2.86-31.46) 2.32E-04 0.048678 merck2 CR7

49241_s_at FRMPD2 5.33 (2.02 - 14.08) 7.23E-04 0.07378 2.15(0.99-4.68) 0.05442 0.41093829 0.11(0.04-0.34) 1.45E-04 0.041504 merck2_CX7

83886_a_at UBE3A 0.15 (0.05-041) 2.16E-04 0.0473 0.18(0.07-0.44) 159E-04 0.042549339 9.65 (2.99-31.13) 1.49E-04 0.041686 merck2_DB4

92896_at ZNF365 0.14 (0.05 -0.39) 1.42E-04 0.04083 0.18(0.07 - 0.43) 1.33E-04 0.04014514 9.35 (2.91-30.01) 1.72E-04 0.043915 merck2_DQ

891843_at I CAM 2 0.16(0.06-044) 4.41E-04 0.0597 0.28(0.14-0.58) 675E-04 0.071481634 9.39 (2.89-30.54) 1.98E-04 0.04626 merck2_ENS

T000003551

04_x_at PRR21 7.04(2.59- 19.15) 1.33E-04 0.04015 2.51(1.07-5.88) 0.03383 0.341840876 0.09 (0.03-0.29) 6.05E-05 0.034824

CT47A1

CT47A10

CT47A11

CT47A12

CT47A2

CT47A3

CT47A4

CT47A5

CT47A6 merck2_ENS CT47A7

T000003712 CT47A8

90_s_at CT47A9 8.54(2.64-27.62) 3.42E-04 0.05425 4.09(1.39-12.05) 0.01068 0.21164556 0.07 (0.02-0.25) 7.02E-05 0.034828 merck2_F25 LINC0140

718_at 5 5.34(2.01-14.21) 7.86E-04 0.07573 1.96(0.92-4.16) 0.08171 0.477550212 0.12(0.04-0.36) 2.29E-04 0.048335 merck2_HSV

1_ORF_UL46 at — 0.08(0.02-028) 9.52E-05 0.03736 0.25(0.12-0.5) 103E-04 0.037511443 21.46(5.17-89.11) 2.43E-05 0.029291 merck2_HSV

2 ORF UL18

_at — 0.1(0.03-0.27) 7.14E-06 0.02725 0.19 (0.09-0.43) 743E-05 0.035381836 9.25 (2.89-29.57) 1.77E-04 0.044526 merck2_JC_ vir_smTAg_a t — 0.16(0.06-042) 2.44E-04 0.04944 0.26(0.12-0.56) 481E-04 0.061918193 8.77(2.75-28.01) 2.47E-04 0.049436

OR4F16 merck2_NM OR4F21

001005224 OR4F29

_s_at OR4F3 6.16(2.33- 16.28) 2.47E-04 0.04944 2.15(1-4.6) 0.04865 0.393922587 0.09 (0.03-0.28) 3.98E-05 0.031905 merck2_NM

001037866 RGPD5

_s_at RGPD6 10.63(353-3197) 2.61E-05 0.03021 3.45(1.3-9.15) 0.01261 0.227520734 0.06(0.02-0.21) 1.26E-05 0.027346 merck2_NM

_001080537

_at SNTN 6.65 (2.44-18.16) 2.17E-04 0.04746 2.35(1.01-5.5) 0.04813 0.392153506 0.11(0.03-0.34) 1.61E-04 0.04262 merck2_NM

_005570_at LMAN1 11.29 (381-3343) 1.2OE-O5 0.02735 2.78(1.06-7.33) 0.03801 0.35718887 0.09 (0.03-0.3) 1.09E-04 0.037798

merck2_NM _006485_at FBLN1 0.12 (0.04-033) 5.44E-05 0.03322 0.22(0.1-0.46) 744E-05 0.035381836 13.28(3.98-44.31) 2.61E-05 0.030212 merck2_NM _022079_at HERC4 9.26(3.1-27.65) 6.61E-05 0.03482 2.84(1.08-7.51) 0.03503 0.34676014 0.1(0.03-0.33) 2.13E-04 0.047264 merck2_NM _022747_at CCDC85C 0.13 (0.05-036) 7.38E-05 0.03538 0.21(0.1-0.47) 152E-04 0.041766283 9.83(3.06-31.53) 1.22E-04 0.039022 merck2_NM _025214_at CCDC68 6.36(2.25- 17.95) 4.81E-04 0.06192 2.94(1.18-7.31) 0.02005 0.27727444 0.09(0.03-0.3) 8.72E-05 0.037305 merck2_NM _030813_at CLPB 0.24 (0.09-065) 0.005245 0.15777 0.29(0.14 - 0.62) 0.00133 0.092706923 9.77 (3.02-31.63) 1.42E-04 0.040832 merck2_NM _032260_s_ RGPD5 at RGPD6 9.17 (3.33-25.24) 1.81E-05 0.02848 2.57(1.1-6.01) 0.02965 0.324340319 0.07(0.02-0.24) 1.32E-05 0.027346 merck2_NM _032639_at PLEKHA8 6.94 (2.26-21.31) 7.18E-04 0.0737 3.53(1.23- 10.15) 0.01913 0.271891726 0.09 (0.02-0.31) 1.74E-04 0.044177 merck2_NM _052996_a_ at PRDM7 7.48 (2.67 - 20.96) 1.28E-04 0.04009 2.68 (1.09 - 6.61) 0.03226 0.334917286 0.1(0.03-0.31) 1.02E-04 0.037435 merck2_NM 205833 at IGSF1 0.1(0.04-0.26) 5.36E-06 0.02725 0.2(0.1-0.44) 415E-05 0.032528361 10.24(3.25-32.27) 7.18E-05 0.034986 merck2_VZV

_OKA_O32_ up_at — 14.48(449-4666) 7.55E-06 0.02725 4.06(1.41-11.73) 0.0095 0.201373437 0.05 (0.01-0.18) 6.62E-06 0.027253 merck2_VZV

_OKA_O47_ up_at — 0.13 (0.05-036) 9.59E-05 0.03736 0.26(0.12-0.54) 312E-04 0.052591683 10.14(3.06-33.64) 1.53E-04 0.041846

SH2D1A

STAG2

HSPA8P20

NPM1P34 merck2_XM TEX13D

_938193_at ZIK1P1 0.18(0.07-0.48) 7.18E-04 0.0737 0.24(0.11-0.51) 232E-04 0.048677914 12.5(3.82 - 40.9) 2.96E-05 0.030943

LOC10192 8402 merck AB05

8756_a_at SRRM4 11.07 (3.8 -32.27) 1.07E-05 0.02735 1.69(0.81-3.52) 0.15845 0.601270337 0.07 (0.02-0.23) 1.88E-05 0.028478 merck AF03

8451_a_at AGR2 8.28 (2.81 - 24.46) 1.30E-04 0.04009 2.85(1.08-7.5) 0.03408 0.342860298 0.1(0.03-0.34) 2.47E-04 0.049436 merck AF08

5981_at ENTPD4 10.97(396-3038) 4.01E-06 0.02725 2.04(0.93-4.46) 0.07442 0.460959791 0.07 (0.02-0.22) 7.63E-06 0.027253 merck_AFll

8083_a_at EXOC5 7.93 (2.68 - 23.45) 1.80E-04 0.0448 2.94(1.11-7.79) 0.03039 0.327726409 0.1(0.03-0.34) 2.35E-04 0.0488

FOXP1

F0XP1- merck_AF14 AS1

3326_at MIR1284 7.83 (2.92-20.97) 4.27E-05 0.03286 2.45(1.09-5.53) 0.03058 0.328203492 0.08(0.02-0.24) 1.33E-05 0.027346 merck_AF14

