Claims for Patent: 10,233,503

Summary for Patent: 10,233,503

Title:	Method for the identification of the origin of a cancer of unknown primary origin by methylation analysis
Abstract:	The invention relates to methods and reagents for the identification of the origin of a carcinoma of unknown primary origin (CUP) based on the determination of the methylation profile in the genome of the CUP. The invention relates as well to methods for selecting a suitable therapy for a patient suffering a CUP as well as to methods for personalized medicine of patient suffering a CUP based on the use of a treatment which is adequate for the primary tumor from which the CUP is derived. The invention also relates to kits comprising reagents adequate for performing the above methods as well as to computer systems and programs which can be used for implementing the methods of the invention.
Inventor(s):	Badosa; Manel Esteller (Barcelona, ES)
Assignee:	FUNDACIO INSTITUT D\'INVESTIGACIO BIOM DICA DE BELLVITGE (IDIBELL) (Barcelona, ES)
Application Number:	14/402,736
Patent Claims:	1. A method for diagnosing and treating a primary tumor in a subject suffering from a cancer of unknown primary origin (CUP), the method in a subject comprising: (i) obtaining a biological sample from the CUP, (ii) isolating DNA from the biological sample, (iii) determining a methylation profile of a selected region of the DNA isolated from the CUP, wherein determining the methylation profile comprises detecting methylation statuses of at least 9 CpG sites within the DNA isolated from the CUP by contacting the DNA with a plurality of probes specific for each CpG site and a reagent for detecting methylation, (iv) comparing the methylation profile of the selected region of the DNA isolated from the CUP with a methylation profile of the same selected region in a DNA sample isolated from a primary tumor, (v) diagnosing the subject as having the primary tumor when the methylation profile of the selected region of the DNA isolated from the CUP is identified as having the same methylation profile as the same region in the DNA sample isolated from the primary tumor, and (vi) treating the subject with a therapy targeted to the primary tumor according to the following Table: TABLE-US-00033 Type of Cancer Therapy Lung Cancer Platinum-based compounds Colon Cancer Antimetabolites Melanoma Cytokines Pancreatic Cancer Antimetabolites Prostate Cancer Hormonal therapy and/or mitotic inhibitors for resistant patients Glioma DNA-alkylating drugs Bladder Cancer Antimetabolites and/or platinum-based compounds Ovarian epithelial Platinum-based compounds Cancer Hepatobiliary Antimetabolites and/or EGFR-targeted drugs Cancer Breast Cancer Hormonal therapy; hormonal therapy combined with cytostatic drugs selected from the group consisting of anthracycline, DNA- alkylating drug, and antimetabolite, and combinations thereof; and/or HER2-targeted drugs Lymphoma CD20-targeted drugs Head and Neck Mitotic inhibitors; and/or mitotic Cancer inhibitors in combination with platinum- based compounds and/or antimetabolites Endometrial Cancer Hormonal therapy Myeloma Corticosteroids; proteasome inhibitors; thalidomide; and/or lenalidomide Testicular Cancer Topoisomerase inhibitors in combination with platinum-based compounds Stomach Cancer DNA intercalating agents and/or DNA cross-linking agents. 2. The method according to claim 1 wherein the primary tumor is selected from the group consisting of a lymphoid neoplasia, head and neck cancer, pancreatic cancer, endometrial cancer, colon cancer, prostate cancer, glioma, ovarian cancer, lung cancer, bladder cancer, melanoma, breast cancer, a myeloid neoplasia, testicular cancer, and stomach cancer. 3. The method according to claim 2 wherein detecting the methylation status comprises detecting the methylation status in one or more CpG sites as defined in Tables 1A and 1B, wherein the methylation status in one or more CpG sites as defined in Table 1A TABLE-US-00034 Lymphoid neoplasias Lymphoid neoplasias hypermetylation (n:200) CGI hypomethylation (n:54) CGI DBC1_P351_R Y DDR1_P332_R N NEFL_P209_R Y BLK_P14_F N HTR1B_P222_F Y LTA_P214_R N HS3ST2_E145_R Y NOTCH4_P938_F N IGSF4_P86_R Y RUNX3_P393_R Y DLK1_E227_R Y BLK_P668_R N SLC22A3_E122_R Y PADI4_P1011_R N ISL1_P379_F Y RUNX3_P247_F Y MYOD1_E156_F Y PLA2G2A_P528_F N DBC1_E204_F Y HLA-DOB_E432_R N IGFBP3_P423_R Y LCK_E28_F Y SOX1_P294_F Y DES_P1006_R N FAT_P279_R Y PMP22_P975_F N MOS_E60_R Y TMPRSS4_P552_F N SLIT2_P208_F Y RHOH_P953_R N HS3ST2_P171_F Y IL18BP_E285_F N PALM2-AKAP2_P420_R Y KLK11_P103_R N CFTR_P372_R Y RUNX3_E27_R N HTR1B_E232_R Y BGN_P333_R N RAB32_P493_R Y AOC3_P890_R N DIO3_P674_ Y LEFTY2_P561_F N NGFB_E353_F Y CCL3_E53_R N CHGA_E52_ Y IL12B_P1453_F Y IGF2_E134_ Y NOS2A_P288_R N SFRP1_P157_F Y NAT2_P11_F N SFRP1_E398_R Y E2F5_P516_R Y FGFR2_P460_R Y MPL_P657_F N PTGS2_P308_F Y PTHR1_P258_F N SEMA3C_E49_R Y PRSS1_E45_R N EYA4_P794_F Y PLA2G2A_E268_F N GATA6_P726_F Y CPA4_E20_F