Prognostic and diagnostic method for cancer therapy

Abstract

The present invention relates to methods for the diagnosis and prognosis of aggressive forms of cancer using a combination of gene expression signatures.

1 . A method for diagnosing a more aggressive form of prostate, breast, lung, or ovarian cancer in a subject comprising determining a cumulative cancer therapy outcome predictor (CTOP) score for six gene expression signatures, wherein the six gene expression signatures are TEZ, EED, SUZ12/POLII, SUZ12, NANOG/SOX2/OCT4, and PCG-TF, wherein the CTOP score for each signature is determined by measuring the mRNA expression of each gene comprising the signature in a sample from the subject, and wherein a higher cumulative CTOP score indicates a more aggressive form of the cancer. 
     
     
         2 . The method of  claim 1 , further comprising determining the CTOP score for one or more additional gene expression signatures selected from the group consisting of BCD TF, ESC3, BMI-1 pathway, PcG methylation, and histones H3/H2A. 
     
     
         3 . The method of  claim 1 , wherein the cancer is breast cancer or lung cancer and the one or more CTOP signatures comprises a 36-transcript TEZ CTOP signature comprising transcripts of the following genes: GNG10, SOX9, BCI2, PURA, LIF, MN1, HOXD, BAI3, GFRA2, SIX1, CACNAL, SIX2, SMARCA2, and SMARCA2. 
     
     
         4 . The method of  claim 1 , wherein the cancer is breast cancer or lung cancer and the one or more CTOP signatures comprises a 20-transcript EED CTOP signature consisting of transcripts of the following genes: CCND2, YYL, SOX9, PDGFRA, EZH2, KIT, PAX6, DICERL, LHX2, BMP6, HOXC6, PAX9, SOX5, WNT8B, ESRRB, FOXIL, EED, YYL, CKAP2, and CBX8. 
     
     
         5 . The method of  claim 1 , wherein the cancer is prostate cancer and the one or more CTOP signatures comprises a 36-transcript EED CTOP signature consisting of transcripts of the following genes: PAX8, YYL, PCNA, IGF2, HPRTL, SOX9, PDGFRA, EZH2, FGFR3, HOXB7, BMPRLA, TCF21, TALI, CRABP1, HOXB2, GATA4, FGF7, BMP6, HOXA4, CBX4, HOXC5, HOXC6, DIX2, FOXHI, SOX21, NEUROG1, EED, GATA3, GATAL, MYST4, YYL, HOXA2, PAX8, PDGFRA, TALL, and DKK2. 
     
     
         6 . The method of  claim 1 , wherein the cancer is breast cancer or lung cancer and the one or more CTOP signatures comprises a 20-transcript SUZ12/POLII CTOP signature consisting of transcripts of the following genes: CXCR4, KIAA0368, PLD1, NID2, ATF3, KIAA0427, DUSP4, SMTN, GADD45B, PRKCH, JUN, PCDH17, TIMP3, PLEC1, LIF, SOX9 and CDH11. 
     
     
         7 . The method of  claim 1 , wherein the cancer is prostate cancer and the one or more CTOP signatures comprises a 22-transcript SUZ12/POLII CTOP signature consisting of transcripts of the following genes: PAK1, ING1, POLR3K, PLD1, BAIAP2, BDNF, EGFR, FBN2, KIAA0427, CAST, GADD45B, PRKCH, CYP1B1, and JUN. 
     
     
         8 . The method of  claim 1 , wherein the cancer is breast cancer or lung cancer and the one or more CTOP signatures comprises a 25-transcript SUZ12 CTOP signature consisting of transcripts of the following genes: SFRP1, COL15A1, DFNA5, THBD, PSMB9, MYO5A, MN1, RASGRP1, SYNGR3, RELN, SALL1, MMP25, RASGRP2, GATA3, GATA6, PCDH7, HLA-G, TFAP2B, FLJ10159, DLL3, GNA14, TGFB2, WNT5B, and BACH2. 
     
     
         9 . The method of  claim 1 , wherein the cancer is breast cancer or lung cancer and the one or more CTOP signatures comprises a 41-transcript NANOG/SOX2/OCT4 CTOP signature consisting of transcripts of the following genes: RPS3A, TOP2A, BUB3, TALDO1, USP7, SNRPN, ZFP36L1, GNG10, SFRP1, LAMA4, FEZ1, BUB1B, MTM1, TIF1, NFE2L3, DTNA, CA4, TDGF1, 1F116, TLE3, SPAG9, ZIC3, FGFR2, 1F116, STATS, PPAP2A, PPAP2A, FGFR2, PHF8, LARGE, RPS18, FUS, FLJ10769, DUSP12, FLJ10652, FLJ11029, RAD54B, NANOG, FEZ1, FEZ1, and MTM1. 
     
