US 11,746,380 B2
Classification and prognosis of cancer
Bogdan-Alexandru Luca, Norfolk (GB); Vincent Moultion, Norfolk (GB); Daniel Simon Brewer, Norfolk (GB); and Colin Stephen Cooper, Norfolk (GB)
Assigned to UNIVERSITY OF EAST ANGLIA, Norfolk (GB)
Appl. No. 16/339,463
Filed by UNIVERSITY OF EAST ANGLIA, Norfolk (GB)
PCT Filed Oct. 5, 2017, PCT No. PCT/EP2017/075368
§ 371(c)(1), (2) Date Apr. 4, 2019,
PCT Pub. No. WO2018/065525, PCT Pub. Date Apr. 12, 2018.
Claims priority of application No. 1616912 (GB), filed on Oct. 5, 2016.
Prior Publication US 2020/0263255 A1, Aug. 20, 2020
Int. Cl. C12Q 1/68 (2018.01); C12Q 1/6886 (2018.01)
CPC C12Q 1/6886 (2013.01) [C12Q 2600/112 (2013.01); C12Q 2600/118 (2013.01); C12Q 2600/158 (2013.01)] 4 Claims
 
1. A method of predicting prostate cancer progression, comprising:
a) determining the expression status of at least 50 genes selected from the group consisting of: TGM4, RLN1, ORM1, OLFM4, OR51E2, SERPINB11, CRISP3, TDRD1, SLC14A1, IGJ, ERG, GDEP, TMEFF2, CST1, LTF, AMACR, SERPINA3, NEFH, ACSM1, OR51E1, MT1G, ANKRD36B, LOC100510059, PLA2G2A, TARP, REXO1L1, ANPEP, HLA-DRB5, PLA2G7, NCAPD3, OR51F2, SPINK1, RCN1, CP, SMU1, ACTC1, AGR2, SLC26A4, IGKC, MYBPC1, NPY, PI15, SLC22A3, PIGR, MME, RBPMS, HLA-DRB1, FOLH1, LUZP2, MSMB, GSTT1, MMP7, ODZ1, ACTB, SPON2, SLC38A11, FOS, OR51T1, HLA-DMB, KRT15, ITGA8, CXADR, LYZ, CEACAM20, C8orf4, DPP4, PGC, C15orf21, CHORDC1, LRRN1, MT1M, EPHA6, PDE11A, TMSB15A, LYPLA1, FOSB, F5, C15orf48, MIPEP, HSD17B6, SLPI, CD38, MMP23B, OR51A7, CFB, CCL2, POTEM, TPMT, FAM3B, FLRT3, C7, NTN4, FAM36A, CNTNAP2, SC4MOL, CH17-189H20.1, TRGC2, RAP1B, SLC4A4, LCE2D, EGR1, MT1L, SCUBE2, FAM55D, PDK4, CXCL13, CACNA1D, GPR160, CPM, PTGS2, TSPAN8, BMP5, GOLGA8A, OR4N2, FAM135A, DYNLL1, DSC3, C4orf3, HIST1H2BK, LCN2, STEAP4, RPS27L, TRPM8, ID2, LUM, EDNRB, PGM5, SFRP4, STEAP1, FADS2, CXCL11, CWH43, SNRPN, GPR110, THBS1, APOD, HPGD, LEPREL1, LCE1D, GSTM5, SLC30A4, SEMA3D, CACNA2D1, GPR116, C7orf63, FAM198B, SCD, NR4A2, ARG2, ZNF385B, RGS1, DNAH5, NPR3, RAB3B, CHRDL1, ZNF208, MBOAT2, ATF3, ST6GAL1, GDF15, ANXA1, FOLH1, C4B, ELOVL2, GSTM1, GLIPR1, C3, MYO6, ORM2, RAET1L