Colorectal cancer markers and their applications

Abstract

The present invention belongs to the field of diagnostic technology, and specifically relates to colorectal cancer markers and their applications. The present invention discloses for the first time one or more of 90 markers as markers for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer, and early screening, diagnosis, severity evaluation, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer can be achieved by detecting the content, expression and / or activity of the above markers.

Description

Technical Field

[0001] The present invention belongs to the field of diagnostic technologies, and particularly relates to colorectal cancer markers and their applications. Background Art

[0002] Colorectal cancer (CRC) is currently the third most common cancer globally, with approximately 1.9 million new cases diagnosed each year, accounting for 10.2% of all cancer diagnoses. The mortality rate of colorectal cancer ranks second among all cancers, accounting for 9.4% of the total cancer mortality rate. Early-stage colorectal cancer usually has no obvious symptoms, but when obvious symptoms appear, it often indicates that the cancer has progressed to a relatively advanced stage and may have spread to nearby lymph nodes or organs, causing certain impacts on the patient's body. Therefore, early screening and diagnosis of colorectal cancer are particularly important for timely taking treatment intervention measures to improve the treatment effect, reduce the mortality rate, and enhance the national health level.

[0003] For the early detection of colorectal cancer, currently available common methods include colonoscopy, fecal occult blood test, imaging examination, etc. Although these technologies are relatively mature, they still have the following limitations: 1) The compliance of colonoscopy is low. The bowel preparation and cleaning before colonoscopy take a long time, the examination process can cause discomfort or pain to the patient, the price is relatively high, and colonoscopy requires professional doctors and equipment, and medical resources are mainly concentrated in urban hospitals, increasing the risk of patients missing the best treatment window. 2) Patients with cardiovascular diseases, coagulation disorders, and the risk of intestinal perforation are not suitable for colonoscopy.

[0004] The rapid development of liquid biopsy technology has provided a new approach for the early screening and diagnosis of colorectal cancer. For example, ctDNA detection technology diagnoses colorectal cancer by performing genomic or methylation analysis on ctDNA (circulating tumor DNA) fragments released from tumor cells into the blood, and assists in determining the nature, size, and disease progression of the tumor. The ctDNA technology diagnoses in a non-invasive manner, avoiding the pain and discomfort of traditional tissue section examination. However, this technology still has quite limitations: 1) DNA fragments generated by apoptosis or tissue damage can interfere with ctDNA detection, having a certain impact on the specificity of ctDNA; 2) The half-life of ctDNA is only 2 hours 1-2 , and in the early stage, the concentration of tumor ctDNA in the blood is very low, resulting in limited sensitivity of ctDNA; 3) The location of metastatic foci can affect the concentration and detection rate of ctDNA. For patients with only peritoneal metastasis and only pulmonary metastasis, RAS mutant fragments are more difficult to detect in the plasma of such patients 3 . 4) The related costs of ctDNA detection cannot be ignored.

[0005] 1. Lu L, Bi J, Bao L. Genetic profiling of cancer with circulating tumor DNA analysis. J Genet Genomics 2018; 45: 79–85.

[0006] 2. Diehl F, Schmidt K, Choti MA, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med 2008; 14: 985–90.

[0007] 3. Bando H, Nakamura Y, Taniguchi H, et al. Effects of metastatic sites on circulating tumor DNA in patients with metastatic colorectal cancer. JCO Precis Oncol 2022; 6: e2100535. Summary of the Invention

[0008] An object of the first aspect of the present invention is to provide the use of a substance for detecting a biomarker in the preparation of a product for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer.

[0009] An object of the second aspect of the present invention is to provide a biomarker combination for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer.

[0010] An object of the third aspect of the present invention is to provide a product for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer.

[0011] An object of the fourth aspect of the present invention is to provide a method for constructing a model for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer.

[0012] An object of the fifth aspect of the present invention is to provide a device or system for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer.

[0013] An object of the sixth aspect of the present invention is to provide a computer device.

[0014] An object of the seventh aspect of the present invention is to provide a computer-readable storage medium.

[0015] The object of the eighth aspect of the present invention is to provide a method for constructing a colorectal cancer model.

[0016] The object of the ninth aspect of the present invention is to provide a method for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer.

[0017] In order to achieve the above object, the technical solutions adopted by the present invention are as follows:

[0018] The first aspect of the present invention provides the application of a substance for detecting a biomarker in the preparation of a product:

[0019] The product is used for: early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer;

[0020] The biomarker is A, and A includes at least one of B, that is, it can be 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, 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, or 90 species of B;

[0021] B is: ADAMTS8, ADGRE1, ADGRE2, ADGRE5, ADGRG2, AGR3, ANGPTL4, AREG, ASAH2, BAG3, BMP4, C9, CCL7, CD48, CDH23, CEACAM16, CEACAM5, CFP, CKAP4, CLEC3B, CNTN1, CNTN4, CNTN5, COMP, CRTAC1, DCC, DLK1, EDA2R, ENPP6, ESM1, EXTL1, FAP, FASLG, FCER2, FCRL1, FGF21, GCG, GDF15, GNAS, GRK5, GSN, HMCN2, IFNL1, IGDCC4, IGFBP1, IGSF3, IL4R, IL6, ITGA11, ITGA2, ITGAM, ITGB1, ITGB7, ITIH3, ITM2A, KRT19, LBP, LMNB2, LPL, MEGF9, MMP12, NOTCH1, NOTCH3, NOS2, NPY, NT5C1A, NTRK2, PCDH7, PGA4, PKD1, PLXDC1, PLXDC2, POF1B, PROK1, PTPRS, PTX3, RBFOX3, RET, SELL, SERPINA1, SOD3, SPON2, SPP1, TCL1A, THBS4, TMPRSS15, TNC, TNFRSF10B, TNFRSF11A, VSIG4.

[0022] Preferably, A comprises any 1, 2, 3, 4, 5, 6, 7, or 8 of B.

[0023] Preferably, the A comprises a single marker, and the single marker is any one of the Bs, such as: ADAMTS8, ADGRE1, ADGRE2, ADGRE5, ADGRG2, AGR3, ANGPTL4, AREG, ASAH2, BAG3, BMP4, C9, CCL7, CD48, CDH23, CEACAM16, CEACAM5, CFP, CKAP4, CLEC3B, CNTN1, CNTN4, CNTN5, COMP, CRTAC1, DCC, DLK1, EDA2R, ENPP6, ESM1, EXTL1, FAP, FASLG, FCER2, FCRL1, FGF21, GCG, GDF15, GNAS, GRK5, GSN, HMCN2, IFNL1, IGDCC4, IGFBP1, IGSF3, IL4R, IL6, ITGA11, ITGA2, ITGAM, ITGB1, ITGB7, ITIH3, ITM2A, KRT19, LBP, LMNB2, LPL, MEGF9, MMP12, NOTCH1, NOTCH3, NOS2, NPY, NT5C1A, NTRK2, PCDH7, PGA4, PKD1, PLXDC1, PLXDC2, POF1B, PROK1, PTPRS, PTX3, RBFOX3, RET, SELL, SERPINA1, SOD3, SPON2, SPP1, TCL1A, THBS4, TMPRSS15, TNC, TNFRSF10B, TNFRSF11A, or VSIG4;Among them, the contents, expression levels, and / or activities of SPP1, PTX3, ANGPTL4, C9, GDF15, IGFBP1, CEACAM5, KRT19, MMP12, ESM1, TNFRSF10B, SERPINA1, ITIH3, AREG, LBP, SPON2, NT5C1A, VSIG4, POF1B, PGA4, IL6, ITM2A, IL4R, EDA2R, CCL7, RBFOX3, CKAP4, LMNB2, FGF21, PROK1, TNC, TNFRSF11A, NOS2 are increased relative to the reference level, while the contents, expression levels, and / or activities of TMPRSS15, RET, PLXDC2, ENPP6, FASLG, ITGA11, PLXDC1, ITGAM, PTPRS, COMP, CNTN5, NTRK2, ADGRG2, FCRL1, ITGB1, HMCN2, ADAMTS8, GNAS, CNTN4, TCL1A, ITGB7, CNTN1, CLEC3B, BMP4, GCG, MEGF9, ITGA2, ADGRE5, LPL, SELL, THBS4, FAP, NOTCH1, ADGRE2, DLK1, AGR3, NOTCH3, ASAH2, CEACAM16, GSN, CFP, IGDCC4, NPY, CRTAC1, IGSF3, DCC, PCDH7, BAG3, EXTL1, CD48, ADGRE1, GRK5, IFNL1, PKD1, SOD3, CDH23, FCER2 are decreased relative to the reference level, and the reference level represents the contents, expression levels, and / or activities of the same-aged subjects to be tested who do not have colorectal cancer.

[0024] Preferably, the reference level represents the contents, expression levels, and / or activities of healthy same-aged subjects to be tested.

[0025] Preferably, the single marker is: ADGRE1, ADGRE2, AGR3, ANGPTL4, AREG, ASAH2, BAG3, BMP4, C9, CCL7, CD48, CDH23, CEACAM16, CFP, CKAP4, CNTN4, CNTN5, CRTAC1, DCC, DLK1, EDA2R, ESM1, FAP, FCER2, FCRL1, FGF21, GCG, GNAS, GRK5, GSN, IFNL1, IGDCC4, IGFBP1, IGSF3, IL4R, IL6, ITGAM, ITGB1, ITIH3, ITM2A, LBP, LPL, MEGF9, MMP12, NOTCH1, NOTCH3, NOS2, NPY, NT5C1A, NTRK2, PCDH7, PGA4, PKD1, PLXDC1, PROK1, PTPRS, RBFOX3, SELL, SERPINA1, SPON2, TCL1A, TNC, TNFRSF10B, TNFRSF11A, or VSIG4.

[0026] Preferably, the single marker is: FCRL1, NTRK2, CNTN5, ITGB1, GCG, IL4R, MMP12, TNFRSF10B, ITGAM, RBFOX3, IGFBP1, LBP, ESM1, SERPINA1, SELL, DLK1, C9, PLXDC1, EDA2R, CNTN4, CFP, NOTCH3, TCL1A, LPL, IL6, DCC, PTPRS, BMP4, NT5C1A, ITIH3, ANGPTL4, ASAH2, FAP, GNAS, CKAP4, or AREG.

[0027] Preferably, the single marker is: AREG, FCRL1, NTRK2, CNTN5, ITGB1, GCG, IL4R, MMP12, or TNFRSF10B.

[0028] Most preferably, the single marker is: FCRL1 or AREG.

[0029] Preferably, A comprises a combination of 2 markers, and the combination of 2 markers is any 2 of those in B.

[0030] Preferably, the combination of the 2 markers is any two of those in C, where C is: ADGRE5, ADGRG2, AREG, CEACAM5, CLEC3B, CNTN5, COMP, EDA2R, ENPP6, EXTL1, FASLG, FCRL1, GDF15, HMCN2, ITGA11, ITGA2, ITGAM, ITGB7, KRT19, LMNB2, PLXDC1, PLXDC2, POF1B, PTX3, RET, SELL, SOD3, SPP1, THBS4, TMPRSS15.

[0031] Preferably, the 2 - marker combinations are: TMPRSS15 and GDF15, TMPRSS15 and SPP1, TMPRSS15 and KRT19, SPP1 and ADGRE5, GDF15 and ADGRE5, GDF15 and COMP, SPP1 and COMP, TMPRSS15 and POF1B, PTX3 and THBS4, TMPRSS15 and EDA2R, TMPRSS15 and LMNB2, PTX3 and HMCN2, PTX3 and RET, GDF15 and PTX3, TMPRSS15 and FASLG, TMPRSS15 and ENPP6, COMP and LMNB2, PTX3 and ENPP6, GDF15 and ADGRG2, THBS4 and LMNB2, SPP1 and SOD3, PTX3 and KRT19, GDF15 and PLXDC2, PTX3 and POF1B, TMPRSS15 and SOD3, TMPRSS15 and PTX3, COMP and EDA2R, PLXDC2 and POF1B, GDF15 and ITGA2, GDF15 and HMCN2, TMPRSS15 and CEACAM5, TMPRSS15 and AREG, PTX3 and ADGRG2, GDF15 and THBS4, SPP1 and CLEC3B, TMPRSS15 and FCRL1, RET and SOD3, TMPRSS15 and ITGA11, GDF15 and RET, HMCN2 and SPP1, PTX3 and PLXDC2, GDF15 and PLXDC1, SPP1 and PLXDC1, PTX3 and COMP, PTX3 and FASLG, PTX3 and ITGAM, ITGA11 and LMNB2, PLXDC2 and SPP1, PTX3 and CLEC3B, GDF15 and ITGA11, PLXDC2 and KRT19, TMPRSS15 and THBS4, GDF15 and CLEC3B, TMPRSS15 and ITGAM, ENPP6 and SPP1, PTX3 and ITGA2, SPP1 and ITGA2, GDF15 and ITGAM, PLXDC2 and CEACAM5, COMP and KRT19, PTX3 and SELL, SPP1 and ADGRG2, PTX3 and CNTN5, ITGB7 and POF1B, PLXDC2 and LMNB2, TMPRSS15 and SELL, CEACAM5 and COMP, KRT19 and ITGB7, GDF15 and ITGB7, LMNB2 and SOD3, TMPRSS15 and RET, PTX3 and SPP1, POF1B and SOD3, PTX3 and SOD3, ADGRG2 and LMNB2, TMPRSS15 and EXTL1, GDF15 and FCRL1, PTX3 and FCRL1, ITGA11 and POF1B,LMNB2 and ITGAM, ITGA11 and KRT19, TMPRSS15 and ITGA2, PTX3 and EXTL1, TMPRSS15 and ITGB7, GDF15 and CNTN5, TMPRSS15 and CLEC3B, PTX3 and ITGA11, TMPRSS15 and HMCN2, PLXDC2 and AREG, TMPRSS15 and COMP, THBS4 and POF1B, POF1B and ITGA2, LMNB2 and ITGB7, TMPRSS15 and ADGRG2, KRT19 and ADGRE5, CEACAM5 and SOD3, TMPRSS15 and PLXDC2, THBS4 and EDA2R, HMCN2 and AREG, HMCN2 and POF1B, FCRL1 and COMP, SPP1 and FCRL1, ENPP6 and ITGA11, COMP and POF1B, PTX3 and PLXDC1, FCRL1 and LMNB2, LMNB2 and PLXDC1, KRT19 and ITGA2, SPP1 and FASLG, ADGRE5 and EDA2R, CEACAM5 and ITGB7, LMNB2 and ADGRE5, PTX3 and ITGB7, PTX3 and LMNB2, CEACAM5 and ITGA11, POF1B and ADGRE5, FASLG and PLXDC1, KRT19 and EXTL1, KRT19 and FASLG, PLXDC2 and ITGA11, ENPP6 and EXTL1, FCRL1 and SOD3, LMNB2 and CLEC3B, GDF15 and EXTL1, THBS4 and AREG, POF1B and PLXDC1, ENPP6 and THBS4, CEACAM5 and CLEC3B, PTX3 and CEACAM5, RET and FASLG, FCRL1 and POF1B, ENPP6 and POF1B, and FCRL1, ENPP6 and LMNB2, ADGRG2 and KRT19, CEACAM5 and ITGAM, PTX3 and EDA2R, GDF15 and ENPP6, SPP1 and THBS4, PLXDC2 and EDA2R, ENPP6 and ADGRE5, KRT19 and SELL, FASLG and SOD3, KRT19 and SOD3, ENPP6 and KRT19, TMPRSS15 and CNTN5, SPP1 and RET, GDF15 and CEACAM5, HMCN2 and FASLG, ADGRG2 and POF1B, ITGA2 and EDA2R, RET and POF1B, CEACAM5 and THBS4, TMPRSS15 and PLXDC1, COMP and FASLG, RET and LMNB2, CEACAM5 and ADGRE5, ENPP6 and CEACAM5, CLEC3B and EDA2RITGA11 and CNTN5, SPP1 and EXTL1, ENPP6 and COMP, ADGRG2 and EDA2R, ITGA11 and SOD3, SPP1 and SELL, GDF15 and SOD3, SPP1 and ITGA11, COMP and AREG, PLXDC2 and FASLG, RET and CLEC3B, RET and KRT19, CEACAM5 and RET, LMNB2 and CNTN5, THBS4 and KRT19, FCRL1 and CLEC3B, LMNB2 and ITGA2, HMCN2 and CLEC3B, SPP1 and ITGB7, POF1B and FASLG, POF1B and EXTL1, KRT19 and PLXDC1, HMCN2 and CEACAM5, ADGRG2 and FASLG, FCRL1 and KRT19, PLXDC2 and FCRL1, ENPP6 and AREG, LMNB2 and FASLG, HMCN2 and EDA2R, ITGB7 and EDA2R, PTX3 and ADGRE5, HMCN2 and LMNB2, THBS4 and RET, PLXDC2 and RET, CEACAM5 and ADGRG2, PLXDC2 and EXTL1, RET and ITGB7, FCRL1 and ADGRE5, THBS4 and ITGA11, ENPP6 and PLXDC1, ITGA11 and EDA2R, CEACAM5 and FASLG, RET and ITGA2, ENPP6 and FASLG, ITGA11 and FASLG, COMP and SELL, ENPP6 and RET, THBS4 and FASLG, ITGA11 and COMP, ITGA2 and SOD3, ITGA11 and SELL, TMPRSS15 and ADGRE5, THBS4 and CLEC3B, PLXDC2 and ITGB7, ITGA11 and RET, HMCN2 and KRT19, PLXDC1 and EDA2R, CEACAM5 and EXTL1, FCRL1 and THBS4, RET and AREG, FCRL1 and EXTL1, POF1B and ITGAM, ENPP6 and ITGB7, ADGRG2 and AREG, ITGA11 and CLEC3B, PLXDC2 and ITGAM, CLEC3B and EXTL1, LMNB2 and KRT19, CEACAM5 and ITGA2, FCRL1 and ITGA11, SOD3 and AREG, ENPP6 and ITGAM, ITGA2 and AREG, PLXDC2 and ADGRE5, POF1B and CLEC3B, CNTN5 and CLEC3B, ENPP6 and EDA2R, KRT19 and CLEC3B, GDF15 and POF1B, PTX3 and AREG, FASLG and EXTL1, PLXDC2 and COMP,GDF15 and KRT19, SOD3 and EDA2R, ITGAM and SOD3, KRT19 and ITGAM, GDF15 and SELL, PLXDC2 and CNTN5, CNTN5 and AREG, ENPP6 and HMCN2, CNTN5 and FASLG, FCRL1 and ADGRG2, SPP1 and LMNB2, CEACAM5 and PLXDC1, SPP1 and CEACAM5, ADGRG2 and RET, CNTN5 and EDA2R, ADGRG2 and SOD3, ADGRG2 and EXTL1, THBS4 and CNTN5, ITGB7 and AREG, FCRL1 and EDA2R, SPP1 and CNTN5, GDF15 and FASLG, FASLG and ITGA2, ADGRG2 and PLXDC1, FCRL1 and CNTN5, HMCN2 and ITGA11, HMCN2 and FCRL1, FCRL1 and ITGA2, EXTL1 and AREG, ITGA11 and EXTL1, FASLG and CLEC3B, CEACAM5 and CNTN5, ITGB7 and CLEC3B, SPP1 and ITGAM, GDF15 and SPP1, CNTN5 and ADGRE5, FASLG and ITGAM, ADGRG2 and CLEC3B, ITGAM and AREG, FCRL1 and RET, LMNB2 and EXTL1, HMCN2 and PLXDC1, FASLG and AREG, SPP1 and KRT19, ITGA11 and ITGB7, ITGA11 and AREG, RET and EXTL1, POF1B and SELL, PLXDC2 and HMCN2, CNTN5 and PLXDC1, PLXDC2 and THBS4, THBS4 and EXTL1, KRT19 and CNTN5, CEACAM5 and EDA2R, FCRL1 and ITGB7, CEACAM5 and LMNB2, COMP and RET, CNTN5 and POF1B, POF1B and EDA2R, FCRL1 and FASLG, ITGA2 and EXTL1, ITGB7 and PLXDC1, ADGRG2 and COMP, COMP and EXTL1, PLXDC2 and CLEC3B, ENPP6 and SOD3, PLXDC2 and ITGA2, CNTN5 and EXTL1, ITGA11 and PLXDC1, ADGRG2 and CNTN5, ITGAM and EDA2R, SPP1 and POF1B, CLEC3B and ITGA2, ITGB7 and FASLG, ITGA11 and ADGRE5, PLXDC2 and ENPP6, GDF15 and LMNB2, CNTN5 and SOD3, CNTN5 and ITGA2, ITGA11 and ADGRG2, HMCN2 and CNTN5, CEACAM5 and KRT19,RET and ADGRE5, FASLG and ADGRE5, PLXDC2 and SOD3, HMCN2 and SOD3, SOD3 and PLXDC1, EXTL1 and SOD3, CEACAM5 and SELL, HMCN2 and ADGRG2, CEACAM5 and POF1B, COMP and ITGA2, ADGRE5 and AREG, CLEC3B and ITGAM, FCRL1 and CEACAM5, HMCN2 and ITGA2, FCRL1 and PLXDC1, CLEC3B and ADGRE5, ENPP6 and ITGA2, GDF15 and AREG, LMNB2 and POF1B, HMCN2 and ITGAM, ITGB7 and EXTL1, HMCN2 and EXTL1, LMNB2 and SELL, PLXDC2 and PLXDC1, FCRL1 and ITGAM, ENPP6 and CLEC3B, SOD3 and SELL, THBS4 and ITGAM, COMP and ITGB7, CNTN5 and ITGB7, THBS4 and SELL, HMCN2 and COMP, PLXDC1 and SELL, HMCN2 and SELL, COMP and CNTN5, ITGB7 and ITGA2, PLXDC1 and AREG, SPP1 and AREG, HMCN2 and RET, RET and CNTN5, THBS4 and ITGA2, RET and EDA2R, HMCN2 and ITGB7, RET and ITGAM, ADGRG2 and ITGAM, FCRL1 and AREG, THBS4 and ITGB7, THBS4 and SOD3, AREG and SELL, ITGB7 and SOD3, ENPP6 and CNTN5, COMP and PLXDC1, ITGA2 and SELL, KRT19 and EDA2R, HMCN2 and ADGRE5, ITGA2 and ADGRE5, EXTL1 and ITGAM, THBS4 and PLXDC1, EXTL1 and PLXDC1, GDF15 and EDA2R, KRT19 and POF1B, RET and PLXDC1, THBS4 and ADGRE5, ITGAM and PLXDC1, EXTL1 and SELL, COMP and SOD3, ENPP6 and SELL, ITGA11 and ITGA2, ADGRG2 and ITGA2, ENPP6 and ADGRG2, ADGRG2 and ADGRE5, THBS4 and ADGRG2, ITGA11 and ITGAM, SPP1 and EDA2R, RET and SELL, ADGRG2 and ITGB7, COMP and ITGAM, CLEC3B and SOD3, ITGB7 and ADGRE5, CNTN5 and SELL, PLXDC2 and SELL, ITGB7 and ITGAM, COMP and CLEC3B, ITGB7 and SELLITGA2 and PLXDC1, FCRL1 and SELL, ADGRE5 and SOD3, ADGRE5 and ITGAM, ADGRE5 and SELL, EXTL1 and ADGRE5, EXTL1 and EDA2R, PLXDC2 and ADGRG2, CNTN5 and ITGAM, ITGA2 and ITGAM, COMP and ADGRE5, CLEC3B and PLXDC1, CLEC3B and SELL, HMCN2 and THBS4, KRT19 and AREG, FASLG and EDA2R, THBS4 and COMP, CLEC3B and AREG, ADGRE5 and PLXDC1, or CEACAM5 and AREG.,