7431_at DIS3L 7.53 (2.66-21.33) 1.46E-04 0.0415 2.99(1.2-7.44) 0.01838 0.268016286 0.08(0.02-0.26) 3.88E-05 0.031887 merck_AF16 1340_at 0.1(0.03-0.28) 2.43E-05 0.02929 0.27(0.13-0.56) 402E-04 0.057697091 9.81 (2.89-33.23) 2.47E-04 0.049436 merck_AF16

9158_a_at CABP5 7.26 (2.68 - 19.69) 9.90E-05 0.03736 2.54(1.08-5.96) 0.03208 0.334214231 0.09 (0.03-0.28) 4.75E-05 0.033119 merck AF31

1308_at MGAT1 0.11(0.04-03) 1.36E-05 0.02735 0.2(0.09-0.43) 517E-05 0.033119082 9.95 (3.18-31.12) 7.82E-05 0.036384 merck_AI20 4893_at 0.16(0.06-042) 2.79E-04 0.05083 0.25(0.12-0.53) 304E-04 0.052173629 10.1 (3.14-32.53) 1.06E-04 0.037518 merck_AJ40 6951_s_at KRTAP9-9 0.12(0.04-033) 3.78E-05 0.03163 0.21(0.1-0.45) 682E-05 0.034824234 11.47(3.58-36.77) 4.00E-05 0.031905 merck AJ45

9838_at OR2H1 10.99(4-30.19) 3.36E-06 0.02725 2.67(1.18-6) 0.01793 0.264995899 0.05 (0.02-0.17) 7.21E-07 0.023449

mere k A KOO O932_at 5.04(1.88-13.46) 0.00127 0.09185 2.39(1.06-5.38) 0.03526 0.347755016 0.11 (0.03-0.34) 1.60E-04 0.04262 merck_AKO2

1682_at COL9A2 6.82 (2.58- 17.98) 1.05E-04 0.03752 1.85(0.85-4.02) 0.12078 0.548746405 0.12 (0.04-0.37) 2.04E-04 0.046691 CSTF2T MIR605 PRKG1 RSU1P3 merck_AK02 LOC10272 2168_at 4719 13.73(3.78-49.91) 6.95E-05 0.03482 4.5 (1.35 - 15.03) 0.01452 0.241098101 0.06(0.02-0.26) 1.38E-04 0.040515 CSTF2T MIR605 PRKG1 RSU1P3 merck_AK02 LOC10272 2347_at 4719 9.46 (2.96-30.23) 1.52E-04 0.04177 3.38(1.17-9.78) 0.02458 0.30104221 0.09 (0.03-0.33) 2.51E-04 0.049663 FOXP1 FOXP1- merck AKO2 AS1 2443_at MIR1284 8.11 (2.98-22.07) 4.25E-05 0.03285 2.27(0.97-5.33) 0.05906 0.423367826 0.1(0.03-0.32) 1.03E-04 0.037435 merck_AKO2

3601_at EFR3A 4.64(1.64-13.08) 0.00377 0.13795 3.42(1.37-8.56) 0.00857 0.193122405 0.08 (0.02-0.28) 6.27E-05 0.034824 merck_AK02

4198_at 5.33 (1.88 -15.1) 0.001665 0.10174 2.9(1.16-7.25) 0.02263 0.29077884 0.1(0.03-0.34) 2.19E-04 0.047534 merck_AK02

4231_at 7.92 (2.64-23.79) 2.27E-04 0.0481 4.2(1.56-11.31) 0.00454 0.148604076 0.05 (0.01 - 0.19) 6.61E-06 0.027253 merck_AK02

4810_a_at PRPF40A 10.36(351-3059) 2.34E-05 0.02905 2.73(1.04-7.18) 0.04141 0.369596922 0.1(0.03-0.33) 1.74E-04 0.044237 merck_AK02

52O2_a_at LARGE1 6.19 (2.32-16.51) 2.68E-04 0.05048 2.22(0.99-4.99) 0.05327 0.407683841 0.11(0.03-0.34) 1.23E-04 0.039214 merck_AK02 LOC10192

5621_at 7365 6.56(2.42- 17.77) 2.13E-04 0.04726 2.27(0.97-5.31) 0.05823 0.421379596 0.11 (0.04-0.36) 2.34E-04 0.0488 merck_AKO2

6808_at HERC4 10.59 (376-2982) 8.00E-06 0.02725 2.25(0.92-5.53) 0.07673 0.466503261 0.11 (0.03-0.35) 2.02E-04 0.046589

merck AK05 4931_at MIR9-3HG 0.18(0.07-048) 6.39E-04 0.06996 0.28(0.13-0.58) 639E-04 0.069958172 8.83 (2.81-27.75) 1.94E-04 0.046237 merck_AK05 5172_a_at DLG5 0.13 (0.05-036) 7.40E-05 0.03538 0.22(0.1-0.48) 159E-04 0.042549339 9.55 (3-30.39) 1.33E-04 0.040145 merck_AK05

5584_at STT3B 10.98(3.43-35.17) 5.50E-05 0.03338 3.67(1.26-10.69) 0.01712 0.258886743 0.07 (0.02 - 0.27) 9.11E-05 0.037355 merck_AK09 LOC10192

1999_at 9713 7.57 (2.81-20.38) 6.25E-05 0.03482 2.19(0.94-5.1) 0.06933 0.449887537 0.11 (0.04-0.35) 1.60E-04 0.04262 merck_AK09 3735_s_at CEP83 5.78(2.2- 1519) 3.68E-04 0.05564 2.14(0.98-4.68) 0.0558 0.414908314 0.11 (0.03-0.33) 1.06E-04 0.037518 merck_AK09

5449_at CRK 11.71(391-3506) 1.10E-05 0.02735 3.33(1.26-8.82) 0.01551 0.248286757 0.06(0.02-0.22) 1.37E-05 0.027346 merck_AK09

6712_at USP46 7.5(2.64-2127) 1.51E-04 0.04177 2.87(1.16-7.09) 0.02235 0.288987713 0.08(0.03-0.28) 5.28E-05 0.033119 merck_AK09 LOC10537

7571_s_at 8730 0.13 (0.05-037) 8.91E-05 0.03736 0.22(0.1-0.48) 108E-04 0.037570373 11.45(3.55-36.87) 4.42E-05 0.033064

LOC10537

9589

LOC10798

4097

LOC10798

7409 merck_AK09 LOC10798 7840_a_at 7410 0.15(0.05-041) 2.33E-04 0.0487 0.26(0.13-0.54) 311E-04 0.052591683 10.5 (3.24-34.1) 9.07E-05 0.037355 merck_AK12

3535_at FBXL18 0.12 (0.05-033) 3.OOE-O5 0.03094 0.19(0.08-0.4) 233E-05 0.029051464 12.87(4.08-40.62) 1.31E-05 0.027346 merck_AK12

3655_s_at UCHL5 4.51 (1.7- 1202) 0.002561 0.11983 2.52(1.11-5.71) 0.02708 0.313519552 0.11(0.03-0.35) 1.64E-04 0.042845 merck_AK12

3888_at ZNF555 12.35(432-3534) 2.76E-06 0.02725 2.14(0.92-4.98) 0.07815 0.470065199 0.08(0.03-0.27) 3.54E-05 0.031623 merck_AK12

5149_at CD99P1 9.95 (3.56-27.78) 1.15E-05 0.02735 1.87(0.86-4.07) 0.11536 0.540645886 0.09 (0.03-0.27) 3.52E-05 0.031623

merck AK12

7206_s_at L0NRF2 0.1(0.04-0.28) 9.11E-06 0.02735 0.18(0.08-0.41) 353E-05 0.031623068 10.83(3.41-34.41) 5.36E-05 0.033119 merck AK22

2828_a_at LMAN2L 0.11(0.04 - 0.32) 3.89E-05 0.03189 0.24(0.12-0.51) 1.91E-04 0.045810278 10.47(3.17-34.61) 1.18E-04 0.038642 merck AL04