N CDH13_P88_F Y PI3_P1394_R N CDH13_E102_F Y TRIM29_P135_F N TFAP2C_E260_F Y EPHX1_E152_F N TUSC3_E29_R Y EPHX1_P1358_R N PITX2_E24_R Y DLC1_P695_F N MLF1_E243_F Y DSG1_P159_R N PLS3_E70_F Y SFTPB_P689_R N WNT2_P217_F Y IGF1_P933_F N FRZB_E186_R Y CLDN4_P1120_R N EYA4_E277_F Y IGF1_E394_F N HOXA9_E252_R Y HLA-DPB1_P540_F N ISL1_E87_R Y CSF1R_P73_F N HOXA9_P1141_R Y AIM2_E208_F N FZD9_E458_F Y IL1B_P829_F N ONECUT2_E96_F Y GRB7_P160_R N SOX17_P287_R Y MAGEC3_E307_F N ASCL2_P360_F Y AATK_E63_R N FAT_P973_R Y MMP9_E88_R N KDR_E79_F Y KRT13_P676_F N CDH11_P354_R Y IAPP_E280_F N GABRB3_E42_F Y SMARCB1_P220_R Y HOXA11_P698_F Y IFNG_P188_F N DCC_P471_R Y KRT1_P798_R N DSC2_E90_F Y IMPACT_P234_R Y GALR1_E52_F Y ADAMTS12_E52_R Y TJP1_P390_F Y IGFBP3_E65_R Y SLC5A8_E60_R Y TIMP3_seq_7_538_F Y PENK_P447_R Y KDR_P445_R Y ISL1_P554_F Y ADCYAP1_P398_F Y CDH11_P203_R Y CDH1_P52_R Y ETV1_P515_F Y EGFR_E295_R Y NTRK2_P10_F Y CTSL_P81_F Y SOX1_P1018_R Y SCGB3A1_E55_R Y RBP1_E158_F Y CALCA_E174_R Y HOXI313_P17_R Y ALOX12_E85_R Y FGFR2_P266_R Y DAPK1_P10_F Y RET_seq_54_5260_F Y NGFB_P13_F Y TJP1_P326_R Y PENK_E26_F Y ERBB4_P541_F Y TAL1_P594_F Y NTRK2_P395_R Y IPF1_P234_F Y FGF3_P171_R Y IHH_E186_F Y ASCL1_P747_F Y DES_E228_R Y DCC_P177_F Y SLIT2_E111_R Y SOX2_P546_F Y TPEF_seq_44_588_R Y ASCL2_P609_R Y SOX17_P303_F Y TNK1_P41_R Y DCC_E53_R Y NRG1_E74_F Y AGTR1_P41_F Y MAF_P826_R Y IHH_P246_R Y TMEFF2_P152_R Y PRKCDBP_E206_F Y IGFBP2_P306_F Y COL18A1_P365_R Y TFAP2C_P765_F Y RAB32_E314_R Y CCKBR_P480_F Y SLC5A8_P38_R Y FOSL2_E384_R Y EGFR_P260_R Y EPHA7_E6_F Y DAPK1_E46_R Y PTGS2_P524_R Y WT1_P853_F Y PDGFRA_E125_F N NTSR1_P318_F Y IGSF4_P454_F Y CYP1B1_E83_R Y RBP1_P426_R Y PLXDC2_E337_F Y WT1_E32_F Y PALM2-AKAP2_P183_R Y F2R_P839_F Y RASGRF1_E16_F Y NOTCH3_P198_R Y CEBPA_P706_F Y EVI1_E47_R Y HS3ST2_P546_F Y LOX_P313_R Y DAPK1_P345_R Y CDH11_E102_R Y ERG_E28_F Y GRB1O_E85_R Y GATA6_P21_R Y CCNA1_E7_F Y EPHA5_P66_F Y HOXI313_E21_F Y NPY_E31_R Y EPHB1_E202_R Y IGFBP7_P297_F Y COL18A1_P494_R Y NOTCH3_E403_F Y TUSC3_P85_R Y MT1A_P49_R Y BMP2_E48_R Y IGFBP1_E48_R Y ERBB4_P255_F Y IGFBP2_P353_R Y CALCA_P75_F Y ADCYAP1_P455_R Y PAX6_P50_R Y IGF2AS_E4_F Y GABRB3_P92_F Y RIPK4_P172_F Y TWIST1_E117_R Y ALK_E183_R Y EPHA3_P106_R Y TBX1_P885_R Y PAX6_E129_F Y RET_seq_53_5374_F Y TWIST1_P355_R Y GRB1O_P260_F Y BDNF_E19_R Y CDH1_P45_F Y EPHA5_E158_R Y TRIP6_P1090_F Y DIO3_P90_F Y OPCML_E219_R Y FGF5_P238_R Y HRASLS_E72_R Y ASCL1_E24_F Y EPHA7_P205_R Y HOXA11_E35_F Y HLF_E192_F Y IRAK3_P185_F Y INHA_P1189_F Y PYCARD_P150_F Y MT1A_P600_F Y LOX_P71_F Y PDGFRA_P1429_F Y FLT4_P180_R Y GAS7_E148_F Y DST_E31_F Y TEK_E75_F N THBS1_E207_R Y ROR2_E112_F Y IGFBP1_P12_R Y HIC2_P498_F Y MMP2_E21_R Y IHH_P529_F Y INHA_P1144_R Y PROK2_P390_F Y NRG1_P558_R Y TGFBI_P173_F Y FZD9_P175_F Y MEST_P62_R Y or in Table 1B TABLE-US-00035 Lymphoid neoplasias Lymphoid neoplasias (hypermethylation) (n:69) CGI (hypomethylation) (n:27) CGI IGSF4_P86_R Y DDR1_P332_R N FAT_P279_R Y LTA_P214_R N RAB32_P493_R Y NOTCH4_P938_F N IGF2_E134_R Y BLK_P668_R N FGFR2_P460_R Y PLA2G2A_P528_F N PTGS2_P308_F Y LCK_E28_F Y SEMA3C_E49_R Y DES_P1006_R N TFAP2C_E260_F Y PMP22_P975_F N ONECUT2_E96_F Y RHOH_P953_R N FAT_P973_R Y IL18BP_E285_F N IMPACT_P234_R Y BGN_P333_R N TJP1_P390_F Y NAT2_P11_F N IGFBP3_E65_R Y E2F5_P516_R Y CDH11_P203_R Y MPL_P657_F N CDH1_P52_R Y PLA2G2A_E268_F N ETV1_P515_F Y EPHX1_E152_F N EGFR_E295_R Y EPHX1_P1358_R N NTRK2_P10_F Y SFTPB_P689_R N CTSL_P81_F Y IGF1_P933_F N RBP1_E158_F Y IGF1_E394_F N FGFR2_P266_R Y HLA-DPB1_P540_F N DAPK1_P10_F Y CSF1R_P73_F N RET_seq_54_5260_F Y I_L1B_P829_F N TJP1_P326_R Y GRB7_P160_R N ERBB4_P541_F Y MMP9_E88_R N NTRK2_P395_R Y KRT13_P676_F N SOX2_P546_F Y SMARCB1_P220_R Y TNK1_P41_R Y MAF_P826_R Y IHH_P246_R Y IGFBP2_P306_F Y COL18A1_P365_R Y RAB32_E314_R Y CCKBR_P480_F Y EGFR_P260_R Y EPHA7_E6_F Y DAPK1_E46_R Y PDGFRA_E125_F N IGSF4_P454_F Y PD(DC2_E337_F Y PALM2-AKAP2_P183_R Y F2R_P839_F Y CEBPA_P706_F Y EVI1_E47_R Y LOX_P313_R Y DAPK1_P345_R Y GRB1O_E85_R Y HOXI313_E21_F Y NOTCH3_E403_F Y MT1A_P49_R Y BMP2_E48_R Y IGFBP1_E48_R Y ERBB4_P255_F Y IGFBP2_P353_R Y PAX6_P50_R Y RIPK4_P172_F Y PAX6_E129_F Y GRBIO_P260_F Y CDH1_P45_F Y HRASLS_E72_R Y EPHA7_P205_R Y HLF_E192_F Y INHA_P1189_F Y LOX_P71_F Y PDGFRA_P1429_F Y DST_E31_F Y THBS1_E207_R Y IHH_P529_F Y INHA_P1144_R Y is compared with the methylation status of a lymphoid neoplasia, wherein CGI is CpG island associated, Y is yes, and N is not. 4. The method of claim 1, wherein the methylation profile is determined by a method selected from the group consisting of: Methylation-Specific PCR (MSP); an enrichment-based method selected from the group consisting of MeDIP, MBD-seq, and MethylCap; a bisulfite-based method selected from the group consisting of RRBS, bisulfite sequencing, Infinium, GoldenGate, COBRA, MSP, and MethyLight; a MRE-seq restriction-digestion method; differential-conversion; and differential restriction. 