[0032] Preferably, the 2 - markers combination is any one of a1) to a2):

[0033] a1) Any two of D;

[0034] a2) Any one of C, and any one of D;

[0035] D is ADAMTS8, ADGRE1, ADGRE2, AGR3, ANGPTL4, ASAH2, BAG3, BMP4, C9, CCL7, CD48, CDH23, CEACAM16, CFP, CKAP4, CNTN1, CNTN4, CRTAC1, DCC, DLK1, ESM1, FAP, FCER2, FGF21, GCG, GNAS, GRK5, GSN, IFNL1, IGDCC4, IGFBP1, IGSF3, IL4R, IL6, ITGB1, ITIH3, ITM2A, LBP, LPL, MEGF9, MMP12, NOTCH1, NOTCH3, NOS2, NPY, NT5C1A, NTRK2, PCDH7, PGA4, PKD1, PROK1, PTPRS, RBFOX3, SERPINA1, SPON2, TCL1A, TNC, TNFRSF10B, TNFRSF11A, VSIG4 (i.e., the union of D and C is B, and D and C have no intersection).

[0036] Preferably, the 2 - marker combinations are: TMPRSS15 and TNFRSF10B, NOTCH1 and GDF15, TMPRSS15 and MMP12, TMPRSS15 and IL4R, PTX3 and CNTN4, GDF15 and DLK1, NOTCH3 and SPP1, TMPRSS15 and PGA4, GDF15 and ITGB1, TMPRSS15 and CCL7, TNFRSF11A and TMPRSS15, PLXDC2 and ESM1, NT5C1A_TMPRSS15, SPP1 and NTRK2, COMP and TNFRSF10B, SPP1 and PTPRS, CRTAC1 and GDF15, CD48 and GDF15, SPP1 and ITGB1, TMPRSS15 and CKAP4, TMPRSS15 and LBP, ADGRE2 and GDF15, TMPRSS15 and IL6, GNAS and TMPRSS15, NOTCH1 and SPP1, GDF15 and IGSF3, TMPRSS15 and RBFOX3, LMNB2 and ITGB1, PLXDC2 and IGFBP1, GDF15 and NTRK2, GDF15 and PKD1, PTX3 and BMP4, NOTCH3 and GDF15, GDF15 and CNTN1, TMPRSS15 and SPON2, COMP and PGA4, ADGRE5 and TNFRSF10B, TMPRSS15 and FGF21, TMPRSS15_VSIG4, GDF15 and CFP, ADGRE1 and GDF15, SPP1 and LPL, TMPRSS15 and TNC, GDF15 and FAP, COMP and RBFOX3, ITGB1 and TNFRSF10B, CRTAC1 and SPP1, ADGRE2 and LMNB2, PTX3 and NTRK2, COMP and MMP12, DLK1 and EDA2R, TNFRSF11A and COMP, THBS4 and MMP12, ADGRG2 and ESM1, PTX3 and LPL, ITGB7 and IL4R, SPP1 and PKD1, HMCN2 and MMP12, GDF15 and C9, TMPRSS15 and ITM2A, GSN and PTX3, GDF15 and GCG, NOTCH3 and PTX3, GDF15 and AGR3, NTRK2 and ESM1, GDF15 and PCDH7, TMPRSS15 and ESM1, TNFRSF10B and DLK1, GDF15 and MEGF9, THBS4 and IL4R, TMPRSS15 and GCG, COMP and IL4R, THBS4 and TNFRSF10B, TMPRSS15 and SERPINA1, SOD3 and PGA4, ADGRE2 and SPP1, COMP and VSIG4,NTRK2 and TNFRSF10B, PLXDC2 and GCG, NT5C1A and COMP, NOTCH3 and TNFRSF10B, SPP1 and BAG3, COMP and CKAP4, ITGB1 and EDA2R, TMPRSS15 and ASAH2, TMPRSS15 and C9, PLXDC2 and IL4R, TMPRSS15 and BMP4, NOTCH3 and LMNB2, CD48 and SPP1, NOTCH1 and TNFRSF10B, PTX3 and GCG, TMPRSS15 and TCL1A, TMPRSS15 and ADAMTS8, LMNB2 and DLK1, TMPRSS15 and NOS2, SPP1 and CNTN1, SPP1 and DLK1, NOTCH1 and LMNB2, DCC and TMPRSS15, TMPRSS15 and PKD1, GDF15 and CNTN4, PTX3 and ADAMTS8, NOTCH1 and KRT19, ADGRE2 and PTX3, PLXDC2 and SPON2, PLXDC2 and RBFOX3, TMPRSS15 and ITIH3, TMPRSS15 and NTRK2, TMPRSS15 and CFP, THBS4 and CKAP4, DCC and PTX3, FASLG and ESM1, PTX3 and PTPRS, PTX3 and ITGB1, SPP1 and CNTN4, TNFRSF10B and PLXDC1, ADGRE2 and TNFRSF10B, PTX3 and TCL1A, GSN and SPP1, COMP and ESM1, ESM1 and CNTN4, PTX3 and MMP12, NT5C1A and ITGB1, ADGRE1 and LMNB2, GDF15 and ADAMTS8, ADGRE1 and PTX3, PTX3 and CNTN1, PLXDC2 and TCL1A, TMPRSS15 and CNTN4, CKAP4 and DLK1, NOTCH3 and KRT19, ADGRG2 and SERPINA1, PTX3 and ITM2A, CLEC3B and TNFRSF10B, TNFRSF11A and THBS4, POF1B and NPY, NOTCH3 and ESM1, GDF15 and PROK1, POF1B and PCDH7, ADGRE2 and CEACAM5, ADGRE1 and KRT19, ENPP6 and ESM1, CLEC3B and PGA4, SPP1 and ADAMTS8, ITGB7 and TNFRSF10B, HMCN2 and SERPINA1, ADGRE2 and KRT19, PTX3 and ASAH2, PTX3 and AGR3, ADGRG2 and TNFRSF10B, KRT19 and GCG, VSIG4 and DLK1, TMPRSS15 and LPL, LMNB2 and CNTN1TMPRSS15 and CDH23, PTX3 and PCDH7, SPP1 and PROK1, SPP1 and FAP, CNTN4 and CKAP4, TMPRSS15 and GRK5, TMPRSS15 and CNTN1, IL4R and SOD3, TMPRSS15 and CEACAM16, PTX3 and IL4R, HMCN2 and IGFBP1, THBS4 and SERPINA1, TMPRSS15 and FAP, THBS4 and ESM1, TMPRSS15 and ANGPTL4, TMPRSS15 and IGFBP1, IL4R and DLK1, THBS4 and PGA4, PLXDC2 and TNFRSF10B, GDF15 and LPL, TNFRSF10B and CNTN4, GDF15 and BAG3, GDF15 and TCL1A, ADGRG2 and ANGPTL4, CNTN5 and ESM1, SPP1 and PCDH7, GDF15 and NPY, LMNB2 and CNTN4, ADGRE5 and PGA4, ENPP6 and MMP12, NOTCH3 and MMP12, COMP and LBP, SPP1 and FCER2, THBS4 and ANGPTL4, GDF15 and FCER2, NTRK2 and LMNB2, GNAS and GDF15, NTRK2 and PGA4, KRT19 and TCL1A, SPP1 and GCG, HMCN2 and TNFRSF10B, CEACAM5 and NTRK2, HMCN2 and IL4R, RET and MMP12, ENPP6 and ASAH2, TMPRSS15 and MEGF9, SPP1 and TCL1A, COMP and CCL7, IGDCC4 and TMPRSS15, KRT19 and NPY, POF1B and ITGB1, GDF15 and BMP4, TMPRSS15 and PROK1, PTX3 and PGA4, TNFRSF11A and DLK1, NOTCH3 and EDA2R, CD48 and TMPRSS15, PLXDC1 and LBP, HMCN2 and ESM1, ITGA11 and RBFOX3, KRT19 and PKD1, NTRK2 and EDA2R, ITGB1 and PGA4, KRT19 and DLK1, IL4R and PTPRS, KRT19 and CFP, ENPP6 and IGFBP1, SOD3 and ESM1, HMCN2 and C9, MMP12 and PLXDC1, HMCN2 and ITIH3, COMP and IL6, SPP1 and IGSF3, PTX3 and IL6, NOTCH1 and PTX3, SPON2 and DLK1, TNFRSF10B and NPY, ENPP6 and TNFRSF10B, KRT19 and PCDH7, ITGB1 and MMP12, LMNB2 and PTPRS, CD48 and TNFRSF10B,ADGRE1 and TMPRSS15, GSN and GDF15, PGA4 and DLK1, HMCN2 and PGA4, PTX3 and FCER2, GDF15 and PTPRS, NTRK2 and POF1B, COMP and TCL1A, ENPP6 and BMP4, HMCN2 and CFP, GDF15 and ASAH2, MMP12 and SOD3, IL4R and PLXDC1, POF1B and ADAMTS8, GNAS and PTX3, RET and TNFRSF10B, ADGRG2 and IL4R, ADGRE2 and RBFOX3, MMP12 and NPY, ADGRE1 and IL4R, ITGB1 and ANGPTL4, NTRK2 and IL4R, NTRK2 and KRT19, KRT19_ANGPTL4, POF1B and PKD1, NOTCH3 and SERPINA1, TMPRSS15 and PCDH7, MMP12 and ADGRE5, ITGB1 and ESM1, CEACAM5 and CNTN4, TMPRSS15 and IFNL1, TNFRSF10B and BAG3, NT5C1A and DLK1, TMPRSS15 and ITGB1, SPP1 and CFP, NT5C1A and ADGRE5, IGFBP1 and BMP4, ITGA11 and IGFBP1, CLEC3B and CKAP4, SERPINA1 and CNTN4, MMP12 and PTPRS, PTX3 and IGSF3, ITGA2 and MMP12, KRT19 and ITGB1, NOTCH3 and POF1B, COMP and ASAH2, POF1B and LPL, PTX3 and TNFRSF10B, NT5C1A and THBS4, RET and ANGPTL4, ENPP6 and GCG, FCRL1 and TNFRSF10B, CEACAM5 and GCG, or NOTCH1 and POF1B.,

[0037] Preferably, the combination of the 2 markers is any 2 of those in E, and E is: AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1.

[0038] Preferably, the 2 - markers combination is: TMPRSS15 and GDF15, GDF15 and COMP, TMPRSS15 and EDA2R, GDF15 and PTX3, TMPRSS15 and PTX3, COMP and EDA2R, TMPRSS15 and CEACAM5, TMPRSS15 and AREG, TMPRSS15 and FCRL1, PTX3 and COMP, CEACAM5 and COMP, GDF15 and FCRL1, PTX3 and FCRL1, TMPRSS15 and COMP, FCRL1 and COMP, PTX3 and CEACAM5, PTX3 and EDA2R, GDF15 and CEACAM5, COMP and AREG, PTX3 and AREG, FCRL1 and EDA2R, CEACAM5 and EDA2R, FCRL1 and CEACAM5, GDF15 and AREG, FCRL1 and AREG, GDF15 and EDA2R, CEACAM5 and AREG, NOTCH1 and GDF15, TMPRSS15 and TNC, TMPRSS15 and SERPINA1, NOTCH1 and PTX3, NOTCH1 and TMPRSS15, PTX3 and TNC, COMP and SERPINA1, NOTCH1 and CEACAM5, COMP and TNC, FCRL1 and SERPINA1, NOTCH1 and SERPINA1, CEACAM5 and SERPINA1, PTX3 and SERPINA1, NOTCH1 and AREG, NOTCH1 and FCRL1, FCRL1 and TNC, CEACAM5 and TNC, NOTCH1 and TNC, NOTCH1 and COMP, AREG and TNC, SERPINA1 and TNC, or SERPINA1 and AREG.

[0039] Preferably, A includes a 3 - markers combination, and the 3 - markers combination is any 3 of those in B.