4815_at MTMR6 10.53(332-3406) 6.99E-05 0.03482 3.77 (1.3 - 10.9) 0.01445 0.240575759 0.07 (0.02-0.25) 5.64E-05 0.033693 merck_AL13 LOC10798 3569_at 7180 12.2 (4.09 - 36.36) 7.11E-06 0.02725 3.34(1.27-8.78) 0.01443 0.240368307 0.06(0.02-0.2) 6.91E-06 0.027253

PCDH9 merck_AL16 PCDH9-

2044_at AS4 7.9 (2.88 - 2163) 5.86E-05 0.03413 2.14(0.92-4.99) 0.07918 0.472518668 0.11(0.04-0.36) 2.35E-04 0.0488 merck_AL35

3936_at PSD3 9.11 (3.22-25.77) 3.12E-05 0.03148 2.61(1.06-6.44) 0.03724 0.354817133 0.09(0.03-0.29) 6.76E-05 0.034824 merck_AV76 2307_at 0.12 (0.04-033) 5.08E-05 0.03312 0.24(0.11-0.5) 146E-04 0.041503557 11.17(3.4-36.67) 6.91E-05 0.034824 merck_AW3

70282_at 7.97 (2.94-21.62) 4.52E-05 0.03306 2.52(1.07-5.9) 0.03385 0.341896174 0.08(0.03-0.27) 3.39E-05 0.031623 merck AW6

65698_at USP3-AS1 7.66(2.58-22.74) 2.43E-04 0.04944 3.24(1.22 - 8.62) 0.0187 0.269833526 0.08(0.02-0.29) 9.86E-05 0.037355 merck_AW7

71625_a_at MAP3K6 0.11 (0.04-029) 1.23E-05 0.02735 0.2(0.09-0.44) 458E-05 0.033063805 11.32(3.53-36.26) 4.43E-05 0.033064 merck_AW8

09224_at CSNK1G1 6.41 (2.4-171) 2.05E-04 0.04676 2.3(1.06-5.03) 0.03611 0.350871956 0.09 (0.03-0.27) 2.87E-05 0.030943 merck_AW8

43987_at GTPBP1 7.81 (2.76-22.07) 1.06E-04 0.03752 2.67(1.08-6.57) 0.0329 0.337647514 0.09 (0.03-0.31) 9.98E-05 0.037355 merck_AW9

77003 at 0.17 (0.06-047) 5.70E-04 0.0672 0.29(0.14-0.59) 739E-04 0.074014184 8.9(2.82-28.08) 1.90E-04 0.04581

merck AY05 4391_at BDNF-AS 7.2(2.63- 1969) 1.21E-04 0.03902 2.41(1.08-5.42) 0.03251 0.335840026 0.08(0.03-0.27) 2.60E-05 0.030212 merck_AY14

7849_a_at MIB1 15.51(425-5662) 3.32E-05 0.03162 4.89(1.46-16.42) 0.01022 0.208143195 0.05 (0.01-0.21) 5.08E-05 0.033119 merck_BCOO 1905_a_at PCSK2 0.13(0.05-0.36) 8.91E-05 0.03736 0.25(0.12-0.53) 267E-04 0.05042853 10.19(3.12-33.22) 1.18E-04 0.038671 merck_BCOO BFSP2-

7984_at AS1 10.67 (381 - 2983) 6.43E-06 0.02725 2.39(1.02-5.58) 0.04436 0.380430327 0.07 (0.02 - 0.24) 1.62E-05 0.027346 merck_BC01 2447_a_at SP110 0.13(0.05-034) 5.30E-05 0.03312 0.22(0.1-0.46) 854E-05 0.03697849 11.23(3.52-35.84) 4.39E-05 0.033064 merck BCOl LINC0082 4119_at 4 0.11(0.04-032) 6.47E-05 0.03482 0.27(0.13-0.56) 431E-04 0.059118332 10.63(3.08-36.66) 1.82E-04 0.044798 merck BCOl

5877_a_at CDH19 0.15(0.06-041) 2.13E-04 0.04726 0.19(0.08-0.45) 161E-04 0.042620248 9.98(3.11-32.06) 1.11E-04 0.037864 merck_BCOl 9893_s_at CD99P1 9.24(3.26-26.2) 2.91E-05 0.03094 2.88(1.16-7.1) 0.022 0.28730361 0.07 (0.02-0.24) 1.97E-05 0.028478 merck_BCO2

2892_at IWS1 10.67(378-3008) 7.62E-06 0.02725 2.49(1.06-5.82) 0.03559 0.348813403 0.07 (0.02-0.23) 1.20E-05 0.027346 merck_BCO3

4596_at 6.56 (2.31 - 18.6) 4.08E-04 0.05788 3.74(1.49-9.36) 0.00491 0.153538799 0.06(0.02-0.2) 6.59E-06 0.027253 merck BCO3 LINC0172

6594_at 5 7.3(2.69- 1979) 9.36E-05 0.03736 2.22(1.02-4.83) 0.04496 0.382213679 0.08(0.03-0.27) 2.73E-05 0.0306 merck_BCO3

9321_at 10.04 (367 - 2746) 6.94E-06 0.02725 1.99(0.85-4.65) 0.11045 0.532729553 0.11 (0.04-0.35) 1.72E-04 0.043915

TISP43 merck_BCO6 LOC64674

4385_at 3 0.2(0.07-0.6) 0.003781 0.13795 0.18(0.07-0.5) 883E-04 0.07968467 12.07(3.38-43.14) 1.27E-04 0.040085 merck_BCll O326_at TRIQK 11.14(307-4048) 2.50E-04 0.04966 4.95(1.48-16.52) 0.00928 0.199553608 0.06(0.01-0.23) 6.87E-05 0.034824 merck_BCll

0867 s at CDH24 0.2(0.07-0.52) 0.001152 0.08859 0.25(0.11-0.54) 436E-04 0.059402273 10.18(3.23-32.04) 7.32E-05 0.035382

merck BE21 LOC10192

9852_at 7472 7.16(2.67- 19.2) 9.28E-05 0.03736 2.14(0.95-4.81) 0.06537 0.440652363 0.1(0.03-0.32) 1.03E-04 0.037435 merck_BE54 6828_at 0.11 (0.04-0.32) 6.43E-05 0.03482 0.24(0.12-0.49) 1.01E-04 0.037355406 14.01(4.06-48.31) 2.94E-05 0.030943 merck_BF34 2524_at 0.13 (0.04-036) 9.92E-05 0.03736 0.23(0.11-0.5) 165E-04 0.042993636 12.11(3.59-40.82) 5.79E-05 0.034089 merck_BF67 9703_at 0.11 (0.04-034) 9.04E-05 0.03736 0.28(0.14-0.58) 567E-04 0.067095592 10.21(2.97-35.11) 2.28E-04 0.04813 merck_BF96

5720_at — 7.12 (2.48-20.42) 2.61E-04 0.05029 3.57(1.41-9.06) 0.00725 0.181228186 0.06(0.02-0.22) 1.43E-05 0.027346 merck_BG23

6239_a_at SIRPD 6.77 (2.47 - 18.54) 1.97E-04 0.04626 2.8(1.19-6.54) 0.01788 0.264611925 0.08(0.02-0.26) 2.36E-05 0.029051 merck_BG28

7007_at — 0.15(0.05-041) 2.27E-04 0.0481 0.26(0.12-0.53) 276E-04 0.050785873 10.9 (3.33-35.63) 7.76E-05 0.03619 merck_BG67 5291_at 0.09 (0.03-026) 1.06E-05 0.02735 0.25(0.12-0.51) 152E-04 0.041766283 11.28(3.31-38.46) 1.08E-04 0.03757 merck BG74