5. The method according to claim 2, wherein detecting the methylation status comprises detecting the methylation status in one or more CpG sites as defined in Tables 2A and 2B, wherein the methylation status in one or more CpG sites as defined in Table 2A TABLE-US-00036 Head and neck cancer Head and neck cancer (hypermethylation) (n:171) CGI (hypomethylation) (n:20) CGI LCN2_P141_R N MMP2_P303_R Y PI3_P274_R N ERN1_P809_R Y KRT13_P341_R N MT1A_P600_F Y SLC22A18_P216_R N DLC1_E276_F N TMPRSS4_E83_F N RAB32_P493_R Y LCN2_P86_R N ICAM1_P386_R Y VAMP8_P241_F N JAK3_P156_R N KRT5_E196_R Y RUNX3_P247_F Y TRIP6_P1274_R Y TNFSF8_E258_R N TRIM29_P261_F N HLA-DPA1_P28_R N DSG1_P159_R N RUNX3_P393_R Y PENK_E26_F Y OSM_P188_F Y LY6G6E_P45_R N MPO_P883_R N TRIP6_P1090_F Y DLC1_P695_F N PSCA_P135_F N FANCE_P356_R Y JAK3_P1075_R N RUNX3_E27_R N STAT5A_P704_R N SERPINA5_P156_F N MST1R_E42_R Y HLA-DPA1_P205_R N HLA-DOB_E432_R N TNFSF8_P184_F Y EMR3_P39_R N DLC1_P88_R N NBLI_E205_R N NBLI_P24_F N ZIM3_P718_R N FGF1_P357_R N MAP3K8_P1036_F Y TGFB3_E58_R N AATK_E63_R N SERPINB5_P19_R Y MSH2_P1008_F Y CREBBP_P712_R Y MMP14_P13_F Y GRB7_P160_R N SFN_E118_F Y GLI2_E90_F N MST1R_P87_R Y TNFRSF1A_P678_F N GLI2_P295_F Y IL1RN_E42_F N BCR_P422_F Y CXCL9_E268_R N FGF1_E5_F N FER_P581_F N SEPT9_P58_R Y TRIM29_P135_F N SRC_P164_F N WEE1_P924_R N ALOX12_E85_R Y KCNK4_E3_F Y EGF_E339_F N S100A2_P1186_F N MOS_E60_R Y CD9_P585_R Y AATK_P519_R Y HOXA5_E187_F Y EPHA5_P66_F Y PTPN6_P282_R N CLDN4_P1120_R N SNCG_P98_R Y AATK_P709_R Y HOXA9_E252_R Y DHCR24_P652_R N CSF1R_P73_F N KRT5_P308_F N FRK_P36_F N EPHA2_P203_F Y IL1RN_P93_R N IFNGR2_P377_R Y RIPK3_P124_F N IL1213_P392_R N KLK11_P103_R N HS3ST2_E145_R Y HOXA9_P1141_R Y IGF1_E394_F N SLC14A1_P369_R N LEFTY2_P561_F N DDIT3_P1313_R Y PADI4_P1158_R N HOXA11_P698_F Y HOXI32_P99_F Y FASTK_P598_R Y TRIM29_E189_F Y LIG3_P622_R N SNCG_E119_F N SPDEF_P6_R N SNCG_P53_F Y CALCA_E174_R Y ALOX12_P223_R Y OGG1_E400_F Y HS3ST2_P171_F Y CEACAM1_P44_R N CALCA_P171_F Y DI3C1_E204_F Y DES_P1006_R N DDR1_P332_R N NPR2_P1093_F Y NID1_P677_F N GSTM2_P453_R N GRI37_E71_R N KCNK4_P171_R N HTR113_E232_R Y GFAP_P56_R N SOX1_P294_F Y IL1A_E113_R N PITX2_E24_R Y HOXA5_P479_F Y PAD14_P1011_11 N PLAT_E158_F N ASCL1_P747_F Y HTR1B_P222_F Y DSG1_E292_F N PRSS8_E134_11 Y AIM2_E208_F N CSF3_P309_11 N CHI3L2_E1O_F N SOX17_P303_F Y RARA_P176_11 N ZIM3_P451_11 Y DIO3_E230_11 Y DLK1_E227_11 Y ASB4_P391_F N SOX17_P287_11 Y CAPG_E228_F N CSF1R_E26_F N ARHGDIB_P148_11 N FZD9_E458_F Y CYP2E1_P416_F N THBS2_P605_11 N TAL1_P594_F Y MMP14_P208_11 N SEPT9_P374_F Y FGFR4_P610_F N ZP3_P220_F N IGFBP5_P9_11 Y SEPT5_P441_F Y SPARC_P195_F N S100A4_E315_F N PENK_P447_11 Y S100A2_E36_11 N PTHR1_P258_F N TNFRSF10C_P7_F Y CD9_P504_F Y RAD5O_P191_F Y MYH11_P22_F Y IHH_E186_F Y BMP4_P199_11 Y DCC_P471_R Y PTPRH_E173_F N BCR_P346_F Y EYA4_E277_F Y SERPINE1_P519_F N PTK6_E50_F Y TBX1_P885_R Y ESR1_P151_R Y CD81_P272_R Y SEMA3A_P658_R N TGFBI_P173_F Y HGF_E102_R N CTSL_P264_R Y TNK1_P221_F Y NOTCH3_P198_R Y VAMP8_P114_F N EPHA2_P340_R N BAX_E281_R Y CPA4_E20_F N CD82_P557_R Y IGFBP3_P423_R Y CTSD_P726_F Y MYOD1_E156_F Y SEPT5_P464_R Y TPEF_seq_44_588_R Y CPA4_P1265_R N or in Table 2B TABLE-US-00037 Head and neck cancer Head and neck cancer (hypermethylation) (hypomethylation) (n:97) CGI (n:10) CGI LCN2_P141_R N ERN1_P809_R Y PI3_P274_R N MT1A_P600_F Y KRT13_P341_R N DLC1_E276_F N SLC22A18_P216_R N RAB32_P493_R Y TMPRSS4_E83_F N ICAM1_P386_R Y VAMP8_P241_F N JAK3_P156_R N KRT5_E196_R Y TNFSF8_E258_R N TRIP6_P1274_R Y FANCE_P356_R Y DSG1_P159_R N SERPINA5_P156_F N LY6G6E_P45_R N DLC1_P88_R N PSCA_P135_F N JAK3_P1075_R N MST1R_E42_R Y HLA-DOB_E432_R N EMR3_P39_R N NBL1_E205_R N NBL1_P24_F N ZIM3_P718_R N FGF1_P357_R N MAP3K8_P1036_F Y AATK_E63_R N SERPINB5_P19_R Y MSH2_P1008_F Y CREBBP_P712_R Y MMP14_P13_F Y GRB7_P160_R N SFN_E118_F Y GLI2_E90_F N MST1R_P87_R Y TNFRSF1A_P678_F N GLI2_P295_F Y IL1RN_E42_F N CXCL9_E268_R N FGF1_E5_F N FER_P581_F N SEPT9_P58_R Y TRIM29_P135_F N SRC_P164_F N WEE1_P924_R N EGF_E339_F N AATK_P519_R Y CLDN4_P1120_R N CSF1R_P73_F N KRT5_P308_F N FRK_P36_F N EPHA2_P203_F Y RIPK3_P124_F N IL12B_P392_R N KLK11_P103_R N IGF1_E394_F N PADI4_P1158_R N HOXB2_P99_F Y FASTK_P598_R Y TRIM29_E189_F Y LIG3_P622_R N SPDEF_P6_R N OGG1_E400_F Y CEACAM1_P44_R N CALCA_P171_F Y DES_P1006_R N NPR2_P1093_F Y NID1_P677_F N KCNK4_P171_R N GFAP_P56_R N IL1A_E113_R N HOXA5_P479_F Y PAD14_P1011_R N PLAT_E158_F N DSG1_E292_F N PRSS8_E134_R Y AIM2_E208_F N CSF3_P309_R N ZIM3_P451_R Y ASB4_P391_F N CAPG_E228_F N CSF1R_E26_F N CYP2E1_P416_F N THBS2_P605_R N MMP14_P208_R N FGFR4_P610_F N ZP3_P220_F N S100A4_E315_F N S100A2_E36_R N PTHR1_P258_F N RAD5O_P191_F Y PTPRH_E173_F N PTK6_E50_F Y SEMA3A_P658_R N HGF_E102_R N CTSL_P264_R Y TNK1_P221_F Y VAMP8_P114_F N EPHA2_P340_R N CPA4_E20_F N CD82_P557_R Y CTSD_P726_F Y CPA4_P1265_R N is compared with the methylation status of a head and neck cancer, wherein CGI is CpG island associated, Y is yes, and N is not. 6. The method according to claim 2, wherein