[0040] Preferably, the 3 - marker combinations are: SPP1, COMP and FCRL1; TMPRSS15, SPP1 and SOD3; AREG, CEACAM5 and PLXDC2; PTX3, GDF15 and THBS4; SPP1, FCRL1 and SOD3; ADGRE1, TMPRSS15 and GDF15; COMP, GDF15 and PTX3; PTX3, GDF15 and CNTN4; TMPRSS15, SPP1 and COMP; GDF15, NOTCH1 and PTX3; AREG, CEACAM5 and DCC; CRTAC1, TMPRSS15 and GDF15; CRTAC1, TMPRSS15 and SPP1; PTX3, HMCN2 and POF1B; GNAS, TMPRSS15 and GDF15; TMPRSS15, SPP1 and THBS4; AREG, CEACAM5 and RET; COMP, FCRL1 and GDF15; AREG, CEACAM5 and NT5C1A; GDF15, TMPRSS15 and TNC; SPP1, ENPP6 and ADGRE5; SPP1, ENPP6 and COMP; PTX3, POF1B and THBS4; TMPRSS15, COMP and TNFRSF10B; SPP1, PLXDC2 and COMP; PTX3, ENPP6 and THBS4; NOTCH3, GDF15 and PTX3; TMPRSS15, THBS4 and TNFRSF10B; ADGRE2, GDF15 and PTX3; GDF15, PTX3 and TMPRSS15; SPP1, RET and SOD3; TMPRSS15, SOD3 and MMP12; ADGRE2, SOD3 and SPP1; GNAS, TMPRSS15 and RBFOX3; GDF15, COMP and DLK1; SPP1, SOD3 and ADGRE5; ADGRE1, TMPRSS15 and KRT19; GNAS, NT5C1A and TMPRSS15; CEACAM5, COMP and GDF15; PTX3, GDF15 and ADGRG2; PTX3, HMCN2 and CNTN4; PTX3, SPP1 and COMP; GDF15, EXTL1 and DLK1; TMPRSS15, PTX3 and KRT19; TMPRSS15, THBS4 and MMP12; ADGRE2, DLK1 and GDF15; ADGRE1, TMPRSS15 and LMNB2; PTX3, PLXDC2 and POF1B; AREG, CEACAM5 and SELL; NOTCH3, TMPRSS15 and SPP1; PTX3, POF1B and CNTN4; PTX3, GDF15 and HMCN2PTX3, GDF15 and ADGRE5, TMPRSS15, GDF15 and THBS4, ADGRE1, KRT19 and LMNB2, ADGRE1, ITGA11 and LMNB2, ADGRE1, TMPRSS15 and MMP12, AREG, CEACAM5 and TNFRSF10B, FCRL1, GDF15 and TMPRSS15, TMPRSS15, GDF15 and RET, TMPRSS15, KRT19 and LMNB2, NOTCH1, SOD3 and SPP1, NOTCH1, GDF15 and SPP1, TMPRSS15, PTX3 and MMP12, SPP1, COMP and LMNB2, TMPRSS15, SPP1 and FCRL1, PTX3, GDF15 and ITGB1, PTX3, POF1B and SOD3, AREG, CEACAM5 and FCER2, CRTAC1, TMPRSS15 and TNFRSF10B, TMPRSS15, COMP and MMP12, TMPRSS15, FASLG and MMP12, COMP, GDF15 and NOTCH1, TMPRSS15, SPP1 and MMP12, PTX3, KRT19 and THBS4, COMP, EDA2R and FCRL1, COMP, GDF15 and TMPRSS15, ADGRE1, GDF15 and PTX3, ADGRE1, TMPRSS15 and TNFRSF10B, AREG, CEACAM5 and ADAMTS8, NT5C1A, COMP and SPP1, PTX3, RET and SOD3, GDF15, PLXDC2 and DLK1, PTX3, GDF15 and PLXDC2, TMPRSS15, TNFRSF10B and IL4R, COMP, LMNB2 and FCRL1, SPP1, COMP and ITGB1, SPP1, PLXDC2 and SOD3, TMPRSS15, GDF15 and KRT19, TMPRSS15, SPP1 and ENPP6, TMPRSS15, GDF15 and PLXDC2, SPP1, COMP and ADGRE5, TMPRSS15, ENPP6 and TNFRSF10B, SPP1, COMP and CEACAM5, TMPRSS15, FASLG and TNFRSF10B, SPP1, COMP and FASLG, NOTCH3, PLXDC1 and SPP1, ADGRE1, TMPRSS15 and IL4R, TMPRSS15, THBS4 and LMNB2, AREG, CEACAM5 and PROK1, TMPRSS15, SPP1 and KRT19, CEACAM5, GDF15 and TMPRSS15, COMP, EDA2R and TMPRSS15,ADGRE2, TMPRSS15 and GDF15, TMPRSS15, KRT19 and FASLG, NOTCH1, ESM1 and GDF15, NOTCH3, SPP1 and TCL1A, GDF15, COMP and ADGRE5, GDF15, ADGRG2 and ADGRE5, SPP1, FASLG and SOD3, SPP1, FCRL1 and ADGRE5, GDF15, SPP1 and COMP, TMPRSS15, GDF15 and TNFRSF10B, GDF15, SPP1 and ADGRE5, TNFRSF11A, TMPRSS15 and GDF15, PTX3, COMP and POF1B, EDA2R, GDF15 and TMPRSS15, TMPRSS15, CLEC3B and MMP12, PTX3, LMNB2 and CNTN4, ADGRE1, COMP and GDF15, TMPRSS15, SPP1 and CLEC3B, TMPRSS15, GDF15 and ITGB7, SPP1, HMCN2 and SOD3, AREG, CEACAM5 and THBS4, SPP1, ADGRG2 and SOD3, GDF15, COMP and ADGRG2, TMPRSS15, GDF15 and EXTL1, TMPRSS15, MMP12 and IL4R, NOTCH1, LMNB2 and SPP1, TMPRSS15, PTX3 and SPP1, TMPRSS15, KRT19 and TNFRSF10B, NOTCH3, POF1B and PTX3, SPP1, COMP and POF1B, TMPRSS15, GDF15 and POF1B, TMPRSS15, GDF15 and MMP12, NOTCH3, LMNB2 and SPP1, GDF15, ADGRG2 and DLK1, TMPRSS15, GDF15 and DLK1, TMPRSS15, FCRL1 and TNFRSF10B, PTX3, THBS4 and FASLG, PTX3, POF1B and RET, TMPRSS15, COMP and IL4R, NOTCH3, PLXDC2 and SPP1, TMPRSS15, CLEC3B and TNFRSF10B, TMPRSS15, PTX3 and POF1B, TMPRSS15, SPP1 and FASLG, GDF15, NOTCH1 and TMPRSS15, SPP1, THBS4 and ADGRE5, SPP1, COMP and ADGRG2, PTX3, RET and CNTN4, TMPRSS15, SOD3 and TNFRSF10B, SPP1, ITGA11 and SOD3, SPP1, COMP and CLEC3B, TMPRSS15, LMNB2 and MMP12GDF15, CEACAM5, and ADGRE5; GDF15, PLXDC2, and COMP; GDF15, FCRL1, and ADGRE5; TMPRSS15, GDF15, and LMNB2; ADGRE1, POF1B, and PTX3; PTX3, POF1B, and ADGRG2; SPP1, CLEC3B, and ADGRE5; TMPRSS15, SPP1, and TNFRSF10B; SPP1, COMP, and DLK1; ADGRE1, TMPRSS15, and SPP1; ADGRE2, CEACAM5, and GDF15; TMPRSS15, GDF15, and ENPP6; PTX3, THBS4, and IL4R; GDF15, THBS4, and DLK1; SPP1, COMP, and TNFRSF10B; PTX3, SPP1, and THBS4; SPP1, CEACAM5, and ADGRE5; GDF15, HMCN2, and DLK1; GNAS, TMPRSS15, and MMP12; ADGRE1, ADGRG2, and GDF15; DCC, CNTN4, and PTX3; PTX3, PLXDC2, and KRT19; TMPRSS15, SPP1, and ADGRE5; TMPRSS15, SPP1, and ITGA11; CRTAC1, SPP1, and TCL1A; CRTAC1, ADGRE5, and GDF15; COMP, GDF15, and SERPINA1; NOTCH1, EXTL1, and GDF15; COMP, FCRL1, and TNFRSF10B; PTX3, GDF15, and RET; ADGRE2, CRTAC1, and GDF15; GDF15, COMP, and LMNB2; PTX3, CEACAM5, and CNTN4; GDF15, THBS4, and ADGRE5; SPP1, LMNB2, and ADGRE5; PTX3, POF1B, and ITGA2; TMPRSS15, RET, and MMP12; TMPRSS15, SOD3, and IL4R; NOTCH3, FCRL1, and SPP1; TMPRSS15, ENPP6, and MMP12; SPP1, COMP, and SOD3; ADGRE2, CLEC3B, and SPP1; TMPRSS15, GDF15, and ITGA2; NT5C1A, ADGRE5, and SPP1; COMP, GDF15, and TNC; NOTCH3, SPP1, and PTX3; PTX3, SPP1, and SOD3; CEACAM5, GDF15, and NOTCH1; PTX3, ENPP6, and POF1B; ADGRE2, COMP, and GDF15; TMPRSS15, POF1B, and MMP12; PTX3, THBS4, and CNTN4; TMPRSS15, SPP1, and PLXDC2TMPRSS15, PTX3 and THBS4, TMPRSS15, LMNB2 and SOD3, COMP, EDA2R and PTX3, TMPRSS15, GDF15 and HMCN2, GDF15, NOTCH1 and SERPINA1TMPRSS15, RET and TNFRSF10B, GNAS, TMPRSS15 and IL4RGDF15, LMNB2 and DLK1, GDF15, COMP and RET, SPP1, ADGRG2 and ADGRE5, NOTCH1, GDF15 and THBS4, LMNB2, RET and SOD3, ADGRE1, KRT19 and PTX3, GNAS, TNFRSF11A and TMPRSS15, SPP1, PLXDC2 and ADGRE5, TMPRSS15, PTX3 and FASLG, DCC, COMP and SPP1, PTX3, KRT19 and COMP, EDA2R, PTX3 and TMPRSS15, TMPRSS15, ITGA11 and MMP12, GDF15, ITGA2 and DLK1, COMP, POF1B and LMNB2, NOTCH3, TMPRSS15 and GDF15, TMPRSS15, SPP1 and CEACAM5, TMPRSS15, ITGA11 and TNFRSF10B, PTX3, PLXDC2 and THBS4, ADGRE2, ENPP6 and SPP1, NT5C1A, THBS4 and PTX3, TMPRSS15, SPP1 and ITGA2, TMPRSS15, ITGB1 and TNFRSF10B, CRTAC1, GDF15 and PTX3, CEACAM5, RET and SOD3, NOTCH1, LPL and SPP1, TMPRSS15, POF1B and FASLG, TMPRSS15, GDF15 and ADGRG2, NOTCH3, TMPRSS15 and TNFRSF10B, TMPRSS15, FASLG and IL4R, TMPRSS15, COMP and LMNB2, TMPRSS15, KRT19 and ENPP6, GDF15, COMP and HMCN2, TMPRSS15, GDF15 and ITGB1, TMPRSS15, ITGB7 and MMP12, NOTCH1, AGR3 and GDF15, PTX3, EXTL1 and CNTN4, NOTCH1, GDF15 and KRT19, NT5C1A, TMPRSS15 and COMP, SPP1, THBS4 and CLEC3B, TMPRSS15, FCRL1 and MMP12, NOTCH3, ESM1 and PLXDC2, TMPRSS15, ITGB7 and TNFRSF10BTNFRSF11A, TMPRSS15 and MMP12, SPP1, COMP and ITGA2, PTX3, THBS4 and EXTL1, TMPRSS15, PLXDC2 and IL4R, TMPRSS15, SPP1 and EXTL1, PTX3, ITGA11 and POF1B, GDF15, RET and DLK1, AREG, COMP and GDF15, TMPRSS15, PTX3 and IL4R, NOTCH1, FAP and GDF15, PTX3, THBS4 and LMNB2, NOTCH3, NT5C1A and SPP1, PTX3, COMP and TNFRSF10B, PLXDC2, ITGA11 and LMNB2, GNAS, TMPRSS15 and LMNB2, GNAS, TMPRSS15 and SPP1, GNAS, TMPRSS15 and AREG, PTX3, KRT19 and FASLG, PTX3, SPP1 and HMCN2, ADGRE1, GDF15 and ITGA2, PTX3, COMP and IL4R, PTX3, SPP1 and CNTN4, PTX3, POF1B and EXTL1, TMPRSS15, PTX3 and TNFRSF10B, TMPRSS15, GDF15 and ITGA11, PTX3, TNFRSF10B and CNTN4, TMPRSS15, SPP1 and ADGRG2, CD48, TMPRSS15 and GDF15, TMPRSS15, GDF15 and FASLG, ADGRE1, DLK1 and GDF15, TMPRSS15, SPP1 and RET, NOTCH1, CEACAM5 and SPP1, CRTAC1, TMPRSS15 and EDA2R, GDF15, COMP and ITGA11, GDF15, COMP and CLEC3B, PTX3, GDF15 and DLK1, ADGRE2, CLEC3B and GDF15, COMP, RET and TNFRSF10B, PTX3, POF1B and ITGB7, TNFRSF11A, THBS4 and PTX3, CEACAM5, COMP and EDA2R, NOTCH1, SERPINA1 and SPP1, SPP1, KRT19 and ADGRE5, ADGRE1, COMP and LMNB2, GNAS, TMPRSS15 and TNFRSF10B, CEACAM5, PTX3 and TMPRSS15, ADGRE2, POF1B and PTX3, NOTCH1, DLK1 and GDF15, SPP1, SOD3 and EXTL1, PLXDC2, COMP and LMNB2, COMP, POF1B and FCRL1, SPP1, PLXDC2 and THBS4, GSN, TMPRSS15 and PGA4,GDF15, THBS4 and CLEC3B, PLXDC2, KRT19 and LMNB2, TMPRSS15, LMNB2 and FCRL1, TMPRSS15, ITGA2 and MMP12, ADGRE1, COMP and TNFRSF10B, TMPRSS15, TNFRSF10B and DLK1, SPP1, COMP and IL4R, RET, SOD3 and TNFRSF10B, GNAS, TMPRSS15 and POF1B, THBS4, LMNB2 and CLEC3B, GDF15, CLEC3B and ADGRE5, EDA2R, TMPRSS15 and TNC, TNFRSF11A, COMP and GDF15, ADGRE1, CLEC3B and GDF15, GDF15, COMP and ITGB1, PTX3, KRT19 and ENPP6, SPP1, COMP and HMCN2, TMPRSS15, SPP1 and HMCN2, TMPRSS15, GDF15 and SPP1, TMPRSS15, PLXDC2 and LMNB2, PTX3, KRT19 and EXTL1, SPP1, ITGA11 and ADGRE5, GDF15, KRT19 and COMP, EDA2R, FCRL1 and TMPRSS15, TNFRSF11A, TMPRSS15 and PGA4, AREG, CEACAM5 and RBFOX3, DCC, COMP and GDF15, LMNB2, FCRL1 and SOD3, TMPRSS15, POF1B and TNFRSF10B, CD48, GDF15 and PTX3, PTX3, GDF15 and CLEC3B, PTX3, POF1B and FASLG, PTX3, THBS4 and MMP12, NOTCH1, PROK1 and SPP1, COMP, EDA2R and GDF15, NOTCH1, TMPRSS15 and TNFRSF10B, PTX3, SPP1 and ADGRG2, TNFRSF11A, ADGRE5 and SPP1, PTX3, GDF15 and EXTL1, ADGRE2, GDF15 and TCL1A, GNAS, ADGRE5 and GDF15, PTX3, ENPP6 and ITGA11, NOTCH1, COMP and SPP1, NT5C1A, TMPRSS15 and THBS4, ADGRE2, CRTAC1 and SPP1, TMPRSS15, THBS4 and IL4R, TMPRSS15, GDF15 and ADGRE5, NT5C1A, TMPRSS15 and PTX3, ADGRE2, COMP and SPP1, TMPRSS15, GDF15 and SOD3, NOTCH1, GDF15 and POF1B,TMPRSS15, LMNB2 and CNTN4, SPP1, KRT19 and COMP, TMPRSS15, SPP1 and LMNB2, CD48, COMP and GDF15, TMPRSS15, ITGA11 and LMNB2, SPP1, CEACAM5 and SOD3, ADGRE2, TNFRSF11A and GDF15, SPP1, SOD3 and ITGA2, ITGA11, LMNB2 and SOD3, AREG, EDA2R and TMPRSS15, NOTCH1, GDF15 and LMNB2, ADGRE2, GNAS and GDF15, NOTCH1, EXTL1 and SPP1, TMPRSS15, HMCN2 and TNFRSF10B, PTX3, THBS4 and FCRL1, TMPRSS15, ITGA2 and TNFRSF10B, NOTCH1, GDF15 and ITGA11, PTX3, SPP1 and CLEC3B, PTX3, THBS4 and RET, TNFRSF11A, TMPRSS15 and THBS4, NOTCH1, SPP1 and TNFRSF10B, NOTCH1, TMPRSS15 and SPP1, ADGRE1, GDF15 and PKD1, GDF15, LMNB2 and ADGRE5, ADGRE2, GDF15 and THBS4, GDF15, ADGRE5 and DLK1, CD48, CLEC3B and SPP1, NOTCH1, SPP1 and PTX3, GDF15, SERPINA1 and TMPRSS15, TMPRSS15, ITGA11 and IL4R, GNAS, TMPRSS15 and CCL7, TNFRSF11A, BAG3 and PLXDC2, SPP1, POF1B and ADGRE5, ADGRE2, ESM1 and GDF15, GSN, SPP1 and THBS4, ADGRE2, GDF15 and HMCN2, DCC, THBS4 and PTX3, TMPRSS15, ENPP6 and LMNB2, PTX3, KRT19 and SOD3, TMPRSS15, ADGRG2 and MMP12, PTX3, IL4R and CNTN4, SPP1, FCRL1 and CLEC3B, TMPRSS15, MMP12 and TNFRSF10B, ADGRE1, LMNB2 and THBS4, PTX3, PLXDC2 and IL4R, TMPRSS15, GDF15 and CNTN4, GDF15, ITGB1 and DLK1, ADGRE1, GDF15 and ITGA11, TMPRSS15, SPP1 and ITGB1, TMPRSS15, KRT19 and MMP12, TMPRSS15, KRT19 and IL4R, SPP1, THBS4 and FCRL1,SPP1, COMP and MMP12, TMPRSS15, KRT19 and SOD3, PTX3, SOD3 and IL4R, FCRL1, GDF15 and PTX3, NOTCH3, CLEC3B and SPP1, GNAS, TMPRSS15 and KRT19, TMPRSS15, KRT19 and COMP, TMPRSS15, CEACAM5 and MMP12, GSN, TMPRSS15 and TNFRSF10B, NOTCH1, IGFBP1 and SPP1, TMPRSS15, LMNB2 and FASLG, SPP1, COMP and CNTN4, TMPRSS15, PTX3 and ENPP6, TMPRSS15, GDF15 and IL4R, TMPRSS15, SPP1 and DLK1, ADGRE1, ITGA2 and LMNB2, ADGRE2, ADGRG2 and GDF15, NT5C1A, TMPRSS15 and KRT19, GSN, GDF15 and PTX3, NOTCH3, ADGRE5 and SPP1, ADGRE1, CNTN5 and LMNB2, ADGRE1, CRTAC1 and GDF15, COMP, FCRL1 and MMP12, SPP1, SOD3 and ITGB1, ADGRE2, LMNB2 and SPP1, PTX3, HMCN2 and IL4R, PTX3, COMP and LMNB2, NOTCH3, TMPRSS15 and MMP12, GNAS, TMPRSS15 and PGA4, NOTCH1, C9 and GDF15, ADGRE1, PLXDC1 and SPP1, SPP1, RET and ADGRE5, PTX3, KRT19 and RET, NOTCH3, ESM1 and MMP12, NOTCH3, ENPP6 and SPP1, GDF15, COMP and POF1B, ADGRE1, GDF15 and HMCN2, ADGRE1, LMNB2 and SOD3, PTX3, SOD3 and CNTN4, GDF15, COMP and THBS4, GDF15, HMCN2 and ADGRE5, TNFRSF11A, TMPRSS15 and TNFRSF10B, CRTAC1, GDF15 and SPP1, NT5C1A, CNTN4 and PTX3, COMP, CEACAM5 and LMNB2, NOTCH1, GDF15 and PROK1, GDF15, PLXDC2 and ADGRE5, NOTCH1, POF1B and PTX3, ADGRE1, TNFRSF11A and TMPRSS15, SPP1, TNFRSF10B and ADGRE5, PTX3, KRT19 and ADGRG2, GDF15, COMP and ITGB7, TMPRSS15, EXTL1 and IL4R,SPP1, COMP, and EXTL1; ADGRE1, GDF15, and THBS4; CEACAM5, EDA2R, and TMPRSS15; ADGRE1, TMPRSS15, and POF1B; SPP1, COMP, and THBS4; PTX3, THBS4, and ADGRG2; GSN, ADGRE5, and SPP1; ADGRE1, ADGRG2, and LMNB2; ADGRE2, TMPRSS15, and SPP1; SPP1, HMCN2, and CLEC3B; SPP1, COMP, and ITGA11; AREG, GDF15, and TMPRSS15; SPP1, COMP, and RET; GNAS, LMNB2, and PLXDC2; PTX3, GDF15, and ITGA2; SPP1, ENPP6, and SOD3; NOTCH3, CEACAM5, and SPP1; GDF15, HMCN2, and ITGB1; TMPRSS15, PLXDC2, and MMP12; NOTCH3, ADGRG2, and SPP1; TMPRSS15, KRT19, and EXTL1; PTX3, KRT19, and CNTN4; SPP1, ADGRG2, and ITGA2; GNAS, TMPRSS15, and LBP; NOTCH1, GDF15, and HMCN2; CRTAC1, NOTCH1, and GDF15; NOTCH3, COMP, and GDF15; NOTCH3, PROK1, and SPP1; TMPRSS15, SPP1, and IL4R; GDF15, HMCN2, and CLEC3B; GNAS, COMP, and GDF15; TMPRSS15, MMP12, and DLK1; TMPRSS15, KRT19, and CEACAM5; ADGRE2, FCRL1, and GDF15; GNAS, NOTCH1, and GDF15; CEACAM5, COMP, and PTX3; GDF15, LMNB2, and ITGB1; ADGRE2, TMPRSS15, and TNFRSF10B; TMPRSS15, PTX3, and RET; CD48, TMPRSS15, and TNFRSF10B; PTX3, THBS4, and ITGA2; SPP1, LMNB2, and ITGB1; ADGRE1, TMPRSS15, and PGA4; TMPRSS15, PTX3, and CNTN4; TMPRSS15, COMP, and POF1B; SPP1, ADGRG2, and CLEC3B; PTX3, HMCN2, and CLEC3B; SPP1, HMCN2, and ADGRE5; POF1B, FCRL1, and SOD3; GSN, THBS4, and PTX3; COMP, LMNB2, and TNFRSF10B; TMPRSS15, KRT19, and FCRL1; TMPRSS15, DLK1, and IL4RNOTCH3, KRT19 and PTX3, GDF15, COMP and TNFRSF10B, TMPRSS15, SPP1 and ITGB7, COMP, CEACAM5 and TNFRSF10B, TMPRSS15, ENPP6 and IL4R, TMPRSS15, TNFRSF10B and CNTN4, PTX3, HMCN2 and FASLG, PTX3, ITGA11 and CNTN4, PTX3, THBS4 and TNFRSF10B, PTX3, POF1B and FCRL1, GDF15, ENPP6 and DLK1, ITGA11, POF1B and SOD3, NT5C1A, TMPRSS15 and SPP1, SPP1, ENPP6 and THBS4, PTX3, GDF15 and POF1B, NOTCH3, ITM2A and PTX3, GDF15, POF1B and ADGRE5, ADGRE1, COMP and SPP1, TNFRSF11A, ADGRE5 and GDF15, CRTAC1, ADGRE5 and SPP1, PLXDC2, LMNB2 and FCRL1, NOTCH3, TNFRSF10B and PTX3, PTX3, GDF15 and SOD3, PTX3, FASLG and CNTN4, PTX3, GDF15 and ITGA11, PTX3, PLXDC2 and FASLG, GDF15, THBS4 and ITGB1, PTX3, FASLG and ADGRG2, PLXDC2, SOD3 and IL4R, PTX3, KRT19 and ADGRE5, LMNB2, ADGRG2 and SOD3, GNAS, TMPRSS15 and EDA2R, SPP1, ADGRE5 and IL4R, NOTCH1, TMPRSS15 and MMP12, GNAS, TMPRSS15 and FASLG, GSN, TMPRSS15 and SPP1, ITGA11, RET and SOD3, DCC, CLEC3B and PTX3, PTX3, ITGA11 and THBS4, PTX3, COMP and MMP12, ADGRE2, GDF15 and LPL, CRTAC1, GDF15 and TCL1A, NOTCH3, ESM1 and TNFRSF10B, GSN, CNTN4 and PTX3, TMPRSS15, SPP1 and CNTN4, GDF15, COMP and ITGA2, PTX3, ADGRG2 and IL4R, ADGRE1, ENPP6 and LMNB2, SPP1, PLXDC2 and HMCN2, NOTCH1, CLEC3B and SPP1, SPP1, ENPP6 and DLK1, RET, SOD3 and IL4R, TNFRSF11A, CNTN4 and PTX3, NOTCH1, PLXDC1 and SPP1,SPP1, PLXDC2, and ITGA2; SPP1, PLXDC2, and DLK1; GDF15, COMP, and CNTN4; ADGRE1, NOTCH1, and GDF15; TMPRSS15, PLXDC2, and KRT19; TMPRSS15, POF1B, and IL4R; TMPRSS15, POF1B, and THBS4; NOTCH3, PGA4, and PTX3; TNFRSF11A, TMPRSS15, and FASLG; TMPRSS15, PLXDC2, and TNFRSF10B; GDF15, ITGA11, and ADGRE5; SPP1, CLEC3B, and ITGA2; NT5C1A, TMPRSS15, and FAP; NOTCH3, TMPRSS15, and KRT19; GSN, TMPRSS15, and EDA2R; TMPRSS15, POF1B, and SOD3; SPP1, THBS4, and SOD3; NOTCH1, CNTN5, and GDF15; GDF15, KRT19, and ADGRE5; PTX3, ENPP6, and FASLG; NOTCH3, COMP, and SPP1; GNAS, TMPRSS15, and ENPP6; NOTCH3, LPL, and SPP1; GDF15, FCRL1, and DLK1; NOTCH3, SOD3, and SPP1; TMPRSS15, KRT19, and THBS4; ADGRE1, ITGA2, and SPP1; COMP, LMNB2, and ADGRG2; GSN, FASLG, and PTX3; ADGRE2, LMNB2, and SOD3; NOTCH3, ITGA2, and SPP1; TMPRSS15, PTX3, and ADGRG2; CRTAC1, HMCN2, and SPP1; TMPRSS15, TNFRSF10B, and ADGRE5; GDF15, COMP, and MMP12; SPP1, FASLG, and ADGRE5; TMPRSS15, POF1B, and EXTL1; PTX3, ENPP6, and CNTN4; PTX3, KRT19, and FCRL1; PTX3, POF1B, and ITGB1; ADGRE2, PTPRS, and SPP1; PTX3, KRT19, and HMCN2; CD48, SOD3, and SPP1; NOTCH1, KRT19, and SPP1; GDF15, COMP, and FASLG; LMNB2, SOD3, and DLK1; ADGRE1, HMCN2, and PTX3; PTX3, THBS4, and CLEC3B; or FCRL1, GDF15, and NOTCH1; namely, any one of the above 622 3 - markers combinations.