, PCDHB3, C1orf150, ALOX15B, LSAMP, SLC15A2, PCP4, MCCC2, GCNT1, C5orf23, SCGB1D2, CXCL2, AFF3, ATP8A2, PRIM2, ADAMTSL1, NELL2, RPS4Y1, CD24, GOLGA6L9, ZFP36, TRIB1, BNIP3, KL, PDE5A, DCN, LDHB, PCDHB5, ACADL, ZNF99, CPNE4, CCDC144B, SLC26A2, CYP1B1, SELE, CLDN1, KRT13, SFRP2, SLC25A33, HSD17B11, HSD17B13, UGT2B4, CTGF, SCIN, C10orf81, CYR61, PRUNE2, IFI6, MYH11, PPP1R3C, KCNH8, ZNF615, ERV3, F3, TTN, LYRM5, FMOD, NEXN, IL28A, FHL1, CXCL10, SPOCK1, GSTP1, OAT, HIST2H2BF, ACSM3, GLB1L3, SLC5A1, OR4N4, MAOB, BZW1, GENSCAN00000007309, IFI44L, KRT5, SCN7A, GOLM1, HIST4H4, IL7R, CSGALNACT1, A2M, LRRC9, ARHGEF38, ACSL5, SGK1, TMEM45B, AHNAK2, NEDD8, GREB1, UBQLN4, SDHC, TCEAL2, SLC18A2, HIST1H2BE, RARRES1, PLN, OGN, GPR110, CLGN, NIPAL3, ACTG2, RCAN3, KLK11, HMGCS2, EML5, EDIL3, PIGH, GLYATL1, ATP1B1, GJA1, PLA1A, MPPED2, AMD1, EMP1, PRR16, CNN1, GHR, ALDH1A1, TRIM29, IFNA17, TAS2R4, SEPP1, GREM1, RASD1, C1S, CLSTN2, DMXL1, HIST1H2BC, NRG4, ARL17A, GRPR, PART1, CYP3A5, KCNC2, SERPINE1, SLC6A14, EIF4A1, MYOF, PHOSPHO2, GCNT2, AOX1, CCDC80, ATP2B4, UGDH, GSTM2, MEIS2, RGS2, PRKG2, FIBIN, FDXACB1, SOD2, SEPT7, PTPRC, GABRP, CBWD3, TOR1AIP2, CXCR4, OR51L1, SLC12A2, AGAP11, SLC27A2, AZGP1, VCAN, ERAP2, KRT17, SLC2A12, CCL4, RPF2, SLC45A3, SEC11C, IFIT1, PAK1IP1, HIST1H3C, ERRFI1, ADAMTS1, TRIM36, FLNA, CCND2, IFIT3, FN1, PRY, HSPB8, CD177, TP63, IFI44, COL12A1, EDNRA, PCDHB2, HLA-DRA, TUBA3E, ASPN, FAM127A, DMD, DHRS7, ANO7, MEIS1, TSPAN1, CNTN1, TRIM22, GSTA2, SORBS1, GPR81, CSRP1, C3orf14, FGFR2, SNAI2, CALCRL, MON1B, PVRL3, VGLL3, SULF1, LIFR, SH3RF1, C12orf75, GNPTAB, CALM2, KLF6, C7orf58, RDH11, NR4A1, RWDD4, ABCC4, ZNF91, GABRE, SLC16A1, DEGS1, CLDN8, HAS2, ODC1, REEP3, LYRM4, PPFIA2, PGM3, ZDHHC8P1, C6orf72, HIST1H2BD, TES, PDE8B, DNAJB4, RGS5, EPHA3, COX7A2, MT1H, HIST2H2BE, TGFB3, VEGFA, CRISPLD2, TFF1, LOC100128816, SYT1, CPE, TRPC4, RAB27A, CD69, RPL17, PSCA, ATRNL1, MYOCD, MS4A8B, TNS1, BAMBI, IGF1, RALGAPA1, S100A10, PMS2CL, MMP2, SLC8A1, OAS2, ARRDC3, AMY2B, SPARCL1, IQGAP2, ACAD8, LPAR3, HIGD2A, NUCB2, HLA-DPA1, SLITRK6, TPM2, REPS2, EAF2, CAV1, PRUNE2, TMEM178, MFAP4, SYNM, EFEMP1, RND3, SCNN1A, B3GNT5, LMOD1, UBC, LMO3, LOX, NFIL3, C11orf92, C11orf48, BCAP29, EPCAM, PTGDS, A5B5, TUBA1B, SERHL, ITGA5, SPARC, LOC286161, NAALADL2, TMPRSS2, SERPINF1, EPHA7, SDAD1, SOX14, RPL35, HSPA1B, MSN, MTRF1L, PTN, CAMKK2, RBM7, OR52H1, C1R, CHRNA2, MRPL41, PROM1, LPAR6, SAMHD1, SCNN1G, DNAJC10, MOXD1, HIST1H2BG, ID1, and