detecting the methylation status comprises detecting the methylation status in one or more CpG sites as defined in Tables 3A and 3B, wherein the methylation status in one or more CpG sites as defined in Table 3A TABLE-US-00038 Pancreatic cancer Pancreatic cancer (hypermethylation) (n:150) CGI (hypomethylation) (n:98) CGI CDH13_E102_F Y SERPINB5_P19_R Y GAS7_E148_F Y S100A2_P1186_F N TWIST1_E117_R Y PI3_P274_R N CCNA1_P216_F Y SFN_E118_F Y SLIT2_P208_F Y IAPP_E280_F N FLT3_E326_R Y TRIM29_P135_F N CCNA1_E7_F Y PTPRH_P255_F N NPY_P295_F Y NOS2A_E117_R N GALR1_E52_F Y CYP2E1_P416_F N WT1_E32_F Y SFTPA1_E340_R N RASGRF1_E16_F Y CREBBP_P712_R Y SFRP1_E398_R Y NDN_P1110_F N TPEF_seq_44_S88_R Y TRIM29_E189_F Y MYOD1_E156_F Y CSF2_E248_R N NTRK3_P636_R Y ITK_P114_F N MDR1_seq_42_S300_R Y TRIM29_P261_F N DBC1_P351_R Y TRIP6_P1090_F Y EYA4_E277_F Y IL1RN_E42_F N FGF8_P473_F Y SEPT9_P58_R Y HS3ST2_P171_F Y GLI2_P295_F Y SOX1_P294_F Y TFF2_P178_F N CDH13_P88_F Y CXCL9_E268_R N NTRK3_P752_F Y TFF1_P180_R N SEZ6L_P249_F Y MST1R_E42_R Y NTRK3_E131_F Y PI3_E107_F N DLK1_E227_R Y GLI2_E90_F N HOXA9_P1141_R Y NBL1_P24_F N SOX17_P303_F Y CSF2_P605_F N MYH11_P22_F Y NOS3_P38_F N SOX1_P1018_R Y TMPRSS4_P552_F N HIC2_P498_F Y UGT1A1_P315_R N MOS_E60_R Y NID1_P677_F N IGFBP3_P423_R Y NBL1_E205_R N ERG_E28_F Y S100A2_E36_R N HS3ST2_E145_R Y LCN2_P141_R N FLT1_P302_F Y UGT1A1_E11_F N TBX1_P885_R Y PRSS1_E45_R N TAL1_P594_F Y IFNG_E293_F N SOX17_P287_R Y NCL_P1102_F Y HOXA9_E252_R Y APBA2_P305_R N ADCYAP1_P398_F Y SPI1_P929_F N TMEFF2_P152_R Y FGFR4_P610_F N PENK_P447_R Y SRC_P164_F N MMP2_P303_R Y SEPT9_P374_F Y BMP3_P56_R Y EMR3_P39_R N COL1A2_E299_F Y KRT1_P798_R N TFPI2_P9_F Y PRSS8_E134_R Y NGFB_E353_F Y MST1R_P87_R Y TUSC3_E29_R Y CPA4_E20_F N FLT1_P615_R Y IFNG_P188_F N CHGA_E52_F Y NOS2A_P288_R N GABRB3_E42_F Y SLC22A3_P634_F Y SFRP1_P157_F Y KIAA0125_E29_F N NEFL_P209_R Y NOTCH4_E4_F N SEZ6L_P299_F Y SNCG_E119_F N ASCL2_P360_F Y ZP3_P220_F N HS3ST2_P546_F Y PTK6_E50_F Y FLT4_P180_R Y CLDN4_P1120_R N EPHA5_E158_R Y MPO_E302_R N FLT1_E444_F Y BRCA1_P835_R Y GABRB3_P92_F Y LCN2_P86_R N ESR1_P151_R Y GUCY2F_P255_F N CCND2_P898_R Y PTPRH_E173_F N RET_seq_53_S374_F Y PTPN6_P282_R N NEFL_E23_R Y GML_P281_R N COL1A2_P48_R Y PSCA_P135_F N EYA4_P794_F Y LIG3_P622_R N SLC5A8_E60_R Y CEACAM1_P44_R N SLIT2_E111_R Y WNT8B_E487_F N FLI1_E29_F Y BMP4_P199_R Y WT1_P853_F Y GABRG3_E123_R N KDR_P445_R Y MAPK4_E273_R N MYH11_P236_R Y CAPG_E228_F N HOXA11_P698_F Y FGF1_P357_R N THY1_P149_R Y DLC1_P695_F N ADAMTS12_E52_R Y VAMP8_P241_F N SCGB3A1_E55_R Y APOA1_P261_F N ESR1_E298_R Y MAGEC3_E307_F N TMEFF2_E94_R Y CCR5_P630_R N PROK2_P390_F Y PWCR1_P811_F N KIT_P367_R Y TRIP6_P1274_R Y HOXA9_P303_F Y CASP8_E474_F N NPY_E31_R Y CTLA4_P1128_F N TFP12_P152_R Y GABRA5_P862_R N TFP12_E141_F Y GFAP_P56_R N PITX2_E24_R Y MMP1O_E136_R N DES_E228_R Y KLK1O_P268_R N ASCL1_E24_F Y IL12B_P1453_F Y GSTM2_E153_F Y PAD14_P1011_R N NPY_P91_F Y PWCR1_P357_F N FZD9_E458_F Y AATK_E63_R N TIMP3_seq_7_538_F Y HLA-DOB_E432_R N NGFB_P13_F Y IL1RN_P93_R N MMP2_P197_F Y FRK_P36_F N DBC1_E204_F Y EPHA2_P203_F Y GSTM2_P109_R N SPP1_P647_F N CDH11_E102_R Y PTHR1_P258_F N ADCYAP1_P455_R Y BAX_E281_R Y COL1A1_P5_F Y TWIST1_P355_R Y ATP10A_P147_F Y FRZB_E186_R Y SMO_P455_R Y CALCA_E174_R Y HCK_P858_F Y PENK_E26_F Y MMP2_E21_R Y TIAM1_P117_F Y TSP5O_P137_F Y PTCH2_P568_R Y BMP3_E147_F Y GUCY2D_E419_R Y ASCL2_P609_R Y GDF1O_P95_R Y CCND2_P887_F Y GDF1O_E39_F Y FLT3_P302_F Y IGFBP7_P297_F Y SLC5A8_P38_11 Y FGF5_E16_F Y CALCA_P75_F Y POMC_P53_F Y DCC_E53_11 Y KIT_P405_F Y ZIM2_P22_F Y ASCL1_P747_F Y TUSC3_P85_11 Y TMEFF1_P234_F Y POMC_P400_11 Y POMC_E254_F Y FGF3_E198_11 Y BDNF_E19_11 Y EYA4_P508_F Y ROR2_E112_F Y SGCE_E149_F Y HCK_P46_11 Y ADCYAP1_E163_11 Y TPEF_seq_44_536_F Y ADAMTS12_P250_11 Y HOXA5_E187_F Y NRG1_E74_F Y MCAM_P265_11 Y ER_seq_a1_560_F Y MT1A_P600_F Y GSTM1_P266_F Y GSTM2_P453_11 N EPHA5_P66_F Y MFAP4_P197_F N RET_P717_F N HIC2_P528_11 Y or in Table 3B TABLE-US-00039 Pancreatic cancer Pancreatic cancer (hypermethylation) (n:150) CGI (hypomethylation) (n:98) CGI FGF8_P473_F Y CYP2E1_P416_F N SEZ6L_P249_F Y CREBBP_P712_R Y FLT1_P302_F Y NDN_P1110_F N FLT1_P615_R Y CSF2_E248_R N SEZ6L_P299_F Y SEPT9_P58_R Y FLT1_E444_F Y TFF1_P180_R N NEFL_E23_R Y CSF2_P605_F N COL1A2_P48_R Y LCN2_P141_R N MYH11_P236_R Y UGT1A1_E11_F N MMP2_P197_F Y NCL_P1102_F Y COL1A1_P5_ Y SPI1_P929_F N SMO_P455_ Y FGFR4_P610_F N PTCH2_P568R Y SEPT9_P374_F Y GDF1O_P95_R Y MST1R_P87_R N GDF1O_E39_ Y SLC22A3_P634_F Y POMC_P53_F Y KIAA0125_E29_F N ZIM2_P22_F Y SNCG_E119_F N TMEFF1_P234_F Y GUCY2F_P255_F N POMC_E254_F Y GML_P281_R N FGF3_E198_R Y LIG3_P622_R N SGCE_E149_F Y WNT8B_E487_F N ADCYAP1_E163_R Y BMP4_P199_R Y TPEF_seq_44_536_F Y GABRG3_E123_R N MCAM_P265_R Y MAPK4_E273_R N RET_P717_F N FGF1_P357_R N HIC2_P528_R Y APOA1_P261_F N PWCR1_P811_F N CTLA4_P1128_F N GFAP_P56_R N KLK10_P268_R N PWCR1_P357_F N IL1RN_P93_R N FRK_P36_F N EPHA2_P203_F Y is compared with the methylation status