[0041] Preferably, the 3 - markers combination is any 3 of those in E.

[0042] Preferably, the 3 - marker combinations are: COMP, GDF15 and PTX3; GDF15, NOTCH1 and PTX3; COMP, FCRL1 and GDF15; GDF15, TMPRSS15 and TNC; GDF15, PTX3 and TMPRSS15; CEACAM5, COMP and GDF15; FCRL1, GDF15 and TMPRSS15; COMP, GDF15 and NOTCH1; COMP, EDA2R and FCRL1; COMP, GDF15 and TMPRSS15; CEACAM5, GDF15 and TMPRSS15; COMP, EDA2R and TMPRSS15; EDA2R, GDF15 and TMPRSS15; GDF15, NOTCH1 and TMPRSS15; COMP, GDF15 and SERPINA1; COMP, GDF15 and TNC; CEACAM5, GDF15 and NOTCH1; COMP, EDA2R and PTX3; GDF15, NOTCH1 and SERPINA1; EDA2R, PTX3 and TMPRSS15; AREG, COMP and GDF15; CEACAM5, COMP and EDA2R; CEACAM5, PTX3 and TMPRSS15; EDA2R, TMPRSS15 and TNC; EDA2R, FCRL1 and TMPRSS15; COMP, EDA2R and GDF15; AREG, EDA2R and TMPRSS15; GDF15, SERPINA1 and TMPRSS15; FCRL1, GDF15 and PTX3; CEACAM5, EDA2R and TMPRSS15; AREG, GDF15 and TMPRSS15; CEACAM5, COMP and PTX3; FCRL1, GDF15 and NOTCH1; GDF15, NOTCH1 and TNC; CEACAM5, COMP and TMPRSS15; CEACAM5, TMPRSS15 and TNC; AREG, CEACAM5 and TMPRSS15; AREG, COMP and TMPRSS15; PTX3, TMPRSS15 and TNC; EDA2R, SERPINA1 and TMPRSS15; COMP, PTX3 and TMPRSS15; AREG, PTX3 and TMPRSS15; AREG, GDF15 and NOTCH1; COMP, FCRL1 and TMPRSS15; FCRL1, PTX3 and TMPRSS15; AREG, COMP and EDA2R; COMP, EDA2R and SERPINA1; COMP, FCRL1 and PTX3; CEACAM5, COMP and SERPINA1; CEACAM5, NOTCH1 and PTX3AREG, FCRL1 and TMPRSS15, CEACAM5, COMP and TNC, EDA2R, GDF15 and NOTCH1, AREG, TMPRSS15 and TNC, EDA2R, NOTCH1 and TMPRSS15, GDF15, PTX3 and TNC, CEACAM5, SERPINA1 and TMPRSS15, FCRL1, TMPRSS15 and TNC, CEACAM5, COMP and FCRL1, COMP, TMPRSS15 and TNC, COMP, PTX3 and TNC, CEACAM5, GDF15 and PTX3, CEACAM5, FCRL1 and TMPRSS15, FCRL1, SERPINA1 and TMPRSS15, EDA2R, FCRL1 and PTX3, AREG, NOTCH1 and TMPRSS15, PTX3, SERPINA1 and TMPRSS15, AREG, COMP and PTX3, COMP, SERPINA1 and TMPRSS15, CEACAM5, NOTCH1 and SERPINA1, COMP, EDA2R and TNC, EDA2R, NOTCH1 and PTX3, CEACAM5, NOTCH1 and TMPRSS15, AREG, SERPINA1 and TMPRSS15, NOTCH1, PTX3 and TMPRSS15, COMP, FCRL1 and SERPINA1, CEACAM5, FCRL1 and PTX3, COMP, NOTCH1 and PTX3, AREG, CEACAM5 and COMP, EDA2R, GDF15 and PTX3, COMP, FCRL1 and TNC, AREG, COMP and FCRL1, CEACAM5, EDA2R and NOTCH1, NOTCH1, SERPINA1 and TMPRSS15, CEACAM5, FCRL1 and GDF15, CEACAM5, EDA2R and PTX3, FCRL1, NOTCH1 and TMPRSS15, COMP, EDA2R and NOTCH1, EDA2R, NOTCH1 and SERPINA1, AREG, NOTCH1 and PTX3, FCRL1, NOTCH1 and PTX3, GDF15, PTX3 and SERPINA1, COMP, PTX3 and SERPINA1, AREG, GDF15 and PTX3, FCRL1, GDF15 and TNC, FCRL1, GDF15 and SERPINA1, NOTCH1, PTX3 and SERPINA1, SERPINA1, TMPRSS15 and TNC, CEACAM5, COMP and NOTCH1, AREG, FCRL1 and PTX3, NOTCH1, PTX3 and TNC,FCRL1, PTX3 and TNC, CEACAM5, PTX3 and TNC, AREG, EDA2R and NOTCH1, CEACAM5, NOTCH1 and TNC, EDA2R, FCRL1 and NOTCH1, CEACAM5, GDF15 and TNC, FCRL1, NOTCH1 and SERPINA1, AREG, COMP and TNC, AREG, COMP and SERPINA1, CEACAM5, FCRL1 and NOTCH1, AREG, CEACAM5 and NOTCH1, AREG, FCRL1 and GDF15, CEACAM5, EDA2R and GDF15, CEACAM5, FCRL1 and SERPINA1, COMP, FCRL1 and NOTCH1, AREG, CEACAM5 and PTX3, CEACAM5, GDF15 and SERPINA1, AREG, EDA2R and PTX3, NOTCH1, TMPRSS15 and TNC, CEACAM5, EDA2R and FCRL1, COMP, NOTCH1 and SERPINA1, FCRL1, PTX3 and SERPINA1, EDA2R, PTX3 and TNC, EDA2R, FCRL1 and GDF15, AREG, CEACAM5 and GDF15, AREG, COMP and NOTCH1, CEACAM5, PTX3 and SERPINA1, EDA2R, PTX3 and SERPINA1, COMP, SERPINA1 and TNC, NOTCH1, SERPINA1 and TNC, COMP, NOTCH1 and TMPRSS15, EDA2R, FCRL1 and SERPINA1, AREG, EDA2R and FCRL1, AREG, FCRL1 and NOTCH1, EDA2R, NOTCH1 and TNC, COMP, NOTCH1 and TNC, AREG, PTX3 and TNC, GDF15, SERPINA1 and TNC, AREG, NOTCH1 and SERPINA1, CEACAM5, EDA2R and SERPINA1, PTX3, SERPINA1 and TNC, CEACAM5, FCRL1 and TNC, EDA2R, FCRL1 and TNC, AREG, NOTCH1 and TNC, FCRL1, NOTCH1 and TNC, AREG, EDA2R and GDF15, AREG, GDF15 and TNC, CEACAM5, SERPINA1 and TNC, AREG, FCRL1 and TNC, AREG, CEACAM5 and EDA2R, AREG, CEACAM5 and FCRL1, CEACAM5, EDA2R and TNC, EDA2R, GDF15 and SERPINA1AREG, PTX3 and SERPINA1, EDA2R, GDF15 and TNC, FCRL1, SERPINA1 and TNC, AREG, FCRL1 and SERPINA1, AREG, GDF15 and SERPINA1, AREG, CEACAM5 and SERPINA1, AREG, CEACAM5 and TNC, AREG, EDA2R and SERPINA1, EDA2R, SERPINA1 and TNC, AREG, EDA2R and TNC, or AREG, SERPINA1 and TNC.,

[0043] Preferably, A comprises a 4 - markers combination, and the 4 - markers combination is any 4 of B.

[0044] Preferably, the 4 - markers combination is b1) and b2):

[0045] b1) the 3 - markers combination (preferably any one of the above 622 3 - markers combinations);

[0046] b2) any one of B;

[0047] The marker in b2) is different from any one of the markers in the 3 - markers combination in b1).

[0048] Preferably, the 4 - marker combinations are: ADGRE1, GDF15, PTX3 and THBS4; PTX3, HMCN2, POF1B and FASLG; SPP1, COMP, LMNB2 and FCRL1; ADGRE1, GDF15, PTX3 and COMP; AREG, CEACAM5, ADAMTS8 and DCTPP1; SPP1, FCRL1, SOD3 and ADGRE5; PTX3, GDF15, ADGRG2 and ADGRE5; TMPRSS15, SPP1, FCRL1 and SOD3; AREG, CEACAM5, ADAMTS8 and TNFRSF11A; GNAS, LMNB2, PLXDC2 and PROK1; NOTCH1, COMP, GDF15 and PTX3; ADGRE1, GDF15, PTX3 and ADGRG2; TMPRSS15, PTX3, GDF15 and THBS4; PTX3, GDF15, COMP and RET; AREG, CEACAM5, ADAMTS8 and CNTN1; ADGRE2, SOD3, SPP1 and LMNB2; ADGRE2, SOD3, SPP1 and TCL1A; TMPRSS15, PTX3, SPP1 and THBS4; TMPRSS15, SPP1, SOD3 and MMP12; TMPRSS15, SPP1, COMP and FCRL1; CEACAM5, COMP, GDF15 and PTX3; SPP1, COMP, FCRL1 and SOD3; ADGRE1, GDF15, PTX3 and NOTCH3; PTX3, GDF15, THBS4 and ADGRE5; PTX3, POF1B, THBS4 and FASLG; TMPRSS15, PTX3, GDF15 and COMP; PTX3, GDF15, RET and ADGRG2; SPP1, ENPP6, FCRL1 and ADGRE5; NOTCH3, ESM1, PLXDC2 and LMNB2; CEACAM5, GDF15, NOTCH1 and PTX3; SPP1, PLXDC2, COMP and LMNB2; SPP1, PLXDC2, FCRL1 and SOD3; ITGA11, LMNB2, RET and SOD3; TMPRSS15, COMP, PTX3 and PGA4; PTX3, GDF15, PLXDC2 and THBS4; CRTAC1, SPP1, TCL1A and SOD3; TMPRSS15, SPP1, COMP and IL4R; ADGRE2, SOD3, SPP1 and PROK1; PTX3, GDF15, THBS4 and ADGRG2; ADGRE1, GDF15, PTX3 and GSNPTX3, GDF15, THBS4 and EXTL1, SPP1, COMP, FCRL1 and ADGRE5, NT5C1A, TMPRSS15, COMP and SPP1, SPP1, COMP, FCRL1 and IL4R, ADGRE1, GDF15, PTX3 and CNTN4, PTX3, ITGA11, POF1B and THBS4, ADGRE2, SOD3, SPP1 and TNFRSF11A, PTX3, ENPP6, THBS4 and FASLG, PTX3, POF1B, THBS4 and EXTL1, TMPRSS15, SPP1, SOD3 and EXTL1, SPP1, LMNB2, FCRL1 and SOD3, TMPRSS15, SPP1, COMP and CLEC3B, COMP, FCRL1, PTX3 and SPP1, ADGRE1, GDF15, PTX3 and ADGRE2, NOTCH1, COMP, GDF15 and C9, ADGRE1, GDF15, PTX3 and BMP4, PTX3, SPP1, COMP and FCRL1, SPP1, PLXDC2, COMP and IL4R, PTX3, SPP1, ENPP6 and COMP, TMPRSS15, SPP1, COMP and TNFRSF10B, SPP1, COMP, LMNB2 and FASLG, ADGRE1, CRTAC1, GDF15 and PTX3, AREG, COMP, EDA2R and TMPRSS15, COMP, LMNB2, FCRL1 and MMP12, PTX3, GDF15, PLXDC2 and ADGRE5, SPP1, ENPP6, COMP and FCRL1, SPP1, THBS4, LMNB2 and ADGRE5, SPP1, COMP, FCRL1 and CLEC3B, SPP1, COMP, LMNB2 and SOD3, ADGRE1, GDF15, PTX3 and ITGA2, PTX3, GDF15, THBS4 and FASLG, TMPRSS15, SPP1, THBS4 and FCRL1, ADGRE1, GDF15, PTX3 and NOTCH1, PTX3, COMP, POF1B and FASLG, PTX3, GDF15, COMP and THBS4, DCC, COMP, SPP1 and PROK1, ADGRE1, GDF15, PTX3 and TMPRSS15, PTX3, PLXDC2, POF1B and FASLG, GDF15, PLXDC2, LMNB2 and DLK1, GDF15, COMP, LMNB2 and DLK1, SPP1, LMNB2, SOD3 and ADGRE5, CEACAM5, COMP, PTX3 and PGA4,GSN, TMPRSS15, PGA4 and PTX3, PTX3, GDF15, ITGA11 and THBS4, ADGRE1, KRT19, LMNB2 and COMP, PTX3, GDF15, COMP and POF1B, SPP1, ADGRG2, FCRL1 and SOD3, ADGRE1, GDF15, PTX3 and PKD1, ADGRE1, KRT19, LMNB2 and ITGA2, ADGRE1, GDF15, PTX3 and ADGRE5, TMPRSS15, THBS4, CLEC3B and TNFRSF10B, TMPRSS15, SPP1, RET and SOD3, PTX3, THBS4, LMNB2 and CNTN4, PTX3, GDF15, THBS4 and RET, TMPRSS15, PTX3, FASLG and MMP12, SPP1, ITGA11, FCRL1 and SOD3, PTX3, GDF15, COMP and EXTL1, TMPRSS15, COMP, MMP12 and IL4R, PTX3, GDF15, THBS4 and CNTN4, COMP, FCRL1, GDF15 and NOTCH1, TMPRSS15, PTX3, POF1B and THBS4, SPP1, COMP, FASLG and FCRL1, PTX3, THBS4, FASLG and IL4R, PTX3, GDF15, THBS4 and FCRL1, ADGRE1, GDF15, PTX3 and HMCN2, NOTCH1, COMP, GDF15 and SPP1, PTX3, KRT19, FASLG and ADGRG2, PTX3, ITGA11, POF1B and EXTL1, SPP1, RET, FCRL1 and SOD3, SPP1, HMCN2, FCRL1 and SOD3, PTX3, GDF15, PLXDC2 and RET, TMPRSS15, SPP1, SOD3 and IL4R, PTX3, SPP1, COMP and CNTN4, COMP, GDF15, PTX3 and TNC, NOTCH3, ESM1, PLXDC2 and GDF15, TMPRSS15, COMP, PTX3 and SPP1, ADGRE1, GDF15, PTX3 and ADAMTS8, PTX3, GDF15, COMP and ADGRG2, CRTAC1, SPP1, TCL1A and NOTCH1, TMPRSS15, SOD3, MMP12 and IL4R, PTX3, GDF15, ENPP6 and THBS4, TMPRSS15, PTX3, POF1B and FASLG, TMPRSS15, SPP1, FASLG and CLEC3B, TMPRSS15, PTX3, THBS4 and LMNB2,TMPRSS15, PTX3, SPP1 and SOD3, ADGRE2, SOD3, SPP1 and FCRL1, SPP1, LMNB2, CLEC3B and ADGRE5, SPP1, COMP, ADGRE5 and IL4R, ITGA11, LMNB2, FCRL1 and SOD3, PTX3, POF1B, THBS4 and ADGRE5, CD48, CLEC3B, SPP1 and TNFRSF10B, ADGRE1, GDF15, PTX3 and AGR3, SPP1, ADGRG2, FCRL1 and ADGRE5, PTX3, GDF15, COMP and ADGRE5, ADGRE2, SOD3, SPP1 and IL4R, PTX3, SPP1, FCRL1 and SOD3, SPP1, COMP, TNFRSF10B and ADGRE5, SPP1, CLEC3B, TNFRSF10B and ADGRE5, ADGRE1, CRTAC1, GDF15 and TMPRSS15, TMPRSS15, SPP1, COMP and MMP12, PTX3, GDF15, POF1B and THBS4, SPP1, FASLG, SOD3 and ADGRE5, PTX3, SPP1, ITGA11 and SOD3, PTX3, POF1B, THBS4 and RET, PTX3, GDF15, THBS4 and CLEC3B, TMPRSS15, COMP, LMNB2 and MMP12, ADGRE1, GDF15, PTX3 and ITGAM, CD48, CLEC3B, SPP1 and EDA2R, SPP1, FCRL1, SOD3 and ITGA2, SPP1, COMP, LMNB2 and ITGB1, ADGRE1, KRT19, LMNB2 and TMPRSS15, PTX3, ITGA11, POF1B and RET, PTX3, POF1B, THBS4 and FCRL1, TMPRSS15, SPP1, ITGA11 and SOD3, SPP1, COMP, ITGA11 and FCRL1, PTX3, PLXDC2, POF1B and RET, TMPRSS15, SPP1, FASLG and SOD3, DCC, CNTN4, PTX3 and PGA4, CRTAC1, SPP1, TCL1A and LMNB2, PTX3, GDF15, HMCN2 and ADGRE5, PTX3, SPP1, COMP and IL4R, TMPRSS15, PTX3, THBS4 and FASLG, GNAS, NT5C1A, TMPRSS15 and AREG, COMP, FCRL1, PTX3 and POF1B, PTX3, COMP, POF1B and CNTN4, TMPRSS15, PTX3, SPP1 and COMP,TMPRSS15, PTX3, COMP and POF1B, NOTCH1, COMP, GDF15 and ADGRE1, PTX3, GDF15, COMP and FASLG, CRTAC1, SPP1, TCL1A and ADGRE5, SPP1, LMNB2, FCRL1 and ADGRE5, SPP1, ENPP6, COMP and TNFRSF10B, SPP1, COMP, ADGRG2 and FCRL1, NOTCH3, ESM1, PLXDC2 and EDA2R, PTX3, SPP1, ENPP6 and ADGRE5, SPP1, FCRL1, CLEC3B and ADGRE5, NT5C1A, THBS4, PTX3 and EXTL1, ADGRE2, SOD3, SPP1 and FASLG, TMPRSS15, SPP1, PLXDC2 and SOD3, DCC, COMP, SPP1 and PLXDC2, CD48, CLEC3B, SPP1 and LMNB2, ADGRE1, GDF15, PTX3 and ITGB1, SPP1, COMP, FASLG and ADGRE5, TMPRSS15, PTX3, GDF15 and FASLG, COMP, FCRL1, GDF15 and TMPRSS15, TMPRSS15, SPP1, COMP and SOD3, TMPRSS15, SPP1, PLXDC2 and COMP, SPP1, COMP, FCRL1 and DLK1, GDF15, NOTCH1, PTX3 and TMPRSS15, PTX3, GDF15, COMP and LMNB2, SPP1, PLXDC2, COMP and FCRL1, PTX3, COMP, POF1B and RET, PTX3, GDF15, COMP and HMCN2, COMP, FCRL1, PTX3 and EDA2R, GDF15, SPP1, PLXDC2 and COMP, TMPRSS15, SPP1, SOD3 and ADGRE5, PTX3, POF1B, FASLG and CNTN4, TMPRSS15, PTX3, THBS4 and TNFRSF10B, TMPRSS15, SPP1, COMP and FASLG, TMPRSS15, GDF15, SPP1 and COMP, CEACAM5, COMP, GDF15 and TNC, PTX3, GDF15, POF1B and ADGRE5, SPP1, FCRL1, SOD3 and MMP12, PTX3, GDF15, SPP1 and COMP, PTX3, PLXDC2, POF1B and FCRL1, CRTAC1, NOTCH1, GDF15 and SPP1, ADGRE1, GDF15, PTX3 and POF1B,SPP1, SOD3, TNFRSF10B and ADGRE5, GDF15, COMP, LMNB2 and FCRL1, TMPRSS15, SPP1, THBS4 and TNFRSF10B, CRTAC1, NOTCH1, GDF15 and PTX3, SPP1, THBS4, FCRL1 and SOD3, PTX3, PLXDC2, THBS4 and IL4R, ADGRE2, SOD3, SPP1 and TMPRSS15, TMPRSS15, LMNB2, SOD3 and MMP12, PTX3, SPP1, COMP and POF1B, TMPRSS15, SPP1, THBS4 and SOD3, CRTAC1, SPP1, TCL1A and ADGRE2, TMPRSS15, SPP1, THBS4 and LMNB2, PTX3, POF1B, THBS4 and CNTN4, PTX3, GDF15, THBS4 and IL4R, ADGRE1, GDF15, PTX3 and BAG3, SPP1, FCRL1, SOD3 and IL4R, PTX3, LMNB2, SOD3 and CNTN4, PTX3, PLXDC2, POF1B and THBS4, TMPRSS15, GDF15, THBS4 and MMP12, TMPRSS15, THBS4, MMP12 and IL4R, SPP1, KRT19, COMP and FCRL1, COMP, EDA2R, PTX3 and TMPRSS15, SPP1, PLXDC2, COMP and POF1B, ITGA11, POF1B, RET and SOD3, PTX3, GDF15, ADGRG2 and CNTN4, PTX3, GDF15, THBS4 and SOD3, PTX3, SPP1, THBS4 and CNTN4, SPP1, COMP, POF1B and FCRL1, SPP1, THBS4, CLEC3B and ADGRE5, TMPRSS15, PTX3, THBS4 and MMP12, TMPRSS15, GDF15, COMP and LMNB2, PTX3, GDF15, THBS4 and ITGB1, ADGRE1, GDF15, PTX3 and RET, PTX3, HMCN2, POF1B and SOD3, PTX3, PLXDC2, POF1B and SOD3, PTX3, GDF15, HMCN2 and ADGRG2, COMP, FCRL1, GDF15 and PTX3, SPP1, ADGRG2, SOD3 and ADGRE5, ADGRE1, GDF15, PTX3 and ENPP6, TMPRSS15, THBS4, LMNB2 and MMP12, SPP1, ENPP6, ITGA11 and ADGRE5,ADGRE1, GDF15, PTX3 and SOD3, SPP1, COMP, LMNB2 and ADGRE5, TMPRSS15, PTX3, THBS4 and IL4R, SPP1, COMP, CEACAM5 and SOD3, SPP1, COMP, FCRL1 and ITGB1, FCRL1, GDF15, NOTCH1 and PTX3, SPP1, COMP, LMNB2 and ADGRG2, PTX3, COMP, HMCN2 and POF1B, DCC, COMP, SPP1 and TMPRSS15, TMPRSS15, PTX3, COMP and TNFRSF10B, TMPRSS15, PTX3, KRT19 and ENPP6, PTX3, SPP1, PLXDC2 and POF1B, NOTCH1, COMP, GDF15 and TCL1A, ADGRE2, SOD3, SPP1 and ITGA11, DCC, COMP, SPP1 and PTX3, PTX3, GDF15, ADGRG2 and FCRL1, TMPRSS15, POF1B, FASLG and MMP12, PTX3, POF1B, FCRL1 and SOD3, PTX3, POF1B, RET and SOD3, TMPRSS15, PTX3, KRT19 and EXTL1, PTX3, GDF15, PLXDC2 and COMP, PTX3, GDF15, ITGA11 and RET, PTX3, SPP1, COMP and RET, ADGRE2, SOD3, SPP1 and CEACAM16, TMPRSS15, SPP1, KRT19 and COMP, PTX3, ITGA11, POF1B and SOD3, TMPRSS15, COMP, FCRL1 and TNFRSF10B, TMPRSS15, PTX3, GDF15 and PLXDC2, PTX3, COMP, LMNB2 and RET, PTX3, THBS4, ADGRG2 and IL4R, PTX3, GDF15, COMP and DLK1, SPP1, RET, ADGRG2 and SOD3, GDF15, LMNB2, ADGRG2 and DLK1, COMP, GDF15, NOTCH1 and SERPINA1, TMPRSS15, SPP1, ADGRG2 and SOD3, PTX3, COMP, POF1B and FCRL1, TMPRSS15, SPP1, COMP and EXTL1, NT5C1A, THBS4, PTX3 and CNTN4, PTX3, COMP, TNFRSF10B and CNTN4, ADGRE2, SOD3, SPP1 and CEACAM5, PTX3, POF1B, SOD3 and EXTL1, TMPRSS15, PTX3, POF1B and FCRL1,COMP, GDF15, TMPRSS15 and TNC, TMPRSS15, COMP, PTX3 and TNFRSF10B, GNAS, NT5C1A, TMPRSS15 and ITGA11, TMPRSS15, PTX3, GDF15 and KRT19, ADGRE2, SOD3, SPP1 and PTX3, PTX3, SPP1, PLXDC2 and COMP, TMPRSS15, SPP1, LMNB2 and SOD3, PTX3, SPP1, THBS4 and ADGRE5, PTX3, SPP1, COMP and LMNB2, ADGRE1, LMNB2, THBS4 and TMPRSS15, GDF15, SPP1, COMP and FCRL1, GNAS, NT5C1A, TMPRSS15 and PTX3, PTX3, SPP1, COMP and TNFRSF10B, PTX3, COMP, POF1B and EXTL1, NOTCH1, SPP1, TNFRSF10B and COMP, SPP1, ENPP6, CLEC3B and ADGRE5, ADGRE2, SOD3, SPP1 and COMP, NOTCH1, COMP, GDF15 and PROK1, PTX3, HMCN2, POF1B and EXTL1, SPP1, PLXDC2, SOD3 and IL4R, PTX3, POF1B, ITGB7 and EXTL1, COMP, LMNB2, FCRL1 and SOD3, SPP1, COMP, FASLG and CLEC3B, ADGRE2, SOD3, SPP1 and PGA4, COMP, FCRL1, PTX3 and PGA4, PTX3, GDF15, SOD3 and ADGRE5, SPP1, COMP, SOD3 and IL4R, TMPRSS15, PTX3, GDF15 and CNTN4, SPP1, ENPP6, CEACAM5 and ADGRE5, SPP1, ITGA11, ADGRG2 and ADGRE5, PTX3, SPP1, COMP and FASLG, PTX3, POF1B, THBS4 and ITGA2, PTX3, SPP1, COMP and ADGRE5, GDF15, PLXDC2, CEACAM5 and ADGRE5, PTX3, GDF15, PLXDC2 and DLK1, TMPRSS15, THBS4, LMNB2 and CLEC3B, ADGRE1, LMNB2, THBS4 and CLEC3B, GSN, SPP1, THBS4 and PTX3, TMPRSS15, SPP1, THBS4 and CLEC3B, PTX3, GDF15, POF1B and CNTN4, SPP1, FCRL1, SOD3 and ITGB1,Or ADGRE2, SOD3, SPP1 and PLXDC1; that is, any one of the above 332 combinations of 4 markers.