SEMA3C in a sample obtained from a patient to provide a patient expression profile, wherein the expression level of the at least 50 genes selected from the group consisting of TGM4, RLN1, ORM1, OLFM4, OR51E2, SERPINB11, CRISP3, TDRD1, SLC14A1, IGJ, ERG, GDEP, TMEFF2, CST1, LTF, AMACR, SERPINA3, NEFH, ACSM1, OR51E1, MT1G, ANKRD36B, LOC100510059, PLA2G2A, TARP, REXO1L1, ANPEP, HLA-DRB5, PLA2G7, NCAPD3, OR51F2, SPINK1, RCN1, CP, SMU1, ACTC1, AGR2, SLC26A4, IGKC, MYBPC1, NPY, PI15, SLC22A3, PIGR, MME, RBPMS, HLA-DRB1, FOLH1, LUZP2, MSMB, GSTT1, MMP7, ODZ1, ACTB, SPON2, SLC38A11, FOS, OR51T1, HLA-DMB, KRT15, ITGA8, CXADR, LYZ, CEACAM20, C8orf4, DPP4, PGC, C15orf21, CHORDC1, LRRN1, MT1M, EPHA6, PDE11A, TMSB15A, LYPLA1, FOSB, F5, C15orf48, MIPEP, HSD17B6, SLPI, CD38, MMP23B, OR51A7, CFB, CCL2, POTEM, TPMT, FAM3B, FLRT3, C7, NTN4, FAM36A, CNTNAP2, SC4MOL, CH17-189H20.1, TRGC2, RAP1B, SLC4A4, LCE2D, EGR1, MT1L, SCUBE2, FAM55D, PDK4, CXCL13, CACNA1D, GPR160, CPM, PTGS2, TSPAN8, BMP5, GOLGA8A, OR4N2, FAM135A, DYNLL1, DSC3, C4orf3, HIST1H2BK, LCN2, STEAP4, RPS27L, TRPM8, ID2, LUM, EDNRB, PGM5, SFRP4, STEAP1, FADS2, CXCL11, CWH43, SNRPN, GPR110, THBS1, APOD, HPGD, LEPREL1, LCE1D, GSTM5, SLC30A4, SEMA3D, CACNA2D1, GPR116, C7orf63, FAM198B, SCD, NR4A2, ARG2, ZNF385B, RGS1, DNAH5, NPR3, RAB3B, CHRDL1, ZNF208, MBOAT2, ATF3, ST6GAL1, GDF15, ANXA1, FOLH1, C4B, ELOVL2, GSTM1, GLIPR1, C3, MYO6, ORM2, RAET1L, PCDHB3, C1orf150, ALOX15B, LSAMP, SLC15A2, PCP4, MCCC2, GCNT1, C5orf23, SCGB1D2, CXCL2, AFF3, ATP8A2, PRIM2, ADAMTSL1, NELL2, RPS4Y1, CD24, GOLGA6L9, ZFP36, TRIB1, BNIP3, KL, PDE5A, DCN, LDHB, PCDHB5, ACADL, ZNF99, CPNE4, CCDC144B, SLC26A2, CYP1B1, SELE, CLDN1, KRT13, SFRP2, SLC25A33, HSD17B11, HSD17B13, UGT2B4, CTGF, SCIN, C10orf81, CYR61, PRUNE2, IFI6, MYH11, PPP1R3C, KCNH8, ZNF615, ERV3, F3, TTN, LYRM5, FMOD, NEXN, IL28A, FHL1, CXCL10, SPOCK1, GSTP1, OAT, HIST2H2BF, ACSM3, GLB1L3, SLC5A1, OR4N4, MAOB, BZW1, GENSCAN00000007309, IFI44L, KRT5, SCN7A, GOLM1, HIST4H4, IL7R, CSGALNACT1, A2M, LRRC9, ARHGEF38, ACSL5, SGK1, TMEM45B, AHNAK2, NEDD8, GREB1, UBQLN4, SDHC, TCEAL2, SLC18A2, HIST1H2BE, RARRES1, PLN, OGN, GPR110, CLGN, NIPAL3, ACTG2, RCAN3, KLK11, HMGCS2, EML5, EDIL3, PIGH, GLYATL1, ATP1B1, GJA1, PLA1A, MPPED2, AMD1, EMP1, PRR16, CNN1, GHR, ALDH1A1, TRIM29, IFNA17, TAS2R4, SEPP1, GREM1, RASD1, C1S, CLSTN2, DMXL1, HIST1H2BC, NRG4, ARL17A, GRPR, PART1, CYP3A5, KCNC2, SERPINE1, SLC6A14, EIF4A1, MYOF, PHOSPHO2, GCNT2, AOX1, CCDC80, ATP2B4, UGDH, GSTM2, MEIS2, RGS2, PRKG2, FIBIN, FDXACB1, SOD2, SEPT7, PTPRC, GABRP, CBWD3, TOR1AIP2, CXCR4, OR51L1, SLC12A2, AGAP11, SLC27A2, AZGP1, VCAN, ERAP2, KRT17, SLC2A12, CCL4, RPF2, SLC45A3, SEC11C, IFIT1, PAK1IP1, HIST1H3C, ERRFI1, ADAMTS1, TRIM36, FLNA, CCND2, IFIT3, FN1, PRY, HSPB8, CD177, TP63, IFI44, COL12A1, EDNRA, PCDHB2, HLA-DRA, TUBA3E, ASPN, FAM127A, DMD, DHRS7, ANO7, MEIS1, TSPAN1, CNTN1, TRIM22, GSTA2, SORBS1, GPR81, CSRP1, C3orf14, FGFR2, SNAI2, CALCRL, MON1B, PVRL3, VGLL3, SULF1, LIFR, SH3RF1, C12orf75, GNPTAB, CALM2, KLF6, C7orf58, RDH11, NR4A1, RWDD4, ABCC4, ZNF91, GABRE, SLC16A1, DEGS1, CLDN8, HAS2, ODC1, REEP3, LYRM4, PPFIA2, PGM3, ZDHHC8P1, C6orf72, HIST1H2BD, TES, PDE8B, DNAJB4, RGS5, EPHA3, COX7A2, MT1H, HIST2H2BE, TGFB3, VEGFA, CRISPLD2, TFF1, LOC100128816, SYT1, CPE, TRPC4, RAB27A, CD69, RPL17, PSCA, ATRNL1, MYOCD, MS4A8B, TNS1, BAMBI, IGF1, RALGAPA1, S100A10, PMS2CL, MMP2, SLC8A1, OAS2, ARRDC3, AMY2B, SPARCL1, IQGAP2, ACAD8, LPAR3, HIGD2A, NUCB2, HLA-DPA1, SLITRK6, TPM2, REPS2, EAF2, CAV1, PRUNE2, TMEM178, MFAP4, SYNM, EFEMP1, RND3, SCNN1A, B3GNT5, LMOD1, UBC, LMO3, LOX, NFIL3, C11orf92, C11orf48, BCAP29, EPCAM, PTGDS, ASB5, TUBA1B, SERHL, ITGA5, SPARC, LOC286161, NAALADL2, TMPRSS2, SERPINF1, EPHA7, SDAD1, SOX14, RPL35, HSPA1B, MSN, MTRF1L, PTN, CAMKK2, RBM7, OR52H1, C1R, CHRNA2, MRPL41, PROM1, LPAR6, SAMHD1, SCNN1G, DNAJC10, MOXD1, HIST1H2BG, ID1, and SEMA3C are known to vary across prostate cancers;