of a pancreatic cancer, wherein CGI is CpG island associated, Y is yes, and N is not. 7. The method according to claim 2, wherein detecting the methylation status comprises detecting the methylation status in one or more CpG sites as defined in Tables 4A and 4B, wherein the methylation status in one or more CpG sites as defined in Table 4A TABLE-US-00040 Endometrial cancer Endometrial cancer hypermethylation (n:102) CGI hypomethylation (n:22) CGI PENK_E26_F Y BLK_P14_F N DLK1_E227_R Y IFNG_E293_F N SOX1_P294_F Y MEST_P62_R Y NEFL_P209_R Y EMR3_E61_F N HTR1B_P222_F Y PTHLH_E251_F N NPY_P295_F Y NBL1_P24_F N CDH13_P88_F Y SPP1_P647_F N CDH13_E102_F Y CEACAM1_P44_R N HTR1B_E232_R Y WIST1R_E42_R Y DCC_P471_R Y NID1_P677_F N ADCYAP1_P455_R Y PTHLH_P15_R N ADCYAP1_P398_F Y MEST_P4_F Y TPEF_seq_44_S88_R Y PI3E107F N NPY_E31_R Y PTPN6_P282_R N PENK_P447_R Y PTPRH_E173_F N HS3ST2_E145_R Y EMR3_P39_R N HS3ST2_P171_F Y IL2_P607_R N CFTR_P372_R Y CLDN4_P1120_R N DBC1_E204_F Y TRIP6_P1090_F Y ASCL2_P360_F Y ASB4_P52_R N MOS_E60_R Y GFI1_P208_R Y TERT_P360_R Y TRIP6_P1274_R Y EPHA5_E158_R Y DBC1_P351_R Y OPCML_E219_R Y DIO3_P674_F Y DCC_P177_F Y SOX1_P1018_R Y THY1_P149_R Y RASSF1_E116_F Y ASCL1_P747_F Y GSTM2_E153_F Y SLC5A8_E60_R Y MYOD1_E156_F Y ISL1_E87_R Y GUCY2D_E419_R Y HOXA9_E252_R Y HCK_P858_F Y ZNF215_P129_R Y PRKCDBP_E206_F Y SEPT9_P374_F Y PLS3_E70_F Y CD4O_P372_R Y TMEFF2_E94_R Y CALCA_E174_R Y GSTM1_P266_F Y CYP1B1_E83_R Y SPARC_P195_F N SLC22A3_E122_R Y TMEFF2_P152_R Y ISL1_P379_F Y D103_P90_F Y NTRK3_P752_F Y RASSF1_P244_F Y HOXA11_P698_F Y AGTR1_P41_F Y MLF1_E243_F Y EYA4_E277_F Y HLA-F_E402_F Y NTRK3_P636_R Y FLI1_E29_F Y BDNF_E19_R Y TJP2_P330_R Y TSP5O_P137_F Y ISL1_P554_F Y ABO_P312_F Y STAT5A_E42_F N FGF2_P229_F Y MFAP4_P10_R N MME_E29_F Y MDR1_seq_42_S300_R Y MLH1_P381_F Y GSTM2_P109_R N GSTM2_P453_R N NTSR1_P318_F Y JAK3_E64_F Y NRG1_P558_R Y TUSC3_E29_R Y ZNF215_P71_R Y APC_P14_F Y GABRB3_E42_F Y NTRK3_E131_F Y IRAK3_P185_F Y TIMP3_seq_7_538_F Y TAL1_P594_F Y WT1_P853_F Y BMP3_P56_R Y MMP2_P303_R Y BMP3_E147_F Y IRAK3_P13_F Y IRAK3_E130_F Y EPHA3_P106_R Y CD9_P585_R Y FRZB_E186_R Y WNT2_P217_F Y TNFRSF10D_E27_F Y WT1_E32_F Y DAB2IP_E18_R Y TIAM1_P117_F Y CDH11_P354_R Y PITX2_E24_R Y CHFR_P501_F Y or in Table 4B TABLE-US-00041 Endometrial cancer Endometrial cancer (hypermethylation) (n:102) CGI (hypomethylation) (n:22) CGI HLA-F_E402_F Y PTHLH_E251_F N ABO_P312_F Y PTHLH_P15_R N MLH1_P381_F Y IL2_P607_R N JAK3_E64_F Y ASB4_P52_R N GFI1_P208_R Y is compared with the methylation status of a endometrial cancer, wherein CGI is CpG island associated, Y is yes, and N is not. 8. The method according to claim 2, wherein detecting the methylation status comprises detecting the methylation status in one or more CpG sites as defined in Tables 5A and 5B, wherein the methylation status in one or more CpG sites as defined in Table 5A TABLE-US-00042 Colon cancer Colon cancer (hypermethylation) (96) CGI (hypomethylation) (3) EYA4_E277_F Y PI3_E107_F N TWIST1_E117_R Y NEU1_P745_F Y SFRP1_P157_F Y S100A2_E36_R N SLIT2_E111_R Y TMEFF2_E94_R Y SFRP1_E398_R Y NPY_E31_R Y TFP12_P9_F Y NPY_P295_F Y TFP12_P152_R Y FLT4_P180_R Y HS3ST2_E145_R Y SLIT2_P208_F Y DAB2IP_E18_R Y GAS7_E148_F Y NGFB_P13_F Y TMEFF2_P152_R Y NTSR1_P318_F Y FLI1_E29_F Y GSTM2_E153_F Y RASGRF1_E16_F Y MME_E29_F Y NGFB_E353_F Y EYA4_P794_F Y FGF5_P238_R Y CD4O_P372_R Y WNT2_P217_F Y IGFBP3_P423_R Y NTRK3_P752_F Y WT1_E32_F Y SCGB3A1_E55_R Y HS3ST2_P171_F Y AGTR1_P41_F Y DBC1_E204_F Y FLT3_E326_R Y TBX1_P885_R Y DLK1_E227_R Y CDH13_P88_F Y TPEF_seq_44_588_R Y ESR1_E298_R Y NTRK3_E131_F Y THY1_P149_R Y NPY_P91_F Y ER_seq_a1_560_F Y ALK_E183_R Y FGF5_E16_F Y ALK_P28_F Y TWIST1_P355_11 Y ADCYAP1_P398_F Y ESR1_P151_11 Y SOX17_P287_11 Y IRAK3_P13_F Y GABRB3_P92_F Y SOX1_P294_F Y HOXA5_E187_F Y HTR1B_E232_11 Y EPHA5_E158_11 Y CDH13_E102_F Y MOS_E60_R Y MYOD1_E156_F Y CHFR_P501_F Y EYA4_P508_F Y HIC-1_seq_48_5103_11 Y CYP1B1_E83_11 Y KDR_P445_11 Y MYH11_P22_F Y ADAMTS12_E52_11 Y NTRK3_P636_11 Y DCC_P471_11 Y TUSC3_E29_11 Y KDR_E79_F Y CSPG2_E38_F Y PENK_P447_11 Y HCK_P858_F Y ADCYAP1_P455_11 Y CSPG2_P82_11 Y NRG1_P558_11 Y IGF2AS_E4_F Y GABRB3_E42_F Y CCNA1_P216_F Y SOX17_P303_F Y CDH11_P354_R Y FGF3_P171_R Y GSTM2_P109_R N DBC1_P351_R Y OPCML_E219_R Y WT1_P853_F Y COL1A2_E299_F Y TFPI2_E141_F Y PDE1B_P263_R Y IRAK3_E130_F Y HS3ST2_P546_F Y MMP2_P303_R Y NEFL_P209_R Y TIAM1_P117_F Y TUSC3_P85_R Y or in Table 5B TABLE-US-00043 Colon cancer Colon cancer (hypermethylation) (3) CGI (hypomethylation) (1) ALK_P28_F Y NEU1_P745_F Y CSPG2_E38_F Y PDE1B_P263_11 Y is compared with the methylation status of a colon cancer, wherein CGI is CpG island associated, Y is yes, and N is not. 9. The method according to claim 2, wherein detecting the methylation status comprises detecting the methylation status in one or more CpG sites as defined in Tables 6A and 6B, wherein the methylation status in one or more CpG sites as defined in Table 6A TABLE-US-00044 Prostate