[0049] Preferably, the combination of 4 markers is any 4 of those in E.

[0050] Preferably, the 4 - marker combinations are: NOTCH1, COMP, GDF15 and PTX3; CEACAM5, COMP, GDF15 and PTX3; TMPRSS15, PTX3, GDF15 and COMP; CEACAM5, GDF15, NOTCH1 and PTX3; AREG, COMP, EDA2R and TMPRSS15; COMP, FCRL1, GDF15 and NOTCH1; COMP, GDF15, PTX3 and TNC; COMP, FCRL1, GDF15 and TMPRSS15; GDF15, NOTCH1, PTX3 and TMPRSS15; CEACAM5, COMP, GDF15 and TNC; COMP, EDA2R, PTX3 and TMPRSS15; COMP, FCRL1, GDF15 and PTX3; FCRL1, GDF15, NOTCH1 and PTX3; COMP, GDF15, NOTCH1 and SERPINA1; COMP, GDF15, TMPRSS15 and TNC; AREG, CEACAM5, COMP and EDA2R; AREG, CEACAM5, COMP and FCRL1; AREG, CEACAM5, COMP and GDF15; AREG, CEACAM5, COMP and NOTCH1; AREG, CEACAM5, COMP and PTX3; AREG, CEACAM5, COMP and SERPINA1; AREG, CEACAM5, COMP and TMPRSS15; AREG, CEACAM5, COMP and TNC; AREG, CEACAM5, EDA2R and FCRL1; AREG, CEACAM5, EDA2R and GDF15; AREG, CEACAM5, EDA2R and NOTCH1; AREG, CEACAM5, EDA2R and PTX3; AREG, CEACAM5, EDA2R and SERPINA1; AREG, CEACAM5, EDA2R and TMPRSS15; AREG, CEACAM5, EDA2R and TNC; AREG, CEACAM5, FCRL1 and GDF15; AREG, CEACAM5, FCRL1 and NOTCH1; AREG, CEACAM5, FCRL1 and PTX3; AREG, CEACAM5, FCRL1 and SERPINA1; AREG, CEACAM5, FCRL1 and TMPRSS15; AREG, CEACAM5, FCRL1 and TNC; AREG, CEACAM5, GDF15 and NOTCH1; AREG, CEACAM5, GDF15 and PTX3; AREG, CEACAM5, GDF15 and SERPINA1,AREG, CEACAM5, GDF15 and TMPRSS15, AREG, CEACAM5, GDF15 and TNC, AREG, CEACAM5, NOTCH1 and PTX3, AREG, CEACAM5, NOTCH1 and SERPINA1, AREG, CEACAM5, NOTCH1 and TMPRSS15, AREG, CEACAM5, NOTCH1 and TNC, AREG, CEACAM5, PTX3 and SERPINA1, AREG, CEACAM5, PTX3 and TMPRSS15, AREG, CEACAM5, PTX3 and TNC, AREG, CEACAM5, SERPINA1 and TMPRSS15, AREG, CEACAM5, SERPINA1 and TNC, AREG, CEACAM5, TMPRSS15 and TNC, AREG, COMP, EDA2R and FCRL1, AREG, COMP, EDA2R and GDF15, AREG, COMP, EDA2R and NOTCH1, AREG, COMP, EDA2R and PTX3, AREG, COMP, EDA2R and SERPINA1, AREG, COMP, EDA2R and TNC, AREG, COMP, FCRL1 and GDF15, AREG, COMP, FCRL1 and NOTCH1, AREG, COMP, FCRL1 and PTX3, AREG, COMP, FCRL1 and SERPINA1, AREG, COMP, FCRL1 and TMPRSS15, AREG, COMP, FCRL1 and TNC, AREG, COMP, GDF15 and NOTCH1, AREG, COMP, GDF15 and PTX3, AREG, COMP, GDF15 and SERPINA1, AREG, COMP, GDF15 and TMPRSS15, AREG, COMP, GDF15 and TNC, AREG, COMP, NOTCH1 and PTX3, AREG, COMP, NOTCH1 and SERPINA1, AREG, COMP, NOTCH1 and TMPRSS15, AREG, COMP, NOTCH1 and TNC, AREG, COMP, PTX3 and SERPINA1, AREG, COMP, PTX3 and TMPRSS15, AREG, COMP, PTX3 and TNC, AREG, COMP, SERPINA1 and TMPRSS15, AREG, COMP, SERPINA1 and TNC, AREG, COMP, TMPRSS15 and TNC, AREG, EDA2R, FCRL1 and GDF15, AREG, EDA2R, FCRL1 and NOTCH1,AREG, EDA2R, FCRL1 and PTX3, AREG, EDA2R, FCRL1 and SERPINA1, AREG, EDA2R, FCRL1 and TMPRSS15, AREG, EDA2R, FCRL1 and TNC, AREG, EDA2R, GDF15 and NOTCH1, AREG, EDA2R, GDF15 and PTX3, AREG, EDA2R, GDF15 and SERPINA1, AREG, EDA2R, GDF15 and TMPRSS15, AREG, EDA2R, GDF15 and TNC, AREG, EDA2R, NOTCH1 and PTX3, AREG, EDA2R, NOTCH1 and SERPINA1, AREG, EDA2R, NOTCH1 and TMPRSS15, AREG, EDA2R, NOTCH1 and TNC, AREG, EDA2R, PTX3 and SERPINA1, AREG, EDA2R, PTX3 and TMPRSS15, AREG, EDA2R, PTX3 and TNC, AREG, EDA2R, SERPINA1 and TMPRSS15, AREG, EDA2R, SERPINA1 and TNC, AREG, EDA2R, TMPRSS15 and TNC, AREG, FCRL1, GDF15 and NOTCH1, AREG, FCRL1, GDF15 and PTX3, AREG, FCRL1, GDF15 and SERPINA1, AREG, FCRL1, GDF15 and TMPRSS15, AREG, FCRL1, GDF15 and TNC, AREG, FCRL1, NOTCH1 and PTX3, AREG, FCRL1, NOTCH1 and SERPINA1, AREG, FCRL1, NOTCH1 and TMPRSS15, AREG, FCRL1, NOTCH1 and TNC, AREG, FCRL1, PTX3 and SERPINA1, AREG, FCRL1, PTX3 and TMPRSS15, AREG, FCRL1, PTX3 and TNC, AREG, FCRL1, SERPINA1 and TMPRSS15, AREG, FCRL1, SERPINA1 and TNC, AREG, FCRL1, TMPRSS15 and TNC, AREG, GDF15, NOTCH1 and PTX3, AREG, GDF15, NOTCH1 and SERPINA1, AREG, GDF15, NOTCH1 and TMPRSS15, AREG, GDF15, NOTCH1 and TNC, AREG, GDF15, PTX3 and SERPINA1, AREG, GDF15, PTX3 and TMPRSS15, AREG, GDF15, PTX3 and TNC,AREG, GDF15, SERPINA1 and TMPRSS15, AREG, GDF15, SERPINA1 and TNC, AREG, GDF15, TMPRSS15 and TNC, AREG, NOTCH1, PTX3 and SERPINA1, AREG, NOTCH1, PTX3 and TMPRSS15, AREG, NOTCH1, PTX3 and TNC, AREG, NOTCH1, SERPINA1 and TMPRSS15, AREG, NOTCH1, SERPINA1 and TNC, AREG, NOTCH1, TMPRSS15 and TNC, AREG, PTX3, SERPINA1 and TMPRSS15, AREG, PTX3, SERPINA1 and TNC, AREG, PTX3, TMPRSS15 and TNC, AREG, SERPINA1, TMPRSS15 and TNC, CEACAM5, COMP, EDA2R and FCRL1, CEACAM5, COMP, EDA2R and GDF15, CEACAM5, COMP, EDA2R and NOTCH1, CEACAM5, COMP, EDA2R and PTX3, CEACAM5, COMP, EDA2R and SERPINA1, CEACAM5, COMP, EDA2R and TMPRSS15, CEACAM5, COMP, EDA2R and TNC, CEACAM5, COMP, FCRL1 and GDF15, CEACAM5, COMP, FCRL1 and NOTCH1, CEACAM5, COMP, FCRL1 and PTX3, CEACAM5, COMP, FCRL1 and SERPINA1, CEACAM5, COMP, FCRL1 and TMPRSS15, CEACAM5, COMP, FCRL1 and TNC, CEACAM5, COMP, GDF15 and NOTCH1, CEACAM5, COMP, GDF15 and SERPINA1, CEACAM5, COMP, GDF15 and TMPRSS15, CEACAM5, COMP, NOTCH1 and PTX3, CEACAM5, COMP, NOTCH1 and SERPINA1, CEACAM5, COMP, NOTCH1 and TMPRSS15, CEACAM5, COMP, NOTCH1 and TNC, CEACAM5, COMP, PTX3 and SERPINA1, CEACAM5, COMP, PTX3 and TMPRSS15, CEACAM5, COMP, PTX3 and TNC, CEACAM5, COMP, SERPINA1 and TMPRSS15, CEACAM5, COMP, SERPINA1 and TNC,CEACAM5, COMP, TMPRSS15 and TNC, CEACAM5, EDA2R, FCRL1 and GDF15, CEACAM5, EDA2R, FCRL1 and NOTCH1, CEACAM5, EDA2R, FCRL1 and PTX3, CEACAM5, EDA2R, FCRL1 and SERPINA1, CEACAM5, EDA2R, FCRL1 and TMPRSS15, CEACAM5, EDA2R, FCRL1 and TNC, CEACAM5, EDA2R, GDF15 and NOTCH1, CEACAM5, EDA2R, GDF15 and PTX3, CEACAM5, EDA2R, GDF15 and SERPINA1, CEACAM5, EDA2R, GDF15 and TMPRSS15, CEACAM5, EDA2R, GDF15 and TNC, CEACAM5, EDA2R, NOTCH1 and PTX3, CEACAM5, EDA2R, NOTCH1 and SERPINA1, CEACAM5, EDA2R, NOTCH1 and TMPRSS15, CEACAM5, EDA2R, NOTCH1 and TNC, CEACAM5, EDA2R, PTX3 and SERPINA1, CEACAM5, EDA2R, PTX3 and TMPRSS15, CEACAM5, EDA2R, PTX3 and TNC, CEACAM5, EDA2R, SERPINA1 and TMPRSS15, CEACAM5, EDA2R, SERPINA1 and TNC, CEACAM5, EDA2R, TMPRSS15 and TNC, CEACAM5, FCRL1, GDF15 and NOTCH1, CEACAM5, FCRL1, GDF15 and PTX3, CEACAM5, FCRL1, GDF15 and SERPINA1, CEACAM5, FCRL1, GDF15 and TMPRSS15, CEACAM5, FCRL1, GDF15 and TNC, CEACAM5, FCRL1, NOTCH1 and PTX3, CEACAM5, FCRL1, NOTCH1 and SERPINA1, CEACAM5, FCRL1, NOTCH1 and TMPRSS15, CEACAM5, FCRL1, NOTCH1 and TNC, CEACAM5, FCRL1, PTX3 and SERPINA1, CEACAM5, FCRL1, PTX3 and TMPRSS15, CEACAM5, FCRL1, PTX3 and TNC, CEACAM5, FCRL1, SERPINA1 and TMPRSS15, CEACAM5, FCRL1, SERPINA1 and TNC,CEACAM5, FCRL1, TMPRSS15, and TNC; CEACAM5, GDF15, NOTCH1, and SERPINA1; CEACAM5, GDF15, NOTCH1, and TMPRSS15; CEACAM5, GDF15, NOTCH1, and TNC; CEACAM5, GDF15, PTX3, and SERPINA1; CEACAM5, GDF15, PTX3, and TMPRSS15; CEACAM5, GDF15, PTX3, and TNC; CEACAM5, GDF15, SERPINA1, and TMPRSS15; CEACAM5, GDF15, SERPINA1, and TNC; CEACAM5, GDF15, TMPRSS15, and TNC; CEACAM5, NOTCH1, PTX3, and SERPINA1; CEACAM5, NOTCH1, PTX3, and TMPRSS15; CEACAM5, NOTCH1, PTX3, and TNC; CEACAM5, NOTCH1, SERPINA1, and TMPRSS15; CEACAM5, NOTCH1, SERPINA1, and TNC; CEACAM5, NOTCH1, TMPRSS15, and TNC; CEACAM5, PTX3, SERPINA1, and TMPRSS15; CEACAM5, PTX3, SERPINA1, and TNC; CEACAM5, PTX3, TMPRSS15, and TNC; CEACAM5, SERPINA1, TMPRSS15, and TNC; COMP, EDA2R, FCRL1, and GDF15; COMP, EDA2R, FCRL1, and NOTCH1; COMP, EDA2R, FCRL1, and PTX3; COMP, EDA2R, FCRL1, and SERPINA1; COMP, EDA2R, FCRL1, and TMPRSS15; COMP, EDA2R, FCRL1, and TNC; COMP, EDA2R, GDF15, and NOTCH1; COMP, EDA2R, GDF15, and PTX3; COMP, EDA2R, GDF15, and SERPINA1; COMP, EDA2R, GDF15, and TMPRSS15; COMP, EDA2R, GDF15, and TNC; COMP, EDA2R, NOTCH1, and PTX3; COMP, EDA2R, NOTCH1, and SERPINA1; COMP, EDA2R, NOTCH1, and TMPRSS15; COMP, EDA2R, NOTCH1, and TNC; COMP, EDA2R, PTX3, and SERPINA1; COMP, EDA2R, PTX3, and TNC; COMP, EDA2R, SERPINA1, and TMPRSS15,COMP, EDA2R, SERPINA1 and TNC, COMP, EDA2R, TMPRSS15 and TNC, COMP, FCRL1, GDF15 and SERPINA1, COMP, FCRL1, GDF15 and TNC, COMP, FCRL1, NOTCH1 and PTX3, COMP, FCRL1, NOTCH1 and SERPINA1, COMP, FCRL1, NOTCH1 and TMPRSS15, COMP, FCRL1, NOTCH1 and TNC, COMP, FCRL1, PTX3 and SERPINA1, COMP, FCRL1, PTX3 and TMPRSS15, COMP, FCRL1, PTX3 and TNC, COMP, FCRL1, SERPINA1 and TMPRSS15, COMP, FCRL1, SERPINA1 and TNC, COMP, FCRL1, TMPRSS15 and TNC, COMP, GDF15, NOTCH1 and TMPRSS15, COMP, GDF15, NOTCH1 and TNC, COMP, GDF15, PTX3 and SERPINA1, COMP, GDF15, SERPINA1 and TMPRSS15, COMP, GDF15, SERPINA1 and TNC, COMP, NOTCH1, PTX3 and SERPINA1, COMP, NOTCH1, PTX3 and TMPRSS15, COMP, NOTCH1, PTX3 and TNC, COMP, NOTCH1, SERPINA1 and TMPRSS15, COMP, NOTCH1, SERPINA1 and TNC, COMP, NOTCH1, TMPRSS15 and TNC, COMP, PTX3, SERPINA1 and TMPRSS15, COMP, PTX3, SERPINA1 and TNC, COMP, PTX3, TMPRSS15 and TNC, COMP, SERPINA1, TMPRSS15 and TNC, EDA2R, FCRL1, GDF15 and NOTCH1, EDA2R, FCRL1, GDF15 and PTX3, EDA2R, FCRL1, GDF15 and SERPINA1, EDA2R, FCRL1, GDF15 and TMPRSS15, EDA2R, FCRL1, GDF15 and TNC, EDA2R, FCRL1, NOTCH1 and PTX3, EDA2R, FCRL1, NOTCH1 and SERPINA1, EDA2R, FCRL1, NOTCH1 and TMPRSS15, EDA2R, FCRL1, NOTCH1 and TNC, EDA2R, FCRL1, PTX3 and SERPINA1, EDA2R, FCRL1, PTX3 and TMPRSS15,EDA2R, FCRL1, PTX3 and TNC, EDA2R, FCRL1, SERPINA1 and TMPRSS15, EDA2R, FCRL1, SERPINA1 and TNC, EDA2R, FCRL1, TMPRSS15 and TNC, EDA2R, GDF15, NOTCH1 and PTX3, EDA2R, GDF15, NOTCH1 and SERPINA1, EDA2R, GDF15, NOTCH1 and TMPRSS15, EDA2R, GDF15, NOTCH1 and TNC, EDA2R, GDF15, PTX3 and SERPINA1, EDA2R, GDF15, PTX3 and TMPRSS15, EDA2R, GDF15, PTX3 and TNC, EDA2R, GDF15, SERPINA1 and TMPRSS15, EDA2R, GDF15, SERPINA1 and TNC, EDA2R, GDF15, TMPRSS15 and TNC, EDA2R, NOTCH1, PTX3 and SERPINA1, EDA2R, NOTCH1, PTX3 and TMPRSS15, EDA2R, NOTCH1, PTX3 and TNC, EDA2R, NOTCH1, SERPINA1 and TMPRSS15, EDA2R, NOTCH1, SERPINA1 and TNC, EDA2R, NOTCH1, TMPRSS15 and TNC, EDA2R, PTX3, SERPINA1 and TMPRSS15, EDA2R, PTX3, SERPINA1 and TNC, EDA2R, PTX3, TMPRSS15 and TNC, EDA2R, SERPINA1, TMPRSS15 and TNC, FCRL1, GDF15, NOTCH1 and SERPINA1, FCRL1, GDF15, NOTCH1 and TMPRSS15, FCRL1, GDF15, NOTCH1 and TNC, FCRL1, GDF15, PTX3 and SERPINA1, FCRL1, GDF15, PTX3 and TMPRSS15, FCRL1, GDF15, PTX3 and TNC, FCRL1, GDF15, SERPINA1 and TMPRSS15, FCRL1, GDF15, SERPINA1 and TNC, FCRL1, GDF15, TMPRSS15 and TNC, FCRL1, NOTCH1, PTX3 and SERPINA1, FCRL1, NOTCH1, PTX3 and TMPRSS15, FCRL1, NOTCH1, PTX3 and TNC, FCRL1, NOTCH1, SERPINA1 and TMPRSS15, FCRL1, NOTCH1, SERPINA1 and TNC,FCRL1, NOTCH1, TMPRSS15, and TNC; FCRL1, PTX3, SERPINA1, and TMPRSS15; FCRL1, PTX3, SERPINA1, and TNC; FCRL1, PTX3, TMPRSS15, and TNC; FCRL1, SERPINA1, TMPRSS15, and TNC; GDF15, NOTCH1, PTX3, and SERPINA1; GDF15, NOTCH1, PTX3, and TNC; GDF15, NOTCH1, SERPINA1, and TMPRSS15; GDF15, NOTCH1, SERPINA1, and TNC; GDF15, NOTCH1, TMPRSS15, and TNC; GDF15, PTX3, SERPINA1, and TMPRSS15; GDF15, PTX3, SERPINA1, and TNC; GDF15, PTX3, TMPRSS15, and TNC; GDF15, SERPINA1, TMPRSS15, and TNC; NOTCH1, PTX3, SERPINA1, and TMPRSS15; NOTCH1, PTX3, SERPINA1, and TNC; NOTCH1, PTX3, TMPRSS15, and TNC; NOTCH1, SERPINA1, TMPRSS15, and TNC; or PTX3, SERPINA1, TMPRSS15, and TNC.,