0109_a_at CLYBL 6.43 (2.45 - 16.93) 1.62E-04 0.04263 2.03 (0.93 - 4.44) 0.07445 0.461049468 0.11 (0.03-0.33) 9.79E-05 0.037355 merck BG94 THUMPD3

3385_at -AS1 6.38 (2.39 - 17.04) 2.18E-04 0.04747 2.21(0.99-4.96) 0.05307 0.40708177 0.1(0.03-0.32) 9.65E-05 0.037355 merck_BG95

6704_x_at 4.8(1.79-1291) 0.00186 0.10641 2.9(1.19-7.08) 0.01937 0.273642083 0.1(0.03-0.31) 8.62E-05 0.037035 merck_BI04

5425_at 0.14 (0.05 - 0.38) 1.61E-04 0.04262 0.26(0.12-0.54) 307E-04 0.05232964 10.64(3.21-35.28) 1.11E-04 0.037864 merck_BI75

7398_at KLRA1P 0.17 (0.06-047) 5.25E-04 0.06475 0.27(0.13-0.58) 668E-04 0.071121654 8.83 (2.76-28.31) 2.47E-04 0.049436 merck_BM6 LINC0197

76784_at 1 0.14 (0.05-039) 1.82E-04 0.0448 0.23(0.11-0.48) 101E-04 0.037355406 14.31(4.23-48.44) 1.88E-05 0.028478

merck BM8

05663_at — 0.12(0.04-036) 1.48E-04 0.0415 0.21(0.1-0.45) 617E-05 0.034824234 19.56(5.24-73.05) 9.79E-06 0.027346 merck_BU14

5850_at SOGA1 0.17(0.06-0.45) 3.56E-04 0.05498 0.21 (0.09 - 0.48) 232E-04 0.048677914 9.24(2.93-29.14) 1.47E-04 0.041504 merck BU93

5068 a at RIMBP2 8.48 (2.66-27.04) 3.03E-04 0.05215 3.76(1.3-10.9) 0.01463 0.241743445 0.08(0.02-0.28) 1.06E-04 0.037518 merck BX09

5858_at TJP2 4.72 (1.74- 12.77) 0.002271 0.11474 2.77(1.13-6.77) 0.02568 0.306276248 0.11 (0.03-0.35) 1.78E-04 0.044747 merck_BX09 NFATC3

6093_at RPS12P27 9.68 (3.25-28.83) 4.62E-05 0.03306 3.11(1.18-8.2) 0.02148 0.28451743 0.08 (0.02 - 0.27) 5.31E-05 0.033119 merck_BX09

7755_a_at GDAP2 9.79 (3.31-28.93) 3.71E-05 0.03162 2.97(1.12-7.86) 0.02829 0.318670794 0.09(0.03-0.29) 9.06E-05 0.037355 merck_BX10

2791_at 6.89 (2.6-1828) 1.07E-04 0.03757 2.13(0.95-4.8) 0.06672 0.443569893 0.11(0.03-0.33) 1.16E-04 0.038613 merck_BX10

2980_at MSN 0.18(0.07-05) 8.34E-04 0.07759 0.28(0.14-0.59) 713E-04 0.07351598 9.33 (2.94 - 29.55) 1.48E-04 0.041504 merck_BXll

6278_at 0.07 (0.02-024) 3.67E-05 0.03162 0.3(0.15-0.6) 616E-04 0.069085392 14.28 (3.49 - 58.4) 2.15E-04 0.047288 merck BX11 ELFN1-

9057_at AS1 5.46 (2.06 - 14.48) 6.52E-04 0.07064 1.91(0.9-4.04) 0.09022 0.495013892 0.12 (0.04 - 0.36) 2.10E-04 0.047255 merck_BX32

9942_at PNPO 0.05(0.01-019) 7.70E-06 0.02725 0.28(0.14-0.57) 375E-04 0.056102609 14.39(3.54-58.5) 1.95E-04 0.046237 merck_CA30 LOC10192

9176_at 9371 0.13(0.05-0.35) 6.70E-05 0.03482 0.19(0.08 - 0.42) 530E-05 0.033119082 12.84(3.97-41.57) 2.04E-05 0.029019 merck_CA94

2562_at — 9.61 (3 - 30.72) 1.36E-04 0.04048 3.54(1.21-10.31) 0.02073 0.280747546 0.08(0.02-0.31) 1.89E-04 0.045667 merck_CD10

2009_at — 0.08 (0.03 - 023) 2.01E-06 0.02725 0.15(0.06-0.33) 433E-06 0.027252608 14.84(4.59-47.96) 6.56E-06 0.027253

merck CN38

8529_a_at LAMB1 9.94 (3.51-28.2) 1.56E-05 0.02735 2.31(0.94-5.68) 0.06893 0.448927134 0.11(0.03-0.35) 2.04E-04 0.046691 merck CR99

4266_a_at JAK1 7.66 (2.81-20.85) 6.82E-05 0.03482 2.18(0.93-5.11) 0.07246 0.456899351 0.11(0.04-0.36) 2.16E-04 0.047304 merck_CV39 2556_at 17.29 (593-5043) 1.80E-07 0.0209 2.46(1.05-5.75) 0.03763 0.356253395 0.05 (0.01-0.16) 8.97E-07 0.023449 merck_CX78 5712_at 0.13 (0.04-039) 2.49E-04 0.04955 0.29(0.14-0.6) 773E-04 0.075115086 10.04(2.94-34.28) 2.31E-04 0.048611 merck_DA21

4150_a_at NDFIP1 6.85 (2.58- 18.2) 1.14E-04 0.03815 2.06(0.91-4.64) 0.08229 0.478783307 0.11 (0.04-0.36) 1.88E-04 0.045621 merck_DA23

4289_at UHRF2 5.26(1.7- 1627) 0.003933 0.13976 3.74(1.29- 10.82) 0.01489 0.243724747 0.08(0.02-0.31) 1.75E-04 0.044237 merck_DB35

1522_at RIN2 10.08(337-3015) 3.55E-05 0.03162 2.9 (1.1 -7.6) 0.03097 0.329696004 0.09(0.03-0.3) 1.04E-04 0.037518 merck_DB54

6490_at SLC25A48 12.4 (4.35 - 35.32) 2.43E-06 0.02725 1.98(0.85 - 4.62) 0.11515 0.540224786 0.1(0.03-0.31) 9.69E-05 0.037355 merck_DN83

1737_at — 3.64 (1.4 - 9.47) 0.008089 0.18883 3.09(1.32-7.23) 0.00918 0.198567819 0.09(0.03-0.29) 4.18E-05 0.032641 merck DV08

0080_at PHF2P2 10.02(357-2807) 1.18E-05 0.02735 2.19(1-4.76) 0.04868 0.393922587 0.06(0.02-0.21) 7.02E-06 0.027253 merck_ENST

0000024866

8_at LRFN1 0.15(0.05-04) 1.72E-04 0.04391 0.24(0.11-0.5) 190E-04 0.04575582 10.6 (3.31-33.99) 7.15E-05 0.034986 merck_ENST

0000031650

6_a_at OR52B1P 0.07 (0.02-025) 5.12E-05 0.03312 0.23(0.11-0.47) 569E-05 0.033692775 22.93(5.53-95.12) 1.59E-05 0.027346 merck_ENST

0000032349

6_x_at BCAS4 0.12(0.04-031) 1.54E-05 0.02735 0.21(0.1-0.47) 974E-05 0.037355406 8.6(2.79-26.52) 1.81E-04 0.044798

merck_ENST

0000032719 LOC10798

6_at 5946 0.13 (0.05-035) 6.16E-05 0.03482 0.23(0.11-0.48) 115E-04 0.038254005 10.6(3.32-33.83) 6.66E-05 0.034824 merck_ENST

0000033114

6_at RPS17P5 6.82(2.42-19.17) 2.76E-04 0.05079 2.6(1.06-6.41) 0.03766 0.356309272 0.11(0.03-0.35) 2.18E-04 0.047468 merck_ENST