cancer Prostate cancer (hypermethylation ) (n:76) CGI (hypomethylation) (n:4) CGI GSTP1_E322_R Y MEST_P4_F Y GSTM2_E153_F Y DLC1_P695_F N RARB_P60_F Y MEST_P62_R Y COL18A1_P494_R Y PTPN6_P282_R N PDGFRB_P273_F Y APC_P14_F Y MFAP4_P10_R N SCGB3A1_E55_R Y ALOX12_P223_R Y POMC_P400_R Y ALOX12_E85_R Y GSTM2_P109_R N PDGFRB_E195_R N TJP2_P330_R Y IGFBP7_P297_F Y GSTP1_P74_F Y GSTP1_seq_38_5153_R Y RARA_P176_R N RARB_E114_F Y NEU1_P745_F Y ADAMTS12_E52_R Y TRIP6_E33_F Y SERPINE1_E189_R Y SEPT9_P374_F Y MFAP4_P197_F N ADAMTS12_P250_R Y CFTR_P372_R Y KIT_P367_R Y PDGFRB_P343_F Y TERT_P360_R Y GSTM2_P453_R N CD4O_P372_R Y HFE_E273_R Y RASSF1_E116_F Y HHIP_E94_F Y TBX1_P885_R Y NOTCH4_E4_F N FGF2_P229_F Y HDAC9_E38_F N SPARC_P195_F N CD9_P585_R Y KIT_P405_F Y APC_E117_R Y RBP1_P426_R Y HDAC9_P137_R N EYA4_E277_F Y SERPINE1_P519_F N GADD45A_P737_R N NGFR_P355_F Y COL1A2_E299_F Y PTGS2_P524_R Y APC_P280_R Y SPARC_E50_R Y SLC14A1_P369_R N SNCG_E119_F N CDKN1B_P1161_F N CSPG2_P82_R Y PTCH2_E173_F Y PYCARD_P150_F Y CCND2_P887_F Y KLK1O_P268_R N TMEFF1_P626_R Y TRIM29_P261_F N PYCARD_E87_F Y PYCARD_P393_F N CCND2_P898_R Y LEFTY2_P561_F N CHI3L2_E1O_F N CD9_P504_F Y VIM_P811_R Y CDH13_E102_F Y RARA_E128_R N IFNGR2_P377_R Y TEK_E75_F N SLC14A1_E295_F N SLC5A5_E60_F Y or in Table 6B TABLE-US-00045 Prostate cancer (hypermethylation ) (n:28) CGI RARB_P60_F Y PDGFRB_P273_F Y PDGFRB_E195_R N GSTP1_P74_F Y GSTP1_seq_38_S153_R Y RARB_E114_F Y NEU1_P745_F Y TRIP6_E33_F Y SERPINE1_E189_R Y PDGFRB_P343_F Y HFE_E273_R Y HHIP_E94_F Y HDAC9_E38_F N HDAC9_P137_R N GADD45A_P737_R N NGFR_P355_F Y APC_P280_R Y SPARC_E50_R Y CDKN1B_P1161_F N PTCH2_E173_F Y KLK1O_P268_R N TMEFF1_P626_R Y PYCARD_E87_F Y PYCARD_P393_F N VIM_P811_R Y RARA_E128_R N SLC14A1_E295_F N SLC5A5_E60_F Y is compared with the methylation status of a prostate cancer, wherein CGI is CpG island associated, Y is yes, and N is not. 10. The method according to claim 2, wherein detecting the methylation status comprises detecting the methylation status in one or more CpG sites as defined in Tables 7A and 7B, wherein the methylation status in one or more CpG sites as defined in Table 7A TABLE-US-00046 Glioma hypermethylation Glioma hypomethylation (n: 66) CGI (n: 64) CGI FZD9_E458_F Y MPO_P883_R N HOXA11_P698_F Y IL8_E118_R N TES_P182_F Y NOTCH4_E4_F N HOXA9_E252_R Y CASP10_P334_F N CD81_P272_R Y SERPINE1_P519_F N HTR1B_E232_R Y MMP14_P13_F Y TNFRSF10A_P171_F Y CCL3_E53_R N TNFRSF10A_P91_F Y CASP10_P186_F N HOXA9_P1141_R Y S100A2_E36_R N TES_E172_F Y HLA-DPA1_P205_R N TAL1_P594_F Y MMP9_P189_F N HTR1B_P222_F Y JAK3_P1075_R N FLT3_E326_R Y TRIP6_P1090_F Y AHR_P166_R Y PTHR1_P258_F N GATA6_P21_R Y TRIP6_P1274_R Y MEST_E150_F Y PADI4_P1011_R N IRAK3_E130_F Y MMP2_P303_R Y PENK_E26_F Y CSF3R_P8_F N MOS_E60_R Y S100A2_P1186_F N NEFL_P209_R Y SH3BP2_E18_F N HOXA11_E35_F Y GSTM2_E153_F Y NPY_P295_F Y EMR3_P39_R N GATA6_P726_F Y PSCA_E359_F N TNFRSF10D_E27_F Y HDAC1_P414_R Y DSC2_E90_F Y CASP10_E139_F N HOXA5_E187_F Y PRSS1_E45_R N DIO3_P674_F Y ALPL_P433_F Y ALOX12_E85_R Y RIPK3_P24_F N ISL1_P379_F Y EMR3_E61_F N TFAP2C_P765_F Y RIPK3_P124_F N IRAK3_P13_F Y TMPRSS4_P552_F N MEST_P62_R Y HLA-DPA1_P28_R N IRAK3_P185_F Y GFAP_P1214_F N PCTK1_E77_R Y LEFTY2_P561_F N GFI1_P45_R Y STAT5A_P704_R N NPY_E31_R Y CD86_P3_F N DIO3_E230_R Y TNFSF10_E53_F N DDIT3_P1313_R Y NOS2A_P288_R N FLT3_P302_F Y KLK11_P103_R N MEST_P4_F Y FGFR2_P460_R Y IPF1_P750_F Y SPDEF_P6_R N TUSC3_E29_R Y STAT5A_E42_F N BCR_P346_F Y VAV1_P317_F N FZD9_P175_F Y DSG1_P159_R N HOXA9_P303_F Y FAS_P322_R N IPF1_P234_F Y SPP1_E140_R N DNAJC15_P65_F Y CHI3L2_E10_F N PALM2-AKAP2_P420_R Y PGR_P790_F N MDR1_seq_42_S300_R Y TNFSF8_P184_F Y PRKCDBP_E206_F Y TJP2_P518_F Y AHR_E103_F Y GSTM2_P453_R N RASSF1_E116_F Y ITK_P114_F N MYOD1_E156_F Y CPA4_E20_F N DSP_P36_F Y PI3_P1394_R N ISL1_E87_R Y MPO_E302_R N TAL1_E122_F Y ACVR1_P983_F N ICA1_P72_R Y GSTM2_P109_R N IGFBP1_P12_R Y LTB4R_E64_R N RARA_P176_R N CCR5_P630_R N DIO3_P90_F Y KRT1_P798_R N WRN_P969_F Y AOC3_P890_R N PENK_P447_R Y IL10_P85_F N TERT_P360_R Y SPI1_E205_F Y SOX17_P287_R Y IFNG_E293_F N SFRP1_P157_F Y WT1_P853_F Y or in Table 7B TABLE-US-00047 Glioma (hypermethylation) Glioma (hypomethylation) (n: 15) CGI (n: 29) CGI TES_P182_F Y IL8_E118_R N TNFRSF10A_P171_F Y CASP10_P334_F N TNFRSF10A_P91_F Y SERPINE1_P519_F N TES_E172_F Y MMP14_P13_F Y AHR_P166_R Y CASP10_P186_F N MEST_E150_F Y MMP9_P189_F N PCTK1_E77_R Y SH3BP2_E18_F N GFI1_P45_R Y GSTM2_E153_F Y MEST_P4_F Y CASP10_E139_F N DNAJC15_P65_F Y ALPL_P433_F Y AHR_E103_F Y RIPK3_P24_F N DSP_P36_F Y GFAP_P1214_F N TAL1_E122_F Y STAT5A_P704_R N ICA1_P72_R Y CD86_P3_F N WRN_P969_F Y TNFSF10_E53_F N FGFR2_P460_R Y SPDEF_P6_R N STAT5A_E42_F N VAV1_P317_F N FAS_P322_R N SPP1_E140_R N CHI3L2_E10_F N TJP2_P518_F N GSTM2_P453_R N ACVR1_P983_F N GSTM2_P109_R N LTB4R_E64_R N IL10_P85_F N SPI1_E205_F Y is compared with the methylation status of a glioma, wherein CGI is CpG island associated, Y is yes, and N is not. 11. The method