[0051] Preferably, A comprises a combination of 5 markers, and the combination of 5 markers is any five of B.

[0052] Preferably, the combination of 5 markers is c1) and c2):

[0053] c1) the combination of 4 markers (preferably any one of the above 332 combinations of 4 markers);

[0054] c2) any one of B;

[0055] The c2) is different from any one marker in the combination of 4 markers in c1).

[0056] Preferably, the 5 - marker combinations are: TMPRSS15, SPP1, SOD3, MMP12 and ADGRE1; SPP1, COMP, LMNB2, SOD3 and SELL; PTX3, POF1B, THBS4, FASLG and TNC; NOTCH1, COMP, GDF15, PTX3 and FAP; ADGRE1, GDF15, PTX3, THBS4 and IGDCC4; SPP1, COMP, TNFRSF10B, ADGRE5 and PROK1; SPP1, COMP, LMNB2, FCRL1 and PKD1; PTX3, GDF15, RET, ADGRG2 and CD48; TMPRSS15, PTX3, SPP1, THBS4 and PROK1; SPP1, FCRL1, SOD3, ADGRE5 and ITM2A; NOTCH3, ESM1, PLXDC2, LMNB2 and MEGF9; PTX3, HMCN2, POF1B, FASLG and CDH23; PTX3, COMP, POF1B, FASLG and LMNB2; DCC, COMP, SPP1, PROK1 and SOD3; TMPRSS15, SPP1, FCRL1, SOD3 and NOS2; PTX3, POF1B, THBS4, EXTL1 and SPP1; SPP1, LMNB2, FCRL1, SOD3 and THBS4; COMP, GDF15, NOTCH1, PTX3 and TMPRSS15; TMPRSS15, PTX3, GDF15, THBS4 and LPL; NOTCH1, COMP, GDF15, PTX3 and ADAMTS8; SPP1, LMNB2, SOD3, ADGRE5 and BAG3; SPP1, COMP, FCRL1, SOD3 and PGA4; TMPRSS15, SPP1, FCRL1, SOD3 and ADGRE5; ADGRE2, SOD3, SPP1, LMNB2 and CLEC3B; PTX3, ITGA11, POF1B, THBS4 and ENPP6; NOTCH1, SPP1, TNFRSF10B, COMP and TCL1A; TMPRSS15, SPP1, FCRL1, SOD3 and PROK1; SPP1, ENPP6, FCRL1, ADGRE5 and THBS4; TMPRSS15, PTX3, GDF15, THBS4 and FCER2; PTX3, GDF15, PLXDC2, THBS4 and ADGRE2; GNAS, LMNB2, PLXDC2, PROK1 and KRT19; PTX3, GDF15, COMP, ADGRG2 and DCC; TMPRSS15, PTX3, SPP1, THBS4 and IL6,PTX3, GDF15, THBS4, ADGRG2 and FCER2, PTX3, GDF15, PLXDC2, THBS4 and TCL1A, TMPRSS15, PTX3, SPP1, THBS4 and FGF21, GDF15, SPP1, PLXDC2, COMP and PROK1, SPP1, COMP, FCRL1, IL4R and PLXDC2, PTX3, GDF15, RET, ADGRG2 and TCL1A, PTX3, HMCN2, POF1B, FASLG and THBS4, PTX3, GDF15, THBS4, ADGRG2 and BAG3, SPP1, COMP, LMNB2, FCRL1 and ITM2A, ADGRE1, KRT19, LMNB2, COMP and TMPRSS15, DCC, COMP, SPP1, PROK1 and ADAMTS8, PTX3, GDF15, POF1B, THBS4 and CFP, ADGRE1, GDF15, PTX3, THBS4 and DLK1, SPP1, LMNB2, SOD3, ADGRE5 and COMP, TMPRSS15, COMP, PTX3, PGA4 and DCC, GNAS, LMNB2, PLXDC2, PROK1 and IL4R, SPP1, LMNB2, FCRL1, SOD3 and CFP, SPP1, LMNB2, FCRL1, SOD3 and AREG, PTX3, SPP1, COMP, FCRL1 and LMNB2, TMPRSS15, SPP1, FCRL1, SOD3 and CDH23, TMPRSS15, PTX3, GDF15, THBS4 and AREG, SPP1, COMP, LMNB2, FCRL1 and CNTN4, TMPRSS15, SPP1, COMP, FCRL1 and PTPRS, PTX3, POF1B, THBS4, EXTL1 and BMP4, SPP1, LMNB2, FCRL1, SOD3 and PROK1, TMPRSS15, PTX3, GDF15, THBS4 and IL6, SPP1, ADGRG2, FCRL1, SOD3 and BAG3, PTX3, GDF15, COMP, RET and ADGRE1, SPP1, COMP, FCRL1, SOD3 and PLXDC2, GNAS, LMNB2, PLXDC2, PROK1 and LPL, SPP1, COMP, FCRL1, SOD3 and NOS2, TMPRSS15, COMP, PTX3, PGA4 and SOD3, TMPRSS15, PTX3, GDF15, THBS4 and LBP, PTX3, GDF15, RET, ADGRG2 and ITGA11,SPP1, ENPP6, FCRL1, ADGRE5 and AREG, SPP1, PLXDC2, FCRL1, SOD3 and ITGA11, TMPRSS15, SPP1, FCRL1, SOD3 and THBS4, ADGRE2, SOD3, SPP1, LMNB2 and ITGA11, SPP1, COMP, FCRL1, SOD3 and C9, PTX3, GDF15, THBS4, ADGRE5 and CEACAM16, PTX3, GDF15, RET, ADGRG2 and FASLG, PTX3, POF1B, THBS4, FASLG and TMPRSS15, PTX3, COMP, POF1B, FCRL1 and GDF15, TMPRSS15, PTX3, GDF15, COMP and RET, AREG, CEACAM5, SOD3, RET and CFP, SPP1, PLXDC2, COMP, LMNB2 and GCG, ADGRE1, GDF15, PTX3, THBS4 and CEACAM5, PTX3, GDF15, COMP, ADGRG2 and FASLG, TMPRSS15, COMP, PTX3, PGA4 and FCRL1, PTX3, GDF15, COMP, FASLG and TMPRSS15, TMPRSS15, SPP1, COMP, FCRL1 and CCL7, PTX3, GDF15, THBS4, CLEC3B and TMPRSS15, PTX3, SPP1, COMP, CNTN4 and TNC, SPP1, COMP, FCRL1, ADGRE5 and PROK1, SPP1, COMP, TNFRSF10B, ADGRE5 and SERPINA1, TMPRSS15, SPP1, COMP, FCRL1 and PGA4, TMPRSS15, COMP, PTX3, PGA4 and IL6, SPP1, FCRL1, SOD3, ADGRE5 and NOS2, TMPRSS15, SPP1, COMP, IL4R and FCRL1, PTX3, COMP, POF1B, FCRL1 and LMNB2, TMPRSS15, PTX3, GDF15, THBS4 and MEGF9, SPP1, COMP, LMNB2, FCRL1 and EDA2R, SPP1, COMP, LMNB2, FCRL1 and GRK5, TMPRSS15, SPP1, COMP, CLEC3B and PGA4, NOTCH1, COMP, GDF15, PTX3 and SPP1, SPP1, COMP, LMNB2, FCRL1 and ITGB7, ADGRE1, GDF15, PTX3, THBS4 and FGF21, ADGRE1, KRT19, LMNB2, COMP and TCL1A,SPP1, COMP, LMNB2, FCRL1 and ITGB1, TMPRSS15, PTX3, GDF15, THBS4 and PLXDC2, PTX3, POF1B, THBS4, EXTL1 and RET, GNAS, LMNB2, PLXDC2, PROK1 and CNTN4, SPP1, PLXDC2, COMP, IL4R and TNC, PTX3, GDF15, COMP, POF1B and PGA4, SPP1, COMP, LMNB2, FCRL1 and GSN, TMPRSS15, PTX3, SPP1, THBS4 and PGA4, SPP1, COMP, LMNB2, FCRL1 and BAG3, NOTCH1, COMP, GDF15, PTX3 and KRT19, ADGRE1, GDF15, PTX3, THBS4 and SPP1, PTX3, GDF15, THBS4, EXTL1 and AREG, NOTCH1, COMP, GDF15, PTX3 and POF1B, PTX3, GDF15, THBS4, ADGRE5 and GRK5, SPP1, COMP, FCRL1, SOD3 and LPL, ADGRE1, GDF15, PTX3, THBS4 and LBP, SPP1, COMP, FCRL1, IL4R and LPL, AREG, CEACAM5, PLXDC2, COMP and TNFRSF11A, PTX3, GDF15, RET, ADGRG2 and ADGRE2, ADGRE1, KRT19, LMNB2, COMP and PTX3, ADGRE2, SOD3, SPP1, LMNB2 and PLXDC1, PTX3, GDF15, THBS4, ADGRG2 and PGA4, TMPRSS15, SPP1, COMP, FCRL1 and TNC, PTX3, GDF15, THBS4, ADGRE5 and IL6, PTX3, POF1B, THBS4, FASLG and ADGRG2, TMPRSS15, PTX3, SPP1, THBS4 and SOD3, TMPRSS15, PTX3, SPP1, THBS4 and FASLG, PTX3, GDF15, PLXDC2, ADGRE5 and POF1B, TMPRSS15, SPP1, FCRL1, SOD3 and CEACAM16, TMPRSS15, COMP, FCRL1, TNFRSF10B and AREG, ADGRE1, GDF15, PTX3, THBS4 and CKAP4, SPP1, COMP, LMNB2, FASLG and FCRL1, PTX3, SPP1, ENPP6, COMP and DCC, PTX3, GDF15, THBS4, ADGRE5 and TNC,GDF15, COMP, LMNB2, DLK1 and TCL1A, TMPRSS15, PTX3, GDF15, THBS4 and BMP4, SPP1, FCRL1, SOD3, ADGRE5 and COMP, TMPRSS15, SPP1, COMP, FCRL1 and NOS2, TMPRSS15, PTX3, GDF15, THBS4 and PKD1, PTX3, ITGA11, POF1B, THBS4 and EXTL1, ADGRE1, GDF15, PTX3, THBS4 and CNTN1, PTX3, POF1B, THBS4, ADGRE5 and SPP1, TMPRSS15, SPP1, COMP, FCRL1 and LBP, PTX3, POF1B, THBS4, EXTL1 and PROK1, ITGA11, LMNB2, RET, SOD3 and ADGRE1, GNAS, LMNB2, PLXDC2, PROK1 and NTRK2, PTX3, GDF15, RET, ADGRG2 and HMCN2, PTX3, GDF15, PLXDC2, THBS4 and ITM2A, PTX3, GDF15, PLXDC2, ADGRE5 and THBS4, CRTAC1, SPP1, TCL1A, SOD3 and ADGRG2, GNAS, LMNB2, PLXDC2, PROK1 and COMP, PTX3, COMP, HMCN2, POF1B and PGA4, GSN, TMPRSS15, PGA4, PTX3 and POF1B, TMPRSS15, PTX3, SPP1, SOD3 and PGA4, ADGRE1, GDF15, PTX3, THBS4 and GRK5, NOTCH1, COMP, GDF15, PTX3 and C9, SPP1, FCRL1, SOD3, ADGRE5 and ITIH3, ADGRE2, SOD3, SPP1, LMNB2 and COMP, SPP1, PLXDC2, SOD3, IL4R and TCL1A, SPP1, LMNB2, FCRL1, SOD3 and BAG3, GNAS, LMNB2, PLXDC2, PROK1 and CNTN5, AREG, CEACAM5, PTX3, CD48 and LBP, TMPRSS15, SPP1, COMP, TNFRSF10B and PROK1, PTX3, GDF15, THBS4, ADGRE5 and RET, GNAS, LMNB2, PLXDC2, PROK1 and ESM1, SPP1, LMNB2, FCRL1, SOD3 and ADGRG2, SPP1, FCRL1, SOD3, ADGRE5 and ADGRG2, PTX3, GDF15, COMP, POF1B and ADGRE1,PTX3, GDF15, COMP, POF1B and HMCN2, TMPRSS15, PTX3, GDF15, THBS4 and TNC, PTX3, GDF15, COMP, EXTL1 and PGA4, TMPRSS15, PTX3, GDF15, THBS4 and PCDH7, ADGRE1, GDF15, PTX3, THBS4 and BAG3, GNAS, LMNB2, PLXDC2, PROK1 and TMPRSS15, PTX3, ITGA11, POF1B, THBS4 and ADGRE1, SPP1, COMP, LMNB2, SOD3 and TNC, ADGRE1, GDF15, PTX3, THBS4 and ITGB7, PTX3, ITGA11, POF1B, THBS4 and PCDH7, TMPRSS15, SPP1, COMP, FCRL1 and ENPP6, TMPRSS15, COMP, PTX3, PGA4 and CLEC3B, TMPRSS15, SPP1, COMP, FCRL1 and LPL, PTX3, GDF15, ADGRG2, ADGRE5 and THBS4, COMP, LMNB2, FCRL1, MMP12 and SPP1, CRTAC1, SPP1, TCL1A, SOD3 and NT5C1A, SPP1, FCRL1, SOD3, ADGRE5 and PLXDC1, PTX3, GDF15, COMP, RET and PLXDC2, TMPRSS15, PTX3, GDF15, THBS4 and MMP12, GNAS, LMNB2, PLXDC2, PROK1 and NT5C1A, PTX3, SPP1, ENPP6, COMP and TMPRSS15, SPP1, FCRL1, SOD3, ADGRE5 and CEACAM16, TMPRSS15, PTX3, GDF15, THBS4 and PLXDC1, TMPRSS15, SPP1, COMP, FCRL1 and PLXDC1, PTX3, GDF15, COMP, ADGRG2 and FCRL1, PTX3, SPP1, ENPP6, COMP and ADGRE5, TMPRSS15, SPP1, SOD3, MMP12 and CEACAM16, SPP1, LMNB2, FCRL1, SOD3 and AGR3, PTX3, GDF15, PLXDC2, THBS4 and ADGRE1, PTX3, POF1B, THBS4, EXTL1 and ADGRE1, TMPRSS15, PTX3, GDF15, THBS4 and ADGRE5, SPP1, COMP, LMNB2, FCRL1 and GCG, TMPRSS15, SPP1, COMP, FCRL1 and CKAP4,PTX3, GDF15, PLXDC2, THBS4 and TNC, PTX3, GDF15, THBS4, FCRL1 and ADGRE5, SPP1, ENPP6, FCRL1, ADGRE5 and PLXDC1, TMPRSS15, PTX3, GDF15, THBS4 and ITM2A, SPP1, COMP, FCRL1, DLK1 and LPL, SPP1, FCRL1, SOD3, ADGRE5 and CDH23, PTX3, SPP1, COMP, CNTN4 and TCL1A, GNAS, LMNB2, PLXDC2, PROK1 and IGFBP1, ADGRE1, GDF15, PTX3, THBS4 and NPY, ADGRE1, GDF15, PTX3, THBS4 and HMCN2, PTX3, GDF15, POF1B, THBS4 and NPY, PTX3, GDF15, THBS4, ADGRE5 and ITM2A, PTX3, GDF15, THBS4, ADGRE5 and TCL1A, PTX3, GDF15, THBS4, ADGRG2 and FASLG, NOTCH1, COMP, GDF15, PTX3 and ADGRE2, ADGRE1, GDF15, PTX3, THBS4 and EDA2R, PTX3, GDF15, COMP, ADGRG2 and TCL1A, SPP1, LMNB2, FCRL1, SOD3 and GCG, TMPRSS15, SPP1, COMP, FCRL1 and PTX3, PTX3, GDF15, ADGRG2, ADGRE5 and BMP4, TMPRSS15, SPP1, FCRL1, SOD3 and ITIH3, SPP1, COMP, LMNB2, FCRL1 and IFNL1, PTX3, SPP1, ENPP6, COMP and TCL1A, TMPRSS15, SPP1, FCRL1, SOD3 and LMNB2, PTX3, HMCN2, POF1B, FASLG and ADGRE2, TMPRSS15, SPP1, COMP, FCRL1 and NT5C1A, ADGRE1, GDF15, PTX3, THBS4 and CD48, GNAS, LMNB2, PLXDC2, PROK1 and FGF21, SPP1, PLXDC2, COMP, IL4R and PROK1, TMPRSS15, PTX3, THBS4, FASLG and MMP12, PTX3, POF1B, THBS4, FASLG and IL4R, SPP1, HMCN2, FCRL1, SOD3 and PLXDC1, TMPRSS15, COMP, PTX3, PGA4 and ENPP6,TMPRSS15, THBS4, CLEC3B, TNFRSF10B and TNC, PTX3, GDF15, PLXDC2, THBS4 