0000034124

4_a_at TAF4B 8.27 (3.06 - 22.33) 3.1OE-O5 0.03148 2.17(0.93-5.06) 0.07324 0.458339281 0.11 (0.03-0.34) 1.37E-04 0.040494 merck_ENST

0000035942 l_at FAM92A 0.09 (0.03 - 03) 5.40E-05 0.03318 0.11(0.04-0.32) 534E-05 0.033119082 12.13(3.34-43.99) 1.47E-04 0.041504 merck ENST

0000036648

5_at OR14A2 19.28(614-6048) 3.94E-07 0.02345 1.43(0.7-2.95) 0.32532 0.759033056 0.05 (0.01-0.17) 2.91E-06 0.027253 merck ENST

0000037632

5_at SHISA7 0.13(0.04-036) 9.42E-05 0.03736 0.24(0.11-0.51) 187E-04 0.045613476 11.47(3.44-38.28) 7.22E-05 0.034986 merck_ENST

0000037899

9_s_at REXO1L2P 6.15(2.3-1647) 3.00E-04 0.05212 2.12(0.95-4.74) 0.06817 0.447120854 0.12(0.04-0.36) 2.05E-04 0.046764 merck_ENST

0000038143

5_at MCHR1 6.29 (2.38- 16.6) 2.05E-04 0.04674 1.77(0.83-3.75) 0.13924 0.576414125 0.12 (0.04-0.37) 2.43E-04 0.049436 merck_G656

25_at — 11.09(3.46-35.52) 5.08E-05 0.03312 3.81(1.31-11.07) 0.01387 0.236245861 0.07(0.02-0.24) 4.46E-05 0.033064 merck NC 0

01405 0RF 1045_s_at 0.09 (0.03-027) 1.84E-05 0.02848 0.22(0.11-0.46) 512E-05 0.033119082 14.56(4.24-50.04) 2.11E-O5 0.029039 merck NM

000258_at MYL3 9.46 (3.38-26.47) 1.85E-05 0.02848 1.98(0.91-4.29) 0.08476 0.484222405 0.08(0.02-0.26) 2.71E-05 0.0306

merck NM_ 000273_at GPR143 0.13 (0.04-038) 2.19E-04 0.04753 0.28(0.14-0.59) 660E-04 0.070759139 10.6(3.06-36.73) 1.96E-04 0.04626 merck_NM_ 000782_at CYP24A1 0.09 (0.03-027) 2.OOE-O5 0.02857 0.23(0.11-0.49) 114E-04 0.038189964 12.81(3.7-44.31) 5.67E-05 0.033693 merck_NM_

000873_at ICAM2 0.16(0.06-0.44) 4.41E-04 0.05971 0.28(0.14-0.59) 737E-04 0.074014184 9.22 (2.83-30.01) 2.24E-04 0.048058 merck_NM_ 001001706_ at AK9 7.38 (2.48-21.95) 3.23E-04 0.0534 3.04(1.14-8.05) 0.02563 0.306089358 0.1(0.03-0.33) 2.12E-04 0.047264 merck_NM_ 001002247_ at ANAPC11 0.08 (0.02-029) 1.35E-04 0.04037 0.29(0.14-0.58) 524E-04 0.06475289 16.36(3.93-68.13) 1.24E-04 0.039414 merck_NM_

001004434_ s_at SLC30A2 0.07 (0.02-022) 7.31E-06 0.02725 0.26(0.13-0.54) 257E-04 0.050108064 12.24(3.33-45.04) 1.64E-04 0.042833 merck_NM_

001004752_ at OR51F1 10.18(317-3267) 9.62E-05 0.03736 3.57(1.23- 10.33) 0.01912 0.271848701 0.08(0.02-0.29) 1.27E-04 0.040085 merck_NM_

001012505. a_at FOXP1 8.53 (3.02-24.09) 5.23E-05 0.03312 3.41(1.37-8.5) 0.00861 0.1934917 0.06(0.02-0.2) 5.38E-06 0.027253 merck NM

001024599 HIST2H2B s at F 8.88 (3.23 - 24.37) 2.25E-05 0.02905 2.48(1.06-5.81) 0.03723 0.354799945 0.08(0.02-0.26) 2.68E-05 0.030477 merck_NM_

001039753_ s_at EML6 0.12(0.04-033) 5.82E-05 0.03409 0.13(0.05-0.33) 166E-05 0.027345536 17.21(5.08-58.38) 4.94E-06 0.027253 merck_NM_

001039_at SCNN1G 0.13 (0.05-035) 5.37E-05 0.03312 0.17(0.08-0.4) 390E-05 0.031886786 12.72(3.93-41.12) 2.18E-05 0.029051 merck_NM_

001294_at CLPTM1 0.1(0.03-0.29) 2.78E-05 0.0308 0.26(0.13-0.53) 212E-04 0.047263991 11.07(3.27-37.52) 1.13E-04 0.038005 merck_NM_

001431_s_at EPB41L2 6.9 (2.47 - 1929) 2.34E-04 0.04878 2.64(1.07-6.5) 0.03456 0.344844557 0.1(0.03-0.33) 1.53E-04 0.041846

merck NM_ 001494_at GDI2 7.32 (2.75- 19.49) 6.86E-05 0.03482 2.14(0.95-4.83) 0.06614 0.442547335 0.1(0.03-0.32) 8.43E-05 0.036978 merck_NM_

001883_at CRHR2 9.12 (3.1-2688) 6.09E-05 0.03482 3.63(1.38-9.55) 0.00918 0.198588716 0.06(0.02-0.21) 8.09E-06 0.027253 merck_NM_

001993_at F3 12.06 (4.3-33.83) 2.25E-06 0.02725 1.33(0.64-2.76) 0.44992 0.832172801 0.1(0.03-0.32) 1.01E-04 0.037355 merck_NM_

002501_s_at NFIX 0.13 (0.05-037) 9.05E-05 0.03736 0.2(0.09-0.44) 477E-05 0.033119082 14.15(4.31-46.46) 1.25E-05 0.027346 merck_NM_

003920_s_at TIMELESS 0.12 (0.04-035) 7.90E-05 0.03655 0.26(0.13-0.55) 381E-04 0.056284608 9.25(2.84-30.13) 2.22E-04 0.047784 merck_NM_

003954_at MAP3K14 0.12 (0.05-034) 4.60E-05 0.03306 0.22(0.1-0.48) 107E-04 0.037570373 10.58(3.31-33.86) 6.98E-05 0.034824 merck_NM_

004318_at ASPH 6.75 (2.41-18.9) 2.76E-04 0.05083 2.87(1.16-7.12) 0.02268 0.291108094 0.09 (0.03-0.3) 8.16E-05 0.036737 merck_NM_

004387_at NKX2-5 0.11 (0.04-033) 6.70E-05 0.03482 0.27(0.13-0.56) 355E-04 0.054982332 10.66(3.14-36.18) 1.46E-04 0.041504 merck_NM_

004422_at DVL2 0.16(0.06-043) 3.09E-04 0.05243 0.2(0.08-0.47) 208E-04 0.04703142 9.85 (3.07-31.64) 1.21E-04 0.039022 merck_NM_

004683_s_at RGN 0.1(0.04-0.29) 1.86E-05 0.02848 0.14(0.06-0.37) 461E-05 0.033063805 9.95 (3.02-32.85) 1.62E-04 0.042632 merck NM_

005184_s_at CALM3 0.08 (0.02-024) 1.44E-05 0.02735 0.26(0.13-0.53) 213E-04 0.047263991 13.26(3.61-48.7) 9.78E-05 0.037355 merck_NM_

006143_at GPR19 0.13 (0.05-034) 3.72E-05 0.03162 0.22(0.1-0.48) 148E-04 0.041538264 8.57(2.76-26.62) 2.01E-04 0.046463 merck_NM_