according to claim 2, wherein detecting the methylation status comprises detecting the methylation status in one or more CpG sites as defined in Tables 8A and 8B, wherein the methylation status in one or more CpG sites as defined in Table 8A TABLE-US-00048 Ovarian cancer Ovarian cancer hypermethylation (n: 40) CGI hypomethylation (n: 16) CGI CFTR_P372_R Y MEST_P4_F Y HCK_P858_F Y PI3_E107_F N MOS_E60_R Y NBL1_P24_F N HOXA9_E252_R Y PTPN6_P282_R N TAL1_P594_F Y WEE1_P924_R N DIO3_P674_F Y S100A2_P1186_F N PENK_E26_F Y NID1_P677_F N SOX1_P294_F Y CTLA4_E176_R N LEFTY2_P561_F N GLI2_E90_F N CALCA_E174_R Y MST1R_E42_R Y THY1_P149_R Y GPATC3_P410_R N HOXA11_P698_F Y TRIM29_E189_F Y ALOX12_P223_R Y GLI2_P295_F Y DIO3_P90_F Y EMR3_E61_F N GLI3_P453_R Y MSH2_P1008_F Y ATP10A_P147_F Y IFNG_E293_F N ASCL1_P747_F Y MFAP4_P10_R N HS3ST2_E145_R Y ALOX12_E85_R Y DCC_E53_R Y HS3ST2_P171_F Y FRZB_E186_R Y THY1_P20_R Y TNFRSF10C_P7_F Y HOXA9_P303_F Y DDR2_P743_R N RASSF1_P244_F Y DBC1_P351_R Y MFAP4_P197_F N ZNF215_P71_R Y EPHA5_P66_F Y HCK_P46_R Y MMP2_P303_R Y CYP1B1_E83_R Y PITX2_E24_R Y ZNF215_P129_R Y TSP50_P137_F Y SEPT9_P374_F Y SEPT5_P441_F Y or in Table 8B TABLE-US-00049 Ovarian cancer* (n: 3) CGI Ovarian cancer* (n: 4) CGI GLI3_P453_R Y WEE1_P924_R N THY1_P20_R Y CTLA4_E176_R N DDR2_P743_R N GPATC3_P410_R N MSH2_P1008_F Y is compared with the methylation status of an ovarian cancer, wherein CGI is CpG island associated, Y is yes, and N is not. 12. The method according to claim 2, wherein detecting the methylation status comprises detecting the methylation status in one or more CpG sites as defined in Tables 9A and 9B, wherein the methylation status in one or more CpG sites as defined in Table 9A TABLE-US-00050 Lung cancer Lung cancer hypermethylation (n: 39) CGI hypomethylation (n: 1) CGI HOXA9_E252_R Y SPI1_P48_F N MOS_E60_R Y HS3ST2_E145_R Y EYA4_P794_F Y TAL1_P594_F Y STAT5A_E42_F N HOXA9_P1141_R Y TPEF_seq_44_S88_R Y FZD9_E458_F Y DIO3_P90_F Y FRZB_E186_R Y HCK_P858_F Y DLK1_E227_R Y JAK3_P156_R N NOTCH4_E4_F N ASCL2_P609_R Y HOXA11_P698_F Y SOX17_P287_R Y PENK_E26_F Y HS3ST2_P171_F Y HTR1B_E232_R Y GP1BB_P278_R Y SOX1_P294_F Y POMC_P400_R Y CFTR_P372_R Y FGF2_P229_F Y CDH13_P88_F Y RBP1_P426_R Y CALCA_E174_R Y CSPG2_P82_R Y APC_P14_F Y ZNF215_P71_R Y CHGA_E52_F Y HOXB13_P17_R Y COL1A2_E299_F Y TJP2_P518_F Y GAS7_E148_F Y TBX1_P885_R Y GSTM2_E153_F Y or in Table 9B TABLE-US-00051 Lung cancer* (n: 2) CGI Lung cancer* (n: 1) CGI JAK3_P156_R N SPI1_P48_F N GP1BB_P278_R Y is compared with the methylation status of a lung cancer, wherein CGI is CpG island associated, Y is yes, and N is not. 13. The method according to claim 2, wherein detecting the methylation status comprises detecting the methylation status in one or more CpG sites as defined in Tables 10A and 10B, wherein the methylation status in one or more CpG sites as defined in Table 10A TABLE-US-00052 Bladder cancer Bladder cancer hypermethylation (n: 36) CGI hypomethylation (n: 80) CGI HOXA9_E252_R Y TRIM29_P261_F N HOXA11_P698_F Y PI3_E107_F N TJP2_P330_R Y CEACAM1_P44_R N TJP2_P518_F Y IFNG_E293_F N PENK_E26_F Y NOS2A_E117_R N CYP1B1_E83_R Y NOS3_P38_F N WT1_P853_F Y PSCA_P135_F N TAL1_P594_F Y PTPRH_P255_F N DLK1_E227_R Y TMPRSS4_E83_F N SLIT2_P208_F Y SRC_E100_R N HOXA9_P303_F Y CDH17_P376_F N FLT3_E326_R Y AATK_E63_R N SOX17_P287_R Y THBS2_P605_R N PENK_P447_R Y CDH17_E31_F N NPY_E31_R Y KRT5_E196_R Y NPY_P295_F Y P2RX7_P597_F N SOX1_P294_F Y IL1RN_E42_F N CDH11_P354_R Y AIM2_P624_F N TPEF_seq_44_S88_R Y NBL1_P24_F N MYOD1_E156_F Y PI3_P274_R N HOXA11_E35_F Y NID1_P677_F N LEFTY2_P561_F N SERPINB5_P19_R Y GSTM1_P266_F Y S100A2_P1186_F N SLIT2_E111_R Y SLC14A1_E295_F N HS3ST2_E145_R Y CLDN4_P1120_R N GSTM1_P363_F Y EMR3_E61_F N TERT_P360_R Y PTPRH_E173_F N HS3ST2_P171_F Y BCR_P422_F Y PITX2_E24_R Y TRIM29_P135_F N TERT_E20_F Y EMR3_P39_R N NPR2_P618_F Y VAMP8_P114_F N NEFL_P209_R Y MST1R_E42_R Y ISL1_P554_F Y PTPN6_P282_R N TWIST1_P355_R Y TRPM5_P979_F N HIC-1_seq_48_S103_R Y IGFBP1_P12_R Y SOX1_P1018_R Y VAMP8_E7_F N SFN_E118_F Y TFF2_P178_F N IGFBP1_E48_R Y EDNRB_P709_R N GPR116_E328_R N CXCL9_E268_R N VAMP8_P241_F N UGT1A1_P315_R N PGR_P790_F N GLI2_P295_F Y CASP8_E474_F N GABRA5_P862_R N TRIP6_P1090_F Y AIM2_E208_F N NID1_P714_R N HDAC1_P414_R Y TIMP1_P615_R N BRCA1_P835_R Y PTK6_E50_F Y ARHGDIB_P148_R N PRSS8_E134_R Y VAV1_E9_F Y KRT13_P341_R N OSM_P188_F Y GABRA5_P1016_F N RIPK3_P124_F N TRIM29_E189_F Y CSF1R_E26_F N JAK3_P1075_R N NBL1_E205_R N LCN2_P86_R N MMP19_E274_R N GLI2_E90_F N ZP3_P220_F N MMP10_E136_R N HPN_P823_F N AFF3_P122_F N SRC_P164_F N PADI4_E24_F N CAPG_E228_F N MAPK10_E26_F N SFTPA1_E340_R N PSCA_E359_F N APBA2_P305_R N or in Table 10B TABLE-US-00053 Bladder cancer Bladder cancer (hypermethylation) (n: 2) CGI (hypomethylation) (n: 27) TERT_E20_F Y TMPRSS4_E83_F N NPR2_P618_F Y SRC_E100_R N CDH17_P376_F N THBS2_P605_R N CDH17_E31_F N KRT5_E196_R Y P2RX7_P597_F N AIM2_P624_F N SLC14A1_E295_F N BCR_P422_F Y VAMP8_P114_F N