and PROK1, SPP1, COMP, LMNB2, FCRL1 and AREG, ADGRE1, GDF15, PTX3, THBS4 and NOS2, SPP1, COMP, LMNB2, FCRL1 and ENPP6, SPP1, LMNB2, SOD3, ADGRE5 and PROK1, ADGRE1, GDF15, PTX3, THBS4 and CEACAM16, ADGRE1, GDF15, PTX3, THBS4 and GCG, PTX3, ITGA11, POF1B, THBS4 and TCL1A, PTX3, GDF15, ADGRG2, ADGRE5 and TCL1A, ADGRE1, GDF15, PTX3, THBS4 and RET, SPP1, ENPP6, FCRL1, ADGRE5 and ITGA11, AREG, CEACAM5, PTX3, CD48 and MMP12, COMP, LMNB2, FCRL1, MMP12 and TMPRSS15, PTX3, KRT19, FASLG, ADGRG2 and ITM2A, ADGRE1, GDF15, PTX3, THBS4 and PGA4, SPP1, COMP, LMNB2, FCRL1 and ADGRG2, TMPRSS15, SPP1, FCRL1, SOD3 and FGF21, ADGRE1, GDF15, PTX3, THBS4 and PTPRS, ADGRE1, GDF15, PTX3, THBS4 and C9, TMPRSS15, COMP, PTX3, PGA4 and CEACAM5, PTX3, GDF15, COMP, RET and PGA4, PTX3, GDF15, THBS4, ADGRG2 and PROK1, ADGRE1, GDF15, PTX3, THBS4 and IGSF3, SPP1, FCRL1, SOD3, ADGRE5 and PTPRS, ADGRE1, GDF15, PTX3, THBS4 and KRT19, SPP1, COMP, FCRL1, SOD3 and PROK1, GNAS, LMNB2, PLXDC2, PROK1 and AREG, TMPRSS15, SPP1, SOD3, MMP12 and PLXDC1, TMPRSS15, SPP1, FCRL1, SOD3 and NT5C1A, PTX3, GDF15, COMP, ADGRG2 and ADGRE1, TMPRSS15, SPP1, SOD3, MMP12 and PGA4, ADGRE1, GDF15, PTX3, THBS4 and FAP,SPP1, COMP, LMNB2, FCRL1 and ADGRE2, SPP1, COMP, LMNB2, FCRL1 and ASAH2, SPP1, FCRL1, SOD3, ADGRE5 and C9, TMPRSS15, PTX3, SPP1, THBS4 and AREG, PTX3, GDF15, POF1B, THBS4 and PCDH7, SPP1, PLXDC2, COMP, LMNB2 and BAG3, PTX3, GDF15, RET, ADGRG2 and ITM2A, GNAS, LMNB2, PLXDC2, PROK1 and SPP1, COMP, FCRL1, GDF15, NOTCH1 and PTX3, TMPRSS15, COMP, PTX3, PGA4 and IL4R, PTX3, GDF15, POF1B, THBS4 and FASLG, PTX3, GDF15, ADGRG2, ADGRE5 and ADGRE1, SPP1, COMP, LMNB2, FCRL1 and DLK1, SPP1, FCRL1, SOD3, ADGRE5 and THBS4, PTX3, POF1B, THBS4, FASLG and CDH23, PTX3, GDF15, PLXDC2, THBS4 and BAG3, SPP1, ITGA11, FCRL1, SOD3 and TCL1A, ADGRE2, SOD3, SPP1, LMNB2 and CRTAC1, ADGRE1, GDF15, PTX3, THBS4 and ITGA11, GNAS, LMNB2, PLXDC2, PROK1 and BAG3, NOTCH1, COMP, GDF15, PTX3 and THBS4, PTX3, LMNB2, SOD3, CNTN4 and PGA4, ADGRE1, GDF15, PTX3, THBS4 and ASAH2, NOTCH1, COMP, GDF15, PTX3 and DCC, CRTAC1, NOTCH1, GDF15, SPP1 and TCL1A, TMPRSS15, SPP1, SOD3, MMP12 and FCRL1, ADGRE1, GDF15, PTX3, THBS4 and ITGAM, PTX3, GDF15, THBS4, EXTL1 and ITM2A, ADGRE1, GDF15, PTX3, THBS4 and IL6, PTX3, HMCN2, POF1B, FASLG and BMP4, PTX3, GDF15, POF1B, THBS4 and EXTL1, PTX3, SPP1, COMP, FCRL1 and POF1B, ADGRE1, GDF15, PTX3, THBS4 and NT5C1A, NOTCH1, SPP1, TNFRSF10B, COMP and PROK1,NOTCH3, ESM1, PLXDC2, LMNB2 and CEACAM5, PTX3, ITGA11, POF1B, THBS4 and RET, SPP1, COMP, LMNB2, FCRL1 and CDH23, TMPRSS15, PTX3, SPP1, THBS4 and FCRL1, PTX3, POF1B, FCRL1, SOD3 and PGA4, TMPRSS15, COMP, PTX3, PGA4 and MMP12, ADGRE1, GDF15, PTX3, THBS4 and RBFOX3, SPP1, COMP, LMNB2, FCRL1 and PLXDC1, SPP1, LMNB2, FCRL1, SOD3 and PLXDC2, SPP1, COMP, LMNB2, FCRL1 and C9, NOTCH1, COMP, GDF15, PTX3 and AGR3, SPP1, ENPP6, FCRL1, ADGRE5 and COMP, SPP1, COMP, LMNB2, FCRL1 and MEGF9, ADGRE1, GDF15, PTX3, THBS4 and CNTN4, PTX3, GDF15, RET, ADGRG2 and THBS4, PTX3, POF1B, THBS4, EXTL1 and ITM2A, PTX3, GDF15, RET, ADGRG2 and ADGRE1, SPP1, PLXDC2, FCRL1, SOD3 and GCG, TMPRSS15, SPP1, COMP, FCRL1 and AREG, SPP1, LMNB2, FCRL1, SOD3 and ITGB1, SPP1, COMP, LMNB2, SOD3 and PROK1, SPP1, COMP, LMNB2, FCRL1 and NOTCH1, PTX3, POF1B, THBS4, FASLG and BMP4, SPP1, PLXDC2, FCRL1, SOD3 and ESM1, ADGRE1, GDF15, PTX3, THBS4 and CFP, CRTAC1, SPP1, TCL1A, SOD3 and ADGRE5, SPP1, COMP, LMNB2, FCRL1 and LBP, SPP1, COMP, FCRL1, SOD3 and TCL1A, GNAS, LMNB2, PLXDC2, PROK1 and THBS4, TMPRSS15, COMP, PTX3, PGA4 and SPP1, PTX3, HMCN2, POF1B, FASLG and ITGA11, AREG, CEACAM5, SOD3, RET and FCRL1, ADGRE1, GDF15, PTX3, THBS4 and IL4R, PTX3, ITGA11, POF1B, RET and SOD3,ADGRE1, GDF15, PTX3, THBS4 and TCL1A, TMPRSS15, PTX3, GDF15, THBS4 and RET, TMPRSS15, SPP1, FCRL1, SOD3 and PGA4, DCC, CNTN4, PTX3, PGA4 and COMP, ADGRE1, GDF15, PTX3, THBS4 and CCL7, SPP1, COMP, FCRL1, ADGRE5 and LPL, SPP1, COMP, LMNB2, FCRL1 and PTPRS, ADGRE1, GDF15, PTX3, THBS4 and AREG, TMPRSS15, PTX3, GDF15, THBS4 and FGF21, ADGRE1, GDF15, PTX3, THBS4 and LMNB2, DCC, CNTN4, PTX3, PGA4 and SOD3, TMPRSS15, SPP1, FCRL1, SOD3 and LPL, SPP1, PLXDC2, COMP, LMNB2 and FCER2, DCC, COMP, SPP1, PROK1 and PLXDC2, ADGRE1, GDF15, PTX3, THBS4 and CDH23, TMPRSS15, SPP1, ITGA11, SOD3 and FCRL1, SPP1, COMP, LMNB2, FCRL1 and TCL1A, SPP1, LMNB2, FCRL1, SOD3 and ADGRE1, SPP1, THBS4, LMNB2, ADGRE5 and CLEC3B, SPP1, COMP, LMNB2, FCRL1 and TNC, NOTCH3, ESM1, PLXDC2, LMNB2 and AREG, PTX3, POF1B, THBS4, ADGRE5 and PGA4, PTX3, GDF15, COMP, THBS4 and ADGRE1, TMPRSS15, PTX3, GDF15, THBS4 and CCL7, GNAS, LMNB2, PLXDC2, PROK1 and ITGA11, SPP1, COMP, LMNB2, FCRL1 and TMPRSS15, ADGRE1, GDF15, PTX3, THBS4 and TNFRSF10B, PTX3, GDF15, THBS4, ADGRG2 and BMP4, CRTAC1, SPP1, TCL1A, SOD3 and ADGRE2, SPP1, ITGA11, FCRL1, SOD3 and LMNB2, ADGRE1, GDF15, PTX3, THBS4 and IFNL1, PTX3, GDF15, POF1B, THBS4 and ADGRE5, GNAS, LMNB2, PLXDC2, PROK1 and POF1B, DCC, COMP, SPP1, PROK1 and ADGRE5,ADGRE1, GDF15, PTX3, THBS4 and SPON2, SPP1, LMNB2, FCRL1, SOD3 and TCL1A, TMPRSS15, SPP1, FCRL1, SOD3 and COMP, ADGRE1, GDF15, PTX3, THBS4 and SOD3, PTX3, POF1B, SOD3, EXTL1 and PGA4, PTX3, POF1B, THBS4, FASLG and EXTL1, CRTAC1, SPP1, TCL1A, SOD3 and TMPRSS15, PTX3, GDF15, PLXDC2, THBS4 and POF1B, PTX3, HMCN2, POF1B, FASLG and PLXDC1, PTX3, POF1B, THBS4, FASLG and ITM2A, ADGRE1, GDF15, PTX3, THBS4 and CRTAC1, ADGRE1, GDF15, PTX3, THBS4 and PKD1, SPP1, COMP, LMNB2, FCRL1 and PLXDC2, ADGRE1, GDF15, PTX3, THBS4 and ITGA2, SPP1, THBS4, LMNB2, ADGRE5 and PROK1, SPP1, COMP, LMNB2, FCRL1 and ADGRE1, SPP1, COMP, FCRL1, ADGRE5 and LMNB2, PTX3, GDF15, PLXDC2, THBS4 and AGR3, TMPRSS15, COMP, PTX3, PGA4 and EDA2R, ADGRE1, LMNB2, THBS4, TMPRSS15 and GDF15, TMPRSS15, PTX3, GDF15, COMP and ADGRE1, TMPRSS15, SPP1, COMP, FCRL1 and PROK1, TMPRSS15, COMP, PTX3, PGA4 and CCL7, PTX3, COMP, POF1B, FCRL1 and PGA4, ADGRE1, GDF15, PTX3, THBS4 and POF1B, ADGRE1, GDF15, PTX3, THBS4 and NOTCH3, PTX3, GDF15, THBS4, FASLG and TMPRSS15, GNAS, LMNB2, PLXDC2, PROK1 and SOD3, AREG, CEACAM5, RET, LPL and PLXDC2, ADGRE1, GDF15, PTX3, THBS4 and PLXDC1, CRTAC1, SPP1, TCL1A, SOD3 and LMNB2, TMPRSS15, SPP1, COMP, FCRL1 and EDA2R, ADGRE1, GDF15, PTX3, THBS4 and LPL,TMPRSS15, PTX3, GDF15, THBS4 and PGA4, NOTCH1, COMP, GDF15, PTX3 and EXTL1, ADGRE1, GDF15, PTX3, THBS4 and GSN, ADGRE2, SOD3, SPP1, LMNB2 and FCRL1, PTX3, POF1B, THBS4, FASLG and ITGA11, ADGRE1, GDF15, PTX3, THBS4 and BMP4, ADGRE1, GDF15, PTX3, THBS4 and DCC, SPP1, COMP, FCRL1, SOD3 and CFP, PTX3, POF1B, THBS4, EXTL1 and PGA4, SPP1, FCRL1, SOD3, ADGRE5 and NT5C1A, COMP, GDF15, NOTCH1, PTX3 and TNC, SPP1, COMP, LMNB2, FCRL1 and NOS2, ADGRE2, SOD3, SPP1, LMNB2 and TCL1A, ADGRE1, GDF15, PTX3, THBS4 and PCDH7, ADGRE1, GDF15, PTX3, THBS4 and ITM2A, SPP1, LMNB2, FCRL1, SOD3 and PLXDC1, GNAS, LMNB2, PLXDC2, PROK1 and GDF15, PTX3, GDF15, RET, ADGRG2 and COMP, SPP1, COMP, LMNB2, SOD3 and ADGRE1, SPP1, FCRL1, SOD3, ADGRE5 and TCL1A, TMPRSS15, PTX3, POF1B, THBS4 and PGA4, ADGRE1, GDF15, PTX3, THBS4 and NOTCH1, SPP1, FCRL1, SOD3, ADGRE5 and ITGA11, PTX3, GDF15, THBS4, FASLG and ADGRE1, ADGRE1, GDF15, PTX3, THBS4 and ADGRE2, GNAS, LMNB2, PLXDC2, PROK1 and MEGF9, AREG, CEACAM5, RET, LPL and VSIG4, SPP1, FCRL1, SOD3, ADGRE5 and LMNB2, ADGRE1, GDF15, PTX3, THBS4 and IGFBP1, AREG, CEACAM5, PTX3, CD48 and ITIH3, SPP1, LMNB2, SOD3, ADGRE5 and PLXDC1, ADGRE1, GDF15, PTX3, THBS4 and ADGRE5, AREG, CEACAM5, RET, LPL and MEGF9, AREG, CEACAM5, PTX3, CD48 and NOTCH1NOTCH1, COMP, GDF15, PTX3 and TCL1A, ADGRE1, GDF15, PTX3, THBS4 and TNFRSF11A, SPP1, COMP, LMNB2, FCRL1 and LPL, SPP1, COMP, LMNB2, FCRL1 and PROK1, TMPRSS15, COMP, PTX3, PGA4 and KRT19, AREG, CEACAM5, RET, LPL and SELL, SPP1, COMP, LMNB2, FCRL1 and CFP, SPP1, LMNB2, FCRL1, SOD3 and MEGF9, ADGRE1, GDF15, PTX3, THBS4 and AGR3, SPP1, PLXDC2, COMP, IL4R and TCL1A, ADGRE1, GDF15, PTX3, THBS4 and PROK1, TMPRSS15, SPP1, FCRL1, SOD3 and PLXDC1, PTX3, GDF15, THBS4, CLEC3B and ADGRE1, NOTCH1, COMP, GDF15, PTX3 and PGA4, TMPRSS15, COMP, PTX3, PGA4 and GDF15, PTX3, GDF15, ENPP6, THBS4 and ADGRE1, PTX3, GDF15, THBS4, EXTL1 and ADGRE1, PTX3, GDF15, RET, ADGRG2 and BMP4, ADGRE1, GDF15, PTX3, THBS4 and TNC, ADGRE2, SOD3, SPP1, LMNB2 and PROK1, AREG, CEACAM5, PLXDC2, COMP and VSIG4, SPP1, PLXDC2, COMP, LMNB2 and TCL1A, NOTCH1, SPP1, TNFRSF10B, COMP and SERPINA1, TMPRSS15, COMP, PTX3, PGA4 and ITM2A, SPP1, PLXDC2, COMP, LMNB2 and PROK1, AREG, CEACAM5, RET, LPL and THBS4, AREG, CEACAM5, SOD3, RET and VSIG4, SPP1, COMP, LMNB2, SOD3 and TCL1A, AREG, CEACAM5, PTX3, CD48 and MEGF9, AREG, CEACAM5, RET, LPL and TCL1A, AREG, CEACAM5, PTX3, CD48 and ASAH2, TMPRSS15, PTX3, GDF15, THBS4 and ADGRE1, SPP1, COMP, FCRL1, SOD3 and LMNB2, SPP1, LMNB2, SOD3, ADGRE5 and TCL1A,AREG, CEACAM5, SOD3, RET and ADGRG2, ADGRE1, GDF15, PTX3, THBS4 and ADGRG2, SPP1, PLXDC2, SOD3, IL4R and BAG3, SPP1, COMP, LMNB2, FCRL1 and CLEC3B, TMPRSS15, COMP, PTX3, PGA4 and POF1B, AREG, CEACAM5, SOD3, RET and ADGRE2, AREG, CEACAM5, PLXDC2, COMP and ADGRE2, AREG, CEACAM5, RET, LPL and KRT19, AREG, CEACAM5, PTX3, CD48 and KRT19, AREG, CEACAM5, SOD3, RET and CCL7, AREG, CEACAM5, PTX3, CD48 and ITM2A, AREG, CEACAM5, PTX3, CD48 and CCL7, AREG, CEACAM5, PTX3, SPP1 and THBS4, AREG, CEACAM5, PTX3, SPP1 and VSIG4, or AREG, CEACAM5, PTX3, SPP1 and PLXDC2.,