006268_at DPF2 0.16(0.06 - 0.43) 2.66E-04 0.05041 0.23(0.11-0.51) 266E-04 0.050411995 9.49 (3.01-29.94) 1.23E-04 0.039214 merck_NM_ 007179_at INSL6 16.37 (445 - 6029) 2.63E-05 0.03031 5.86(1.74-19.78) 0.00438 0.146142686 0.03(0.01-0.15) 6.21E-06 0.027253 merck_NM_

014184_s_at CNIH4 0.17 (0.06-044) 3.01E-04 0.05212 0.21(0.1-0.47) 151E-04 0.041766283 10.38(3.34-32.3) 5.36E-05 0.033119

merck NM_ 014230_s_at SRP68 0.21 (0.08-058) 0.002323 0.11599 0.29(0.14-0.61) 0.00108 0.086110602 9.25(2.89-29.64) 1.81E-04 0.044798 merck_NM_ 014553_at TFCP2L1 0.18 (0.07-049) 7.24E-04 0.07378 0.24(0.11-0.52) 353E-04 0.054933977 10.63(3.25-34.7) 9.06E-05 0.037355 merck_NM_ 015058_at VWA8 6.11 (2.16-17.31) 6.55E-04 0.07066 3.39(1.3-8.86) 0.01256 0.227192335 0.08 (0.02-0.27) 3.58E-05 0.031623 merck_NM_ 015832_a_a t MBD2 8.52 (3.12-23.31) 2.99E-05 0.03094 1.84(0.87-3.91) 0.1119 0.534970919 0.09(0.03-0.28) 3.75E-05 0.031623 merck_NM_ 016593_at CYP39A1 6.51 (2.42- 17.53) 2.12E-04 0.04726 2.39(1.02-5.57) 0.04379 0.378543596 0.11(0.03-0.33) 1.15E-04 0.038254 merck_NM_ 017916_at PIH1D1 0.08 (0.03-025) 5.65E-06 0.02725 0.17(0.08-0.37) 923E-06 0.027345536 17.69(5.21-60.1) 4.14E-06 0.027253 merck_NM_ 018055_at NODAL 0.11 (0.04-032) 3.93E-05 0.03189 0.23(0.11-0.48) 101E-04 0.037355406 11.97(3.6-39.84) 5.21E-05 0.033119 merck_NM_ 018219_at CCDC87 8.2(2.91-2308) 6.84E-05 0.03482 2.5(1.02-6.13) 0.04531 0.383198098 0.1(0.03-0.33) 1.56E-04 0.042146 merck_NM_ 020457_at THAP11 0.12 (0.04-033) 3.50E-05 0.03162 0.24(0.11-0.51) 188E-04 0.045667188 8.83(2.81-27.71) 1.89E-04 0.045707 merck_NM_ 02065 l_at PELI1 8.02 (2.7-2385) 1.82E-04 0.0448 3.16(1.19-8.35) 0.02052 0.279698435 0.08(0.02-0.29) 1.02E-04 0.037355 merck_NM_ 020677_s_at NMRAL1 0.09 (0.03-027) 1.89E-05 0.02848 0.19(0.09-0.41) 193E-05 0.028478422 19.1 (5.34-68.26) 5.66E-06 0.027253 merck_NM_ 020774_at MIB1 12.73(394-4114) 2.12E-05 0.02904 3.76(1.3-10.86) 0.01455 0.24122981 0.06(0.02-0.23) 3.50E-05 0.031623 merck_NM_ 021912_at GABRB3 0.08 (0.03-023) 2.44E-06 0.02725 0.16(0.07-0.36) 166E-05 0.027345536 12.24(3.72-40.24) 3.72E-05 0.031623 merck_NM_ 021946_s_at BC0RL1 0.1(0.03-0.27) 7.90E-06 0.02725 0.18(0.08-0.4) 222E-05 0.029051464 12.88(3.97-41.78) 2.07E-05 0.029039 merck_NM_ 021983 x at HLA-DRB4 0.09 (0.03-028) 1.94E-05 0.02848 0.27(0.13-0.56) 355E-04 0.054982332 9.81 (2.9-33.2) 2.40E-04 0.049331

merck NM_ 022358_at KCNK15 0.11 (0.04-033) 7.86E-05 0.03646 0.28(0.14-0.57) 446E-04 0.059751206 10.28(3.02-34.97) 1.90E-04 0.045756 merck_NM_ 025214_at CCDC68 5.95 (2.19-16.18) 4.78E-04 0.06192 2.65(1.13-6.24) 0.02569 0.306276248 0.09 (0.03-0.3) 8.00E-05 0.036707 merck_NM_ LINC0059 030944_at 7 9.12 (3.23-25.74) 2.98E-05 0.03094 2.46(1-6.07) 0.05099 0.400428172 0.1(0.03-0.33) 1.37E-04 0.040515 merck_NM_ 032143_a_a t ZRANB3 9.37 (3.39-25.91) 1.64E-05 0.02735 1.83(0.84-4) 0.1281 0.559452987 0.09(0.03-0.3) 7.53E-05 0.035643 merck_NM_ 032594_at INSM2 5.96(2.2-1613) 4.37E-04 0.05942 2.5(1.06-5.86) 0.03572 0.349233007 0.1(0.03-0.33) 1.32E-04 0.040145 merck_NM_ 052910_at SLITRK1 10.91(299-3976) 2.93E-04 0.05172 4.5(1.34-15.11) 0.01487 0.243608058 0.07 (0.02-0.29) 2.55E-04 0.049968 merck_NM_ 058165_at M0GAT1 7.6(2.57-2245) 2.45E-04 0.04944 3.14(1.18-8.34) 0.02139 0.284138026 0.09 (0.03-0.3) 1.18E-04 0.038642 merck_NM_ 058219_at EXOSC6 0.13 (0.05-036) 6.78E-05 0.03482 0.24(0.11-0.51) 225E-04 0.048058073 9.16(2.9-28.93) 1.60E-04 0.04262 merck_NM_ ATP6V1G 133262_at 3 7.71 (2.6-229) 2.34E-04 0.04878 2.94(1.11-7.77) 0.02956 0.324027699 0.1(0.03-0.34) 2.47E-04 0.049436 merck_NM_ 133492_at ACER1 0.14 (0.05-038) 8.86E-05 0.03736 0.22(0.1-0.47) 105E-04 0.037518224 9.88(3.21-30.45) 6.59E-05 0.034824 merck_NM_ 138447_a_a t ZNF689 0.15 (0.06-04) 1.33E-04 0.04015 0.21(0.09-0.48) 176E-04 0.044352246 9.39(2.93-30.07) 1.64E-04 0.042833 merck_NM_ 139174_at ADAD2 0.09 (0.03-029) 5.76E-05 0.03399 0.24(0.12-0.5) 106E-04 0.037518224 16.66(4.47-62.13) 2.82E-05 0.030796 merck_NM_ 139315_s_at TAF6 0.14 (0.05-039) 1.19E-04 0.03867 0.21(0.1-0.48) 200E-04 0.04637483 8.72 (2.78-27.38) 2.07E-04 0.046967 merck_NM_ 145270_at PRR35 0.12 (0.04 -0.34) 5.07E-05 0.03312 0.2(0.09-0.43) 479E-05 0.033119082 13.61(4.12-44.95) 1.83E-05 0.028478 merck_NM_ 152730_s_at TBC1D32 15.24 (524-4429) 5.60E-07 0.02345 2.18(0.94-5.07) 0.0704 0.45214295 0.07 (0.02-0.22) 1.04E-05 0.027346

merck NM

153274_at BEST4 0.1(0.04-0.3) 3.65E-05 0.03162 0.12(0.05-0.32) 194E-05 0.028478422 16.05(4.65-55.4) 1.12E-O5 0.027346 merck_NM_