TRPM5_P979_F N IGFBP1_P12_R Y VAMP8_E7_F N IGFBP1_E48_R Y EDNRB_P709_R N GPR116_E328_R N NID1_P714_R N TIMP1_P615_R N ARHGDIB_P148_R N KRT13_P341_R N GABRA5_P1016_F N CSF1R_E26_F N MMP19_E274_R N HPN_P823_F N PADI4_E24_F N MAPK10_E26_F N is compared with the methylation status of a bladder cancer, wherein CGI is island associated, Y is yes, and N is not. 14. The method according to claim 2, wherein detecting the methylation status comprises detecting the methylation status in one or more CpG sites as defined in Tables 11A and 11B, wherein the methylation status in one or more CpG sites as defined in Table 11A TABLE-US-00054 Melanoma Melanoma hypermethylation (n: 28) CGI hypomethylation (n: 5) CGI ALOX12_P223_R Y EVI2A_P94_R N ALOX12_E85_R Y IFNG_E293_F N MET_E333_F Y PI3_P1394_R N SNCG_E119_F N TNFSF8_P184_F Y GRB7_E71_R N VAV1_E9_F Y AATK_P709_R Y DDR1_P332_R N DHCR24_P652_R N SNCG_P53_F Y RARA_P176_R N IL1RN_P93_R N TGFB3_E58_R N TNFRSF10D_E27_F Y STAT5A_P704_R N COL1A2_P407_R N POMC_P400_R Y IGFBP5_P9_R Y SNCG_P98_R Y BMP4_P123_R Y CYP1B1_E83_R Y KCNK4_E3_F Y IL17RB_P788_R Y IL6_E168_F N BMP4_P199_R Y S100A2_P1186_F N FRZB_E186_R Y TRIP6_P1090_F Y LCN2_P86_R N or in Table 11B TABLE-US-00055 Melanoma Melanoma (hypermethylation) (n: 4) CGI (hypermethylation) (n: 1) CGI MET_E333_F Y EVI2A_P94_R N COL1A2_P407_R N IL17RB_P788_R Y IL6_E168_F N is compared with the methylation status of a melanoma, wherein CGI is CpG island associated, Y is yes, and N is not. 15. The method according to claim 2, wherein detecting the methylation status comprises detecting the methylation status in one or more CpG sites as defined in Table 12A, wherein the methylation status in one or more CpG sites as defined in Table 12A TABLE-US-00056 Breast cancer Breast cancer (hypomethylation) (n: 18) CGI (hypomethylation) (n: 1) CGI CFTR_P372_R Y PI3_E107_F N HOXA9_E252_R Y RBP1_P426_R Y TNFRSF10D_E27_F Y MME_E29_F Y TSP50_P137_F Y TERT_P360_R Y APC_P14_F Y GSTP1_E322_R Y RASSF1_E116_F Y SOX1_P294_F Y SOX17_P287_R Y MOS_E60_R Y CDH13_P88_F Y APC_E117_R Y BMP4_P123_R Y IRAK3_P185_F Y IGFBP3_P423_R Y is compared with the methylation status of a breast cancer, wherein CGI is CpG island associated, Y is yes, and N is not. 16. The method according to claim 2, wherein detecting the methylation status comprises detecting the methylation status in one or more CpG sites as defined in Tables 14A and 14B, wherein the methylation status in one or more CpG sites as defined in Table 14A TABLE-US-00057 Testicular cancer hypermethylation (n: 10) CGI BCR_P346_F Y SEPT5_P464_R Y GSTM1_P363_F Y IPF1_P750_F Y BCR_P422_F Y HOXA5_E187_F Y TBX1_P520_F N HIC-1_seq_48_S103_R Y ARHGDIB_P148_R N GPATC3_P410_R N or in Table 14B TABLE-US-00058 Testis cancer Testis cancer (hypermethylation) (n: 2) CGI (hypomethylation) (n: 1) CGI TBX1_P520_F N H19_P1411_R Y GPATC3_P410_R N is compared with the methylation status of a testicular cancer, wherein CGI is CpG island associated, Y is yes, and N is not. 17. The method according to claim 2, wherein detecting the methylation status comprises detecting the methylation status in one or more CpG sites as defined in Tables 15A and 15B, wherein the methylation status in one or more CpG sites as defined in Table 15A TABLE-US-00059 Stomach cancer Stomach cancer hypermethylation (n: 7) CGI hypomethylation (n: 2) CGI GAS7_E148_F Y TNFSF8_P184_F Y TGFB3_E58_R N CSF3R_P8_F N SFRP1_P157_F Y SOX1_P294_F Y MDR1_seq_42_S300_R Y HS3ST2_E145_R Y CCKAR_P270_F N or in Table 15B TABLE-US-00060 Stomach cancer (hypermethylation) (n: 1) CGI CCKAR_P270_F N is compared with the methylation status of a stomach cancer, wherein CGI is CpG island associated, Y is yes, and N is not. 18. The method according to claim 1, wherein the the primary tumor is lymphoid neoplasia and the therapy targeted to said lymphoid neoplasia is a CD20-targeted drug selected from the group consisting of rituximab, ocrelizumab, PRO70769, rhuH27, ofatumumab, veltuzumab, hA20, IMMU-106, AME-133, LY2469298, PRO131921, GA-101, tositumomab and R05072759. 19. The method according to claim 1, wherein the primary tumor is pancreatic cancer and the therapy targeted to said pancreatic cancer is an antimetabolite selected from the group consisting of aminopterin, denopterin, methotrexate, edatrexate, trimetrexate, nolatrexed, lometrexol, pemetrexed, raltitrexed, piritrexim, pteropterin, leucovorin, 10-propargyl-5,8-dideazafolate, cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, thioguanine, capecitabine, cytarabine, decitabine, fluorouracil, 5-fluorouracil, doxifluridine, floxuridine and gemcitabine.

Details for Patent 10,233,503

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2039-03-23
Novartis Pharmaceuticals Corporation	ARZERRA	ofatumumab	Injection	125326	10/26/2009		2039-03-23
Novartis Pharmaceuticals Corporation	ARZERRA	ofatumumab	Injection	125326	04/01/2011		2039-03-23
Novartis Pharmaceuticals Corporation	KESIMPTA	ofatumumab	Injection	125326	08/20/2020		2039-03-23