     
         10 . The method of  claim 1 , wherein the cancer is prostate cancer and the one or more CTOP signatures comprises a 28-transcript NANOG/SOX2/OCT4 CTOP signature consisting of transcripts of the following genes: JUP, BUB3, ICMT, GNG10, SET, PPAP2A, LARGE, FUS, and NUCKS. 
     
     
         11 . The method of  claim 1 , wherein the cancer is breast cancer or lung cancer and the one or more CTOP signatures comprises a 30-transcript PcG TF CTOP signature consisting of transcripts of the following genes: ATF3, SOX9, ZFHX1B, JUN, CEBPA, NPAS2, NPAS2, DACH1, SIX1, EGR3, FOXF2, CART1, HOXC6, PAX9, DIX2, SIX6, ALX3, HOXB3, POU4F3, POU3F3, NR2F2, MAFA, PAX1, GSH1, WT1, SOX18, LHX6, TBR1, and EN1. 
     
     
         12 . The method of  claim 1 , wherein the cancer is prostate cancer and the one or more CTOP signatures comprises a 21-transcript PcG TF CTOP signature consisting of transcripts of the following genes: JUNB, HOXB2, NPAS2, IRF5, PAX6, SIX1, VVT1, HOXA4, HOXC6, NKX2B, HOXD13, HOXB1, NEUROG1, FOXB1, GATA6, BARX2, LEF1, NHLH2, TALI, and TBR1 BACH2. 
     
     
         13 . The method of  claim 2 , wherein the cancer is breast cancer or lung cancer and the one or more CTOP signatures comprises an 26-transcript BCD TF CTOP signature consisting of transcripts of the following genes: DLX2, EN2, HOXA1, HOXA13, HOXA2, HOXA5, HOXB2, HOXB3, HOXB6, HOXB8, HOXC13, HOXC5, HOXD3, IRX2, IRX4, LMO1, NR2F2, PAX1, PAX2, SATB1, SHH, SIX2, TLX3, ZFHX1B, HOXA7, and TITF1. 
     
     
         14 . The method of  claim 2 , wherein the cancer is prostate cancer and the one or more CTOP signatures comprises a 31-transcript BCD TF CTOP signature consisting of transcripts of the following genes: SATB1, HOXD9, PAX6, LMO4, EBF1, FOXA1, FOXD3, HOXA, HOXB, HOXC, HOXD, IRX4, MAF, MRG1, NKX2-2, and NKX6-2. 
     
     
         15 . The method of  claim 2 , wherein the one or more CTOP signatures comprises an 11-transcript BMI-1 CTOP signature consisting of transcripts of the following genes: GBX2, MK167, CYCLIN B1, BUB1, HEC, KIAAIDG3, HCFC1, RNF2, ANK3, FGFR2, and CES1. (OK— FIG. 10  of  507 ) 
     
     
         16 . The method of  claim 2 , wherein the cancer is breast cancer or lung cancer and the one or more CTOP signatures comprises a 35-transcript ESC3 CTOP signature consisting of transcripts of the following genes: PTPRF, MARCKS, FLNA, TNFAIPL, P1S3, IRAK1, MARCKS, PYCR1, TM4SF2, NDST1, DBN1, NSMAF, FZD7, AQP3, SSBP2, NKAT, CHC1I FST, GSTT2, CDS1, CNTFR, GGT1, FST, GGT1, EPHX2, CDKN2A, CD24A, EFS, BATT, TNNT1, IFITM3, PRDM4, SOX18, LEPREL, and MDFI. 
     
     
         17 . A method for prognosis of prostate, breast, lung, or ovarian cancer in a subject having prostate, breast, lung, or ovarian cancer comprising determining a cumulative cancer therapy outcome predictor (CTOP) score for six gene expression signatures, wherein the six gene expression signatures are TEZ, EED, SUZ12/POLII, SUZ12, NANOG/SOX2/OCT4, and PCG-TF, wherein the cumulative CTOP score is the sum of the CTOP scores for each signature determined by measuring the mRNA expression of each gene comprising the signature in a sample from the subject, and wherein a higher cumulative CTOP score indicates a more aggressive form of the cancer and a poor prognosis.