b) conducting a Latent Process Decomposition (LPD) analysis on the patient expression profile and a reference dataset for the same at least 50 genes selected from the group consisting of TGM4, RLN1, ORM1, OLFM4, OR51E2, SERPINB11, CRISP3, TDRD1, SLC14A1, IGJ, ERG, GDEP, TMEFF2, CST1, LTF, AMACR, SERPINA3, NEFH, ACSM1, OR51E1, MT1G, ANKRD36B, LOC100510059, PLA2G2A, TARP, REXO1L1, ANPEP, HLA-DRB5, PLA2G7, NCAPD3, OR51F2, SPINK1, RCN1, CP, SMU1, ACTC1, AGR2, SLC26A4, IGKC, MYBPC1, NPY, PI15, SLC22A3, PIGR, MME, RBPMS, HLA-DRB1, FOLH1, LUZP2, MSMB, GSTT1, MMP7, ODZ1, ACTB, SPON2, SLC38A11, FOS, OR51T1, HLA-DMB, KRT15, ITGA8, CXADR, LYZ, CEACAM20, C8orf4, DPP4, PGC, C15orf21, CHORDC1, LRRN1, MT1M, EPHA6, PDE11A, TMSB15A, LYPLA1, FOSB, F5, C15orf48, MIPEP, HSD17B6, SLPI, CD38, MMP23B, OR51A7, CFB, CCL2, POTEM, TPMT, FAM3B, FLRT3, C7, NTN4, FAM36A, CNTNAP2, SC4MOL, CH17-189H20.1, TRGC2, RAP1B, SLC4A4, LCE2D, EGR1, MT1L, SCUBE2, FAM55D, PDK4, CXCL13, CACNA1D, GPR160, CPM, PTGS2, TSPAN8, BMP5, GOLGA8A, OR4N2, FAM135A, DYNLL1, DSC3, C4orf3, HIST1H2BK, LCN2, STEAP4, RPS27L, TRPM8, ID2, LUM, EDNRB, PGM5, SFRP4, STEAP1, FADS2, CXCL11, CWH43, SNRPN, GPR110, THBS1, APOD, HPGD, LEPREL1, LCE1D, GSTM5, SLC30A4, SEMA3D, CACNA2D1, GPR116, C7orf63, FAM198B, SCD, NR4A2, ARG2, ZNF385B, RGS1, DNAH5, NPR3, RAB3B, CHRDL1, ZNF208, MBOAT2, ATF3, ST6GAL1, GDF15, ANXA1, FOLH1, C4B, ELOVL2, GSTM1, GLIPR1, C3, MYO6, ORM2, RAET1L, PCDHB3, C1orf150, ALOX15B, LSAMP, SLC15A2, PCP4, MCCC2, GCNT1, C5orf23, SCGB1D2, CXCL2, AFF3, ATP8A2, PRIM2, ADAMTSL1, NELL2, RPS4Y1, CD24, GOLGA6L9, ZFP36, TRIB1, BNIP3, KL, PDE5A, DCN, LDHB, PCDHB5, ACADL, ZNF99, CPNE4, CCDC144B, SLC26A2, CYP1B1, SELE, CLDN1, KRT13, SFRP2, SLC25A33, HSD17B11, HSD17B13, UGT2B4, CTGF, SCIN, C10orf81, CYR61, PRUNE2, IFI6, MYH11, PPP1R3C, KCNH8, ZNF615, ERV3, F3, TTN, LYRM5, FMOD, NEXN, IL28A, FHL1, CXCL10, SPOCK1, GSTP1, OAT, HIST2H2BF, ACSM3, GLB1L3, SLC5A1, OR4N4, MAOB, BZW1, GENSCAN00000007309, IFI44L, KRT5, SCN7A, GOLM1, HIST4H4, IL7R, CSGALNACT1, A2M, LRRC9, ARHGEF38, ACSL5, SGK1, TMEM45B, AHNAK2, NEDD8, GREB1, UBQLN4, SDHC, TCEAL2, SLC18A2, HIST1H2BE, RARRES1, PLN, OGN, GPR110, CLGN, NIPAL3, ACTG2, RCAN3, KLK11, HMGCS2, EML5, EDIL3, PIGH, GLYATL1, ATP1B1, GJA1