173798_at ZCCHC12 0.08 (0.03 - 024) 2.36E-06 0.02725 0.17(0.08-0.37) 834E-06 0.027345536 14.15(4.36-45.92) 1.O2E-O5 0.027346 merck_NM_

174962_x_at SSX9 0.08 (0.02 - 028) 1.02E-04 0.03736 0.3(0.15-0.61) 834E-04 0.077590388 14.35(3.5-58.8) 2.14E-04 0.047288 merck_NM_

176889_at TAS2R2O 9 .8(3.32-2897) 3.64E-05 0.03162 2.97(1.13-7.83) 0.02728 0.314679432 0.08(0.02-0.29) 8.40E-05 0.036978 merck_NM_

178012_at TUBB2B 0.2(0.08-0.55) 0.001562 0.09975 0.22(0.09-0.51) 404E-04 0.057704837 10.97(3.37-35.75) 7.05E-05 0.034828 merck_NM_ KRTAP19-

181608_x_at 2 0.09 (0.03-027) 1.52E-05 0.02735 0.24(0.11-0.49) 996E-05 0.037355406 12.58(3.67-43.14) 5.62E-05 0.033693 merck_NM_

182505_at C9orf85 9 .07 (3.19-25.81) 3.57E-05 0.03162 3(1.22-7.38) 0.01689 0.257661496 0.07 (0.02-0.23) 1.33E-05 0.027346 merck_NM_

182800_at SRRT 0.09 (0.03-03) 6.40E-05 0.03482 0.29(0.14-0.59) 657E-04 0.070660281 11.41(3.13-41.61) 2.27E-04 0.048105 merck_NM_

182905_s_at WASHCI 0.13 (0.05-034) 5.14E-05 0.03312 0.23(0.11-0.5) 162E-04 0.042632345 9.75 (3.03-31.35) 1.32E-04 0.040145 merck_NM_

198994_at TGM6 0.08 (0.03-021) 1.24E-06 0.02504 0.17(0.07-0.37) 130E-05 0.027345536 12.72(3.89-41.56) 2.57E-05 0.030212 merck NM_

199180_at KIRREL2 0.14 (0.05-039) 1.51E-04 0.04177 0.24(0.11-0.51) 225E-04 0.048058073 10(3.14-31.86) 9.92E-05 0.037355 merck VZV

OKA 0RF41 s_at — 0.12 (0.04-033) 3.92E-05 0.03189 0.14(0.06-0.35) 233E-05 0.029051464 12.64(3.9-40.99) 2.38E-05 0.029051 merck_VZV_ OKA_ORF9_ s_at 0.13 (0.05-035) 5.95E-05 0.03444 0.24(0.11-0.51) 234E-04 0.048800286 9.15 (2.87-29.22) 1.84E-04 0.04516 merck_X856 29_at 11.02 (398-3055) 3.95E-06 0.02725 2.66(1.18-6) 0.01867 0.269833526 0.05 (0.02-0.17) 1.03E-06 0.023449

merck X982 ARID1B

06_at MIR4466 8.73(3.07-24.78) 4.73E-05 0.03312 2.84(1.15-7) 0.02339 0.294836152 0.08(0.02-0.26) 3.13E-O5 0.031476 merck_XM_

063314_at OR11H5P 10.56(288-3876) 3.81E-04 0.05628 5.35(1.59-18.01) 0.00681 0.175792963 0.05 (0.01-0.21) 4.70E-05 0.033119 merck_XM_

210303_at 0.12 (0.04 -0.37) 2.92E-04 0.05172 0.29(0.14-0.59) 608E-04 0.068789404 12.85 (3.49 - 47.37) 1.25E-04 0.039651 merck_XM_

373233_x_at 7.64 (2.69-21.66) 1.32E-04 0.04015 2.5(1.02-6.12) 0.04572 0.384379613 0.11(0.03-0.35) 1.96E-04 0.04626 merck_XM_

378090_at 0.1(0.04-0.28) 1.01E-05 0.02735 0.2(0.09-0.45) 929E-05 0.037355406 8.99 (2.81-28.8) 2.16E-04 0.047312 merck_XM_ LOC64251

926011_at 5 0.07 (0.02-02) 9.27E-07 0.02345 0.18(0.08-0.4) 319E-05 0.031578951 10.55(3.24-34.36) 9.27E-05 0.037355 PPIAL4A

PPIAL4C

PPIAL4D

PPIAL4E merck_XM_ PPIAL4F 928173_s_at PPIAL4G 4.9(1.85-1299) 0.001383 0.09443 2.13(0.98-4.66) 0.05729 0.418885847 0.12(0.04-0.37) 2.52E-04 0.049663

FAM207B P merck_XM_ FAM207C 928586_x_at P 0.21 (0.08-055) 0.001728 0.10319 0.27(0.13-0.56) 431E-04 0.059118332 11.73(3.67-37.53) 3.32E-05 0.031623 merck_XM_

933463_at 0.14 (0.05-038) 1.15E-04 0.03825 0.25(0.12-0.52) 252E-04 0.049663475 9.33 (2.95-29.44) 1.40E-04 0.040803 merck_XM_

937104_at 0.17 (0.06-046) 4.63E-04 0.0608 0.26(0.13-0.55) 431E-04 0.059118332 9.53 (3-30.27) 1.31E-04 0.040145 merck_XM_

940419_at SLC9B1P1 0.12 (0.04-036) 1.29E-04 0.04009 0.26(0.13-0.55) 315E-04 0.052817414 11.61(3.4-39.68) 9.21E-05 0.037355 merck_XM_

943662_at 0.12 (0.04-035) 1.21E-04 0.03902 0.29(0.14-0.59) 659E-04 0.070660281 10 (2.91 - 34.3) 2.51E-04 0.049663

merck XM 945363_at 7.59 (2.78-20.73) 7.66E-05 0.03597 1.99(0.89-4.46) 0.09449 0.503642535 0.11 (0.04-0.35) 1.84E-04 0.04516 merck_hCTl 651346_at RPS28P1 9.22 (3.09-27.48) 6.71E-05 0.03482 2.87(1.09-7.56) 0.03333 0.339626483 0.09 (0.03-0.32) 1.69E-04 0.043573 merck_hCTl 651838 3 a LOC10028 t 8437 13.07 (46-37.16) 1.43E-06 0.026 2.82(1.25-6.37) 0.01259 0.227358462 0.04(0.01-0.13) 2.30E-07 0.020898 merck hCTl 812405 2 a t ELOCP31 9.65 (3.39-27.49) 2.19E-05 0.02905 2.87(1.16-7.09) 0.02269 0.291120926 0.07(0.02-0.24) 1.97E-05 0.028478 merck_hCTl 846664_l_a t 9.32 (3.42-25.39) 1.27E-05 0.02735 1.85(0.85-4.01) 0.1215 0.549829621 0.09(0.03-0.29) 5.22E-05 0.033119 merck_hCT2 307348_at 0.07 (0.02-026) 6.24E-05 0.03482 0.3(0.15-0.61) 8.11E-04 0.076586776 14.49(3.5-59.98) 2.26E-04 0.048104 merck hsa mir 153 1 x_at MIR153-1 0.13(0.04-038) 2.24E-04 0.04806 0.27(0.13-0.56) 446E-04 0.059751206 11.51(3.32-39.94) 1.19E-04 0.038671

(b) Pubmed analysis of the gene signature (279 probe sets)

89. The 279 probe sets were linked to 198 genes. Among them, there were 76 genes were associated with colon with 22 linked to colon cancer. These colon cancer associated genes were AGR2, BEST4, CRHR2, CRK, CYP24A1, DVL2, ELFN1-AS1, F3, FIP1L1, FOXP1, ICAM2, JAK1, MAP3K14, MBD2, MIB1, MSN, NKX2-5, NODAL, THUMPD3-AS1, TIMELESS, TJP2, USP46.