, PLA1A, MPPED2, AMD1, EMP1, PRR16, CNN1, GHR, ALDH1A1, TRIM29, IFNA17, TAS2R4, SEPP1, GREM1, RASD1, C1S, CLSTN2, DMXL1, HIST1H2BC, NRG4, ARL17A, GRPR, PART1, CYP3A5, KCNC2, SERPINE1, SLC6A14, EIF4A1, MYOF, PHOSPHO2, GCNT2, AOX1, CCDC80, ATP2B4, UGDH, GSTM2, MEIS2, RGS2, PRKG2, FIBIN, FDXACB1, SOD2, SEPT7, PTPRC, GABRP, CBWD3, TOR1AIP2, CXCR4, OR51L1, SLC12A2, AGAP11, SLC27A2, AZGP1, VCAN, ERAP2, KRT17, SLC2A12, CCL4, RPF2, SLC45A3, SEC11C, IFIT1, PAK1IP1, HIST1H3C, ERRFI1, ADAMTS1, TRIM36, FLNA, CCND2, IFIT3, FN1, PRY, HSPB8, CD177, TP63, IFI44, COL12A1, EDNRA, PCDHB2, HLA-DRA, TUBA3E, ASPN, FAM127A, DMD, DHRS7, ANO7, MEIS1, TSPAN1, CNTN1, TRIM22, GSTA2, SORBS1, GPR81, CSRP1, C3orf14, FGFR2, SNAI2, CALCRL, MON1B, PVRL3, VGLL3, SULF1, LIFR, SH3RF1, C12orf75, GNPTAB, CALM2, KLF6, C7orf58, RDH11, NR4A1, RWDD4, ABCC4, ZNF91, GABRE, SLC16A1, DEGS1, CLDN8, HAS2, ODC1, REEP3, LYRM4, PPFIA2, PGM3, ZDHHC8P1, C6orf72, HIST1H2BD, TES, PDE8B, DNAJB4, RGS5, EPHA3, COX7A2, MT1H, HIST2H2BE, TGFB3, VEGFA, CRISPLD2, TFF1, LOC100128816, SYT1, CPE, TRPC4, RAB27A, CD69, RPL17, PSCA, ATRNL1, MYOCD, MS4A8B, TNS1, BAMBI, IGF1, RALGAPA1, S100A10, PMS2CL, MMP2, SLC8A1, OAS2, ARRDC3, AMY2B, SPARCL1, IQGAP2, ACAD8, LPAR3, HIGD2A, NUCB2, HLA-DPA1, SLITRK6, TPM2, REPS2, EAF2, CAV1, PRUNE2, TMEM178, MFAP4, SYNM, EFEMP1, RND3, SCNN1A, B3GNT5, LMOD1, UBC, LMO3, LOX, NFIL3, C11orf92, C11orf48, BCAP29, EPCAM, PTGDS, ASB5, TUBA1B, SERHL, ITGA5, SPARC, LOC286161, NAALADL2, TMPRSS2, SERPINF1, EPHA7, SDAD1, SOX14, RPL35, HSPA1B, MSN, MTRF1L, PTN, CAMKK2, RBM7, OR52H1, C1R, CHRNA2, MRPL41, PROM1, LPAR6, SAMHD1, SCNN1G, DNAJC10, MOXD1, HIST1H2BG, ID1, and SEMA3C from different patients;
c) optionally repeating the analysis step b) multiple times; and
d) predicting prostate cancer progression,
wherein:
the LPD analysis organises individual patient expression profiles into groups; and
for each expression profile, the LPD analysis determines a continuous contribution (pi) of each group to the overall expression profile for each patient expression profile with DESNT processes contributing to poor prognosis and non-DESNT contributing to non-poor prognosis.