(3) PCA Model

90. PCA was uses to summarize the 279 significant probe sets and showed efficiency of data reduction with the first principal component (PCI) explained 14% 20% total variation, higher than 11% by the use of whole genes. The median cutoff PCI was incorporated in the interaction model with the treatment variable to build a predictive model in estimating treatment effect. Analysis result showed the interaction model was able to predict an AVASTIN® effect and also a chemotherapy effect in terms of OS (p < 0.0001 ; Figure 2A and Table 2). Specifically, patients treated with AVASTIN® tend to improve in survival if the PCI score was high (median OS: 7.27 years in AVASTIN®+chemotherapy versus 2.08 years in chemotherapy only; p < 0.0001; Figure 2B, and Table 3). On the other hand, a patient with a low PCI score seems to have better OS if treated with chemotherapy only (median OS: not reached in chemotherapy only versus 2.91 years in AVASTIN®+chemotherapy; p = 2e-04; Figure 2C and Table 4). Patients received chemotherapy only had worse overall survival if the PCI score from 279 significant probe sets is high (hazard ratio 18.28, 95% CI 4.93-67.73); patients with low PCI also had worse overall survival if they treated with AVASTIN® (hazard ratio 7.11 , 95% CI 2 1-24.08 ); PCI score from 279 significant probe sets and treatment type interacts because the relationship between treatment type and overall survival changes depending on PCI score.

Table 2: Median Survival Time of Interaction Mode] in Moffitt Cohort.

Interaction Model: High PCI

Table 3: Median Survival Time of High PCI in Moffitt Cohort Table 3: Median Survival Time of High PCI in Moffitt Cohort

Interaction Model: Low PCI

Table 4: Median Survival Time of Low PCI in Moffitt Cohort

(4) Validation in Moffitt Consortium cohort

91. Data were collected from 39 mCRC patients in the Moffitt Consortium cohort. Overall survival (OS) was the primary endpoint (n=39 death event; 67%). Nine patients (23%) received Avastin and chemotherapy while 30 patients (77%) had chemotherapy only. Gene expression data were generated using HuRSTA-2a520709 Affymetrix arrays and normalized by the iterative rank order normalization method.

92. The cohort showed the AVASTIN®+Chemo group had a median OS of 2.47 years compared to 2.14 years in the Chemo group (p = 0.63; Figure 3A and Table 5). In contrast, patients classified as high PCI group based on the 279 probe sets identified from the Moffitt training cohort had numerically improved median OS if AVASTIN®+Chemo was given (3.04 years in AVASTIN®+Chemo vs 0.82 year in Chemo; p = 0.096; Figure 3B and Table 6). Further evaluation showed a total of 18 probe sets with significant association with death risk (i. e. , prognostic effect). Among them, there were 14 probe sets linked to 14 genes. The 14 significant genes in the Consortium cohort were BFSP2-AS1, ERICH1, HERC4, HIST2H2BF, IWS1, LINC01405, MCHR1, MTMR6, SLC30A2, SLITRK1, SRP68, SRRM4, TFCP2L1, ZNF462. Among them, there were 8 genes linked to the Avatar cohort (ERICH1, HERC4, HIST2H2BF, IWS1, MTMR6, SRP68, TFCP2L1, ZNF462). The Consortium significant genes showed robust predictive effect in the three cohort

Table 5: Median Survival Time of Treatment in Consortium Cohort

Table 6: Median Survival Time of Treatment in High PCI of the Consortium Cohort

(5) Validation in Moffit Avatar cohort

93. Data were collected from 36 mCRC patients in the Moffitt Avatar cohort. Overall survival (OS) was the primary endpoint (n=36 death event; 61%). Twenty-five patients (69%) received Avastin and chemotherapy while 11 patients (31%) had chemotherapy only. Gene expression data was generated by RNA seq.

94. The cohort had a lower median OS (4.56 years) in the AVASTIN®+Chemo group versus 6.98 years in the Chemo group (p = 0.34; Figure 4A and Table 7). This pattern was different from the Moffitt training and Consortium cohorts with observed median OS higher in the AVASTIN®+Chemo group. Because of its distinctive characteristic, we focused on the overall group and the AVASTIN®+Chemo group to assess the signature effect. While the RNA- seq data used in this cohort had 59368 genes, 25% of them (14686 genes) had positive expression (>2) in at least 10% subjects. Furthermore, only 111 genes were able to link to the 279 probe sets in the Moffitt training cohort. Therefore, PCI score was derived based on the 111 genes to validate the signature. The results showed an optimal PCI cutoff at 0.3 (64%;

Figure 4B). The median OS was higher in high PCI compared to low PCI in the overall group (not reached vs 4.43 years; p = 0.04; Figure 4C and Table 8) and in the AVASTIN®+Chemo sub-group (5.94 vs 4.43 years; p = 0.11; Figure 4D and Table 9). Further evaluation showed 9 genes with significant negative association with death risk (i.e., low expression tended to increase death event). The 8 genes (CLPTM1, GTPBP1, IWS1, MAP3K14, MBD2, PIH1D1, SLC25A27, TJP2) after removing USP46 gene (maximum expression <10) showed robust predictive effect (prediction of AVASTIN®) in Moffitt training cohort. Also showed numerically improved OS for patients with high PCI in overall and in the AVASTIN® group.

Table 7: Median Survival Time of Treatment in Avatar Cohort

Table 8: Median Survival Time of PCI Optima] Cutoff (Overall) in Avatar Cohort Table 8: Median Survival Time of PCI Optimal Cutoff (Overall) in Avatar Cohort

Table 9: Median Survival Time of PCI Optimal Cutoff (AVASTIN®) in Avatar Cohort

(6) Refinement of Avastin Gene Signature

(a) Signature derived from significant genes in Consortium cohort

95. There were 7 significant genes in the Consortium cohort (HERC4, HIST2H2BF, IWS1, MCHR1, SLC30A2, SRP68, ZNF462) with the same up-regulated or down -regulated pattern. Among them, there were 5 genes linked to the Avatar cohort (HERC4, HIST2H2BF, IWS1, SRP68, ZNF462). The Consortium significant genes showed robust predictive effect in the three cohorts Figures 5A, 5B, and 5C).

Interaction Model: High PCI

Table 11: Median Survival Time of High PCI in Moffitt Cohort

Interaction Model: Low PCI

Table 12: Median Survival Time of Low PCI in Moffitt Cohort Moffitt consortium cohort

Interaction Model: High PCI

Table 14: Median Survival Time of High PCI in Moffitt Consortium Cohort

Moffitt Avatar Cohort

Table 15: Median Survival Time of PCI in Moffitt Avatar Cohort

Avatar: Avastin subgroup

Table 16: Median Survival Time of Avastin in Moffitt Avatar Cohort

Signature derived from significant genes in Avatar cohort

The 8 genes (CLPTM1, GTPBP1, IWS1, MAP3K14, MBD2, PIH1D1, SLC25A27, TJP2) after removing USP46 gene (maximum expression <10) showed robust predictive effect (prediction of Avastin) in Moffitt training cohort and also showed numerically improved OS for patients with high PCI in overall and in the Avastin group.

Table 17: Median Survival Time of Interaction Model in Moffitt Cohort

Interaction Model: High PCI

Table 18: Median Survival Time of High PCI in Moffitt Cohort

Interaction Model: Low PCI

Table 19: Median Survival Time of Low PCI in Moffitt Cohort

Moffitt Consortium cohort Interaction Model: High PCI

Table 21: Median Survival Time of High PCI in Moffitt Consortium Cohort

Moffitt Avatar cohort Table 22: Median Survival Time of PCI in Moffitt Avatar Cohort

Avatar: Avastin subgroup

Table 23: Median Survival Time of Avastin in Moffitt Avatar Cohort