[0057] Preferably, the 5 - marker combinations are: COMP, FCRL1, GDF15, NOTCH1 and PTX3; PTX3, COMP, POF1B, FASLG and LMNB2; GDF15, SPP1, PLXDC2, COMP and PROK1; SPP1, ADGRG2, FCRL1, SOD3 and BAG3; PTX3, GDF15, COMP, FASLG and TMPRSS15; PTX3, GDF15, THBS4, CLEC3B and TMPRSS15; SPP1, COMP, TNFRSF10B, ADGRE5 and SERPINA1; SPP1, COMP, FCRL1, IL4R and LPL; ADGRE1, KRT19, LMNB2, COMP and PTX3; SPP1, COMP, LMNB2, FASLG and FCRL1; PTX3, POF1B, THBS4, ADGRE5 and SPP1; ITGA11, LMNB2, RET, SOD3 and ADGRE1; PTX3, COMP, HMCN2, POF1B and PGA4; GSN, TMPRSS15, PGA4, PTX3 and POF1B; PTX3, GDF15, COMP, EXTL1 and PGA4; PTX3, GDF15, COMP, RET and PLXDC2; SPP1, COMP, FCRL1, DLK1 and LPL; PTX3, GDF15, THBS4, ADGRE5 and TCL1A; PTX3, SPP1, ENPP6, COMP and TCL1A; TMPRSS15, PTX3, THBS4, FASLG and MMP12; SPP1, HMCN2, FCRL1, SOD3 and PLXDC1; TMPRSS15, THBS4, CLEC3B, TNFRSF10B and TNC; PTX3, ITGA11, POF1B, THBS4 and TCL1A; COMP, LMNB2, FCRL1, MMP12 and TMPRSS15; PTX3, KRT19, FASLG, ADGRG2 and ITM2A; PTX3, GDF15, THBS4, ADGRG2 and PROK1; PTX3, GDF15, COMP, ADGRG2 and ADGRE1; TMPRSS15, SPP1, SOD3, MMP12 and PGA4; PTX3, LMNB2, SOD3, CNTN4 and PGA4; CRTAC1, NOTCH1, GDF15, SPP1 and TCL1A; PTX3, GDF15, THBS4, EXTL1 and ITM2A; PTX3, SPP1, COMP, FCRL1 and POF1B; PTX3, POF1B, FCRL1, SOD3 and PGA4,PTX3, ITGA11, POF1B, RET and SOD3, PTX3, GDF15, COMP, THBS4 and ADGRE1, SPP1, ITGA11, FCRL1, SOD3 and LMNB2, DCC, COMP, SPP1, PROK1 and ADGRE5, SPP1, THBS4, LMNB2, ADGRE5 and PROK1, SPP1, COMP, FCRL1, ADGRE5 and LMNB2, PTX3, GDF15, PLXDC2, THBS4 and AGR3, ADGRE1, LMNB2, THBS4, TMPRSS15 and GDF15, PTX3, COMP, POF1B, FCRL1 and PGA4, CRTAC1, SPP1, TCL1A, SOD3 and LMNB2, PTX3, POF1B, THBS4, EXTL1 and PGA4, TMPRSS15, PTX3, POF1B, THBS4 and PGA4, SPP1, LMNB2, FCRL1, SOD3 and MEGF9, TMPRSS15, SPP1, FCRL1, SOD3 and PLXDC1, NOTCH1, COMP, GDF15, PTX3 and PGA4, PTX3, GDF15, ENPP6, THBS4 and ADGRE1, PTX3, GDF15, RET, ADGRG2 and BMP4, SPP1, PLXDC2, COMP, LMNB2 and PROK1, SPP1, COMP, LMNB2, SOD3 and TCL1A, TMPRSS15, PTX3, GDF15, THBS4 and ADGRE1, SPP1, LMNB2, SOD3, ADGRE5 and TCL1A, ADGRE1, GDF15, PTX3, THBS4 and ADGRG2, SPP1, PLXDC2, SOD3, IL4R and BAG3, SPP1, COMP, LMNB2, FCRL1 and CLEC3B, TMPRSS15, COMP, PTX3, PGA4 and POF1B, AREG, CEACAM5, PLXDC2, COMP and ADGRE2, AREG, CEACAM5, RET, LPL and KRT19, AREG, CEACAM5, SOD3, RET and CCL7, AREG, CEACAM5, PTX3, CD48 and CCL7, or AREG, CEACAM5, PTX3, SPP1 and PLXDC2; namely any one of the above 63 combinations of 5 markers.,

[0058] Preferably, the combination of 5 markers is any five of those in E.

[0059] Preferably, the 5 - marker combinations are: COMP, GDF15, NOTCH1, PTX3, and TMPRSS15; COMP, FCRL1, GDF15, NOTCH1, and PTX3; COMP, GDF15, NOTCH1, PTX3, and TNC; COMP, EDA2R, GDF15, NOTCH1, and PTX3; CEACAM5, COMP, GDF15, NOTCH1, and PTX3; COMP, FCRL1, GDF15, PTX3, and TMPRSS15; COMP, EDA2R, GDF15, PTX3, and TMPRSS15; COMP, GDF15, PTX3, TMPRSS15, and TNC; COMP, GDF15, NOTCH1, TMPRSS15, and TNC; COMP, EDA2R, FCRL1, PTX3, and TMPRSS15; CEACAM5, COMP, GDF15, PTX3, and TNC; AREG, CEACAM5, COMP, GDF15, and NOTCH1; COMP, EDA2R, FCRL1, TMPRSS15, and TNC; COMP, EDA2R, PTX3, TMPRSS15, and TNC; CEACAM5, GDF15, NOTCH1, PTX3, and TNC; COMP, GDF15, NOTCH1, PTX3, and SERPINA1; AREG, COMP, FCRL1, GDF15, and TMPRSS15; CEACAM5, COMP, GDF15, NOTCH1, and TNC; AREG, COMP, EDA2R, PTX3, and TMPRSS15; CEACAM5, COMP, GDF15, PTX3, and TMPRSS15; GDF15, NOTCH1, PTX3, TMPRSS15, and TNC; AREG, COMP, GDF15, NOTCH1, and PTX3; CEACAM5, GDF15, NOTCH1, TMPRSS15, and TNC; CEACAM5, COMP, GDF15, TMPRSS15, and TNC; AREG, COMP, EDA2R, FCRL1, and TMPRSS15; COMP, FCRL1, GDF15, PTX3, and TNC; AREG, CEACAM5, COMP, EDA2R, and TMPRSS15; COMP, FCRL1, GDF15, NOTCH1, and TMPRSS15; AREG, CEACAM5, COMP, GDF15, and PTX3; AREG, CEACAM5, COMP, GDF15, and TMPRSS15; COMP, EDA2R, FCRL1, GDF15, and PTX3; COMP, FCRL1, GDF15, NOTCH1, and SERPINA1COMP, EDA2R, FCRL1, SERPINA1 and TMPRSS15, COMP, EDA2R, GDF15, TMPRSS15 and TNC, COMP, FCRL1, GDF15, NOTCH1 and TNC, COMP, GDF15, PTX3, SERPINA1 and TMPRSS15, COMP, EDA2R, FCRL1, NOTCH1 and TMPRSS15, AREG, COMP, EDA2R, TMPRSS15 and TNC, COMP, EDA2R, FCRL1, NOTCH1 and PTX3, COMP, EDA2R, FCRL1, GDF15 and TMPRSS15, AREG, COMP, EDA2R, SERPINA1 and TMPRSS15, AREG, COMP, EDA2R, GDF15 and TMPRSS15, COMP, EDA2R, GDF15, NOTCH1 and SERPINA1, FCRL1, GDF15, NOTCH1, PTX3 and TMPRSS15, COMP, FCRL1, GDF15, TMPRSS15 and TNC, CEACAM5, COMP, FCRL1, GDF15 and PTX3, AREG, CEACAM5, GDF15, NOTCH1 and PTX3, AREG, COMP, GDF15, PTX3 and TMPRSS15, CEACAM5, COMP, EDA2R, PTX3 and TMPRSS15, CEACAM5, GDF15, NOTCH1, PTX3 and SERPINA1, CEACAM5, COMP, GDF15, SERPINA1 and TMPRSS15, EDA2R, FCRL1, GDF15, PTX3 and TMPRSS15, CEACAM5, COMP, GDF15, NOTCH1 and TMPRSS15, CEACAM5, COMP, EDA2R, FCRL1 and TMPRSS15, AREG, COMP, GDF15, NOTCH1 and TMPRSS15, CEACAM5, COMP, GDF15, NOTCH1 and SERPINA1, CEACAM5, COMP, EDA2R, FCRL1 and PTX3, AREG, FCRL1, GDF15, NOTCH1 and PTX3, AREG, COMP, EDA2R, NOTCH1 and TMPRSS15, AREG, COMP, GDF15, TMPRSS15 and TNC, FCRL1, GDF15, NOTCH1, PTX3 and TNC, COMP, FCRL1, GDF15, PTX3 and SERPINA1, FCRL1, GDF15, NOTCH1, PTX3 and SERPINA1,CEACAM5, GDF15, NOTCH1, PTX3 and TMPRSS15, EDA2R, GDF15, NOTCH1, PTX3 and TNC, COMP, EDA2R, FCRL1, GDF15 and NOTCH1, COMP, EDA2R, SERPINA1, TMPRSS15 and TNC, COMP, EDA2R, GDF15, SERPINA1 and TMPRSS15, FCRL1, GDF15, PTX3, TMPRSS15 and TNC, COMP, GDF15, NOTCH1, SERPINA1 and TNC, AREG, COMP, FCRL1, GDF15 and NOTCH1, AREG, COMP, EDA2R, FCRL1 and PTX3, COMP, GDF15, SERPINA1, TMPRSS15 and TNC, AREG, COMP, GDF15, NOTCH1 and SERPINA1, CEACAM5, EDA2R, GDF15, NOTCH1 and PTX3, CEACAM5, COMP, EDA2R, GDF15 and PTX3, CEACAM5, COMP, EDA2R, TMPRSS15 and TNC, FCRL1, GDF15, NOTCH1, TMPRSS15 and TNC, AREG, COMP, EDA2R, GDF15 and PTX3, CEACAM5, COMP, EDA2R, FCRL1 and SERPINA1, CEACAM5, GDF15, NOTCH1, SERPINA1 and TNC, CEACAM5, COMP, FCRL1, GDF15 and TMPRSS15, CEACAM5, COMP, FCRL1, GDF15 and NOTCH1, COMP, EDA2R, FCRL1, PTX3 and TNC, COMP, GDF15, PTX3, SERPINA1 and TNC, COMP, FCRL1, GDF15, SERPINA1 and TMPRSS15, AREG, FCRL1, GDF15, NOTCH1 and TMPRSS15, CEACAM5, COMP, EDA2R, GDF15 and TMPRSS15, COMP, EDA2R, FCRL1, PTX3 and SERPINA1, AREG, COMP, FCRL1, GDF15 and PTX3, COMP, EDA2R, NOTCH1, PTX3 and TMPRSS15, COMP, EDA2R, GDF15, PTX3 and TNC, COMP, EDA2R, FCRL1, NOTCH1 and SERPINA1, AREG, EDA2R, GDF15, NOTCH1 and PTX3, CEACAM5, COMP, EDA2R, PTX3 and TNC,CEACAM5, COMP, FCRL1, GDF15 and SERPINA1, AREG, COMP, GDF15, SERPINA1 and TMPRSS15, AREG, GDF15, NOTCH1, PTX3 and TNC, CEACAM5, COMP, EDA2R, FCRL1 and TNC, GDF15, NOTCH1, PTX3, SERPINA1 and TMPRSS15, COMP, EDA2R, NOTCH1, PTX3 and SERPINA1, CEACAM5, FCRL1, GDF15, NOTCH1 and PTX3, AREG, COMP, EDA2R, FCRL1 and GDF15, COMP, EDA2R, FCRL1, GDF15 and TNC, AREG, CEACAM5, GDF15, NOTCH1 and TMPRSS15, AREG, CEACAM5, COMP, EDA2R and PTX3, FCRL1, GDF15, NOTCH1, SERPINA1 and TMPRSS15, CEACAM5, FCRL1, GDF15, PTX3 and TMPRSS15, EDA2R, GDF15, NOTCH1, PTX3 and TMPRSS15, CEACAM5, COMP, FCRL1, GDF15 and TNC, COMP, GDF15, NOTCH1, SERPINA1 and TMPRSS15, COMP, EDA2R, NOTCH1, TMPRSS15 and TNC, CEACAM5, COMP, GDF15, SERPINA1 and TNC, EDA2R, GDF15, NOTCH1, TMPRSS15 and TNC, AREG, COMP, GDF15, NOTCH1 and TNC, COMP, EDA2R, FCRL1, SERPINA1 and TNC, AREG, COMP, EDA2R, FCRL1 and NOTCH1, COMP, EDA2R, NOTCH1, PTX3 and TNC, AREG, CEACAM5, COMP, EDA2R and FCRL1, COMP, FCRL1, PTX3, TMPRSS15 and TNC, GDF15, NOTCH1, PTX3, SERPINA1 and TNC, AREG, GDF15, NOTCH1, TMPRSS15 and TNC, CEACAM5, FCRL1, GDF15, NOTCH1 and TNC, CEACAM5, FCRL1, GDF15, NOTCH1 and TMPRSS15, FCRL1, GDF15, NOTCH1, SERPINA1 and TNC, AREG, COMP, FCRL1, GDF15 and SERPINA1,CEACAM5, COMP, EDA2R, NOTCH1 and PTX3, AREG, COMP, FCRL1, GDF15 and TNC, CEACAM5, COMP, EDA2R, GDF15 and TNC, COMP, EDA2R, GDF15, NOTCH1 and TMPRSS15, AREG, EDA2R, FCRL1, PTX3 and TMPRSS15, AREG, COMP, EDA2R, NOTCH1 and PTX3, AREG, GDF15, NOTCH1, PTX3 and SERPINA1, AREG, CEACAM5, COMP, GDF15 and TNC, AREG, CEACAM5, COMP, PTX3 and TMPRSS15, COMP, EDA2R, FCRL1, GDF15 and SERPINA1, CEACAM5, COMP, EDA2R, GDF15 and NOTCH1, CEACAM5, EDA2R, GDF15, TMPRSS15 and TNC, COMP, EDA2R, GDF15, PTX3 and SERPINA1, AREG, COMP, EDA2R, FCRL1 and SERPINA1, CEACAM5, FCRL1, GDF15, TMPRSS15 and TNC, AREG, FCRL1, GDF15, TMPRSS15 and TNC, AREG, CEACAM5, COMP, EDA2R and GDF15, AREG, CEACAM5, COMP, FCRL1 and GDF15, EDA2R, FCRL1, GDF15, TMPRSS15 and TNC, COMP, EDA2R, GDF15, NOTCH1 and TNC, EDA2R, GDF15, NOTCH1, PTX3 and SERPINA1, CEACAM5, EDA2R, FCRL1, TMPRSS15 and TNC, COMP, EDA2R, PTX3, SERPINA1 and TMPRSS15, AREG, CEACAM5, COMP, GDF15 and SERPINA1, EDA2R, FCRL1, GDF15, NOTCH1 and TMPRSS15, AREG, GDF15, NOTCH1, PTX3 and TMPRSS15, COMP, FCRL1, GDF15, SERPINA1 and TNC, EDA2R, FCRL1, GDF15, NOTCH1 and PTX3, CEACAM5, COMP, FCRL1, PTX3 and TMPRSS15, AREG, COMP, EDA2R, FCRL1 and TNC, AREG, CEACAM5, COMP, TMPRSS15 and TNC, AREG, CEACAM5, GDF15, NOTCH1 and SERPINA1CEACAM5, COMP, PTX3, TMPRSS15 and TNC, FCRL1, GDF15, PTX3, SERPINA1 and TMPRSS15, CEACAM5, COMP, EDA2R, FCRL1 and GDF15, EDA2R, FCRL1, NOTCH1, TMPRSS15 and TNC, CEACAM5, COMP, EDA2R, SERPINA1 and TNC, AREG, CEACAM5, EDA2R, TMPRSS15 and TNC, EDA2R, GDF15, PTX3, TMPRSS15 and TNC, AREG, COMP, GDF15, PTX3 and TNC, CEACAM5, EDA2R, FCRL1, GDF15 and TMPRSS15, AREG, CEACAM5, EDA2R, PTX3 and TMPRSS15, GDF15, NOTCH1, SERPINA1, TMPRSS15 and TNC, AREG, GDF15, PTX3, TMPRSS15 and TNC, AREG, EDA2R, GDF15, NOTCH1 and TMPRSS15, CEACAM5, FCRL1, GDF15, NOTCH1 and SERPINA1, CEACAM5, COMP, EDA2R, NOTCH1 and SERPINA1, CEACAM5, COMP, EDA2R, PTX3 and SERPINA1, AREG, EDA2R, GDF15, PTX3 and TMPRSS15, AREG, EDA2R, FCRL1, TMPRSS15 and TNC, COMP, EDA2R, NOTCH1, SERPINA1 and TMPRSS15, EDA2R, FCRL1, SERPINA1, TMPRSS15 and TNC, AREG, GDF15, NOTCH1, SERPINA1 and TMPRSS15, CEACAM5, EDA2R, NOTCH1, TMPRSS15 and TNC, AREG, CEACAM5, EDA2R, FCRL1 and TMPRSS15, CEACAM5, COMP, GDF15, PTX3 and SERPINA1, AREG, COMP, EDA2R, PTX3 and TNC, AREG, COMP, EDA2R, GDF15 and NOTCH1, AREG, EDA2R, NOTCH1, TMPRSS15 and TNC, AREG, EDA2R, FCRL1, NOTCH1 and TMPRSS15, EDA2R, FCRL1, NOTCH1, PTX3 and TMPRSS15, EDA2R, GDF15, NOTCH1, SERPINA1 and TMPRSS15,CEACAM5, EDA2R, FCRL1, PTX3 and TMPRSS15, AREG, COMP, GDF15, PTX3 and SERPINA1, CEACAM5, EDA2R, PTX3, TMPRSS15 and TNC, CEACAM5, COMP, EDA2R, SERPINA1 and TMPRSS15, AREG, COMP, FCRL1, PTX3 and TMPRSS15, AREG, FCRL1, GDF15, PTX3 and TMPRSS15, CEACAM5, EDA2R, GDF15, NOTCH1 and TNC, CEACAM5, COMP, FCRL1, TMPRSS15 and TNC, AREG, EDA2R, NOTCH1, SERPINA1 and TMPRSS15, CEACAM5, COMP, EDA2R, FCRL1 and NOTCH1, CEACAM5, COMP, SERPINA1, TMPRSS15 and TNC, AREG, CEACAM5, GDF15, TMPRSS15 and TNC, CEACAM5, EDA2R, GDF15, NOTCH1 and TMPRSS15, AREG, CEACAM5, FCRL1, GDF15 and NOTCH1, AREG, EDA2R, GDF15, NOTCH1 and SERPINA1, AREG, FCRL1, GDF15, NOTCH1 and SERPINA1, CEACAM5, GDF15, PTX3, TMPRSS15 and TNC, AREG, EDA2R, FCRL1, GDF15 and TMPRSS15, AREG, EDA2R, NOTCH1, PTX3 and TMPRSS15, AREG, COMP, EDA2R, PTX3 and SERPINA1, AREG, COMP, PTX3, TMPRSS15 and TNC, CEACAM5, EDA2R, GDF15, PTX3 and TMPRSS15, CEACAM5, GDF15, NOTCH1, SERPINA1 and TMPRSS15, CEACAM5, GDF15, SERPINA1, TMPRSS15 and TNC, AREG, CEACAM5, GDF15, NOTCH1 and TNC, CEACAM5, EDA2R, GDF15, NOTCH1 and SERPINA1, AREG, FCRL1, GDF15, NOTCH1 and TNC, AREG, CEACAM5, EDA2R, NOTCH1 and TMPRSS15, AREG, EDA2R, FCRL1, SERPINA1 and TMPRSS15, AREG, EDA2R, PTX3, TMPRSS15 and TNC,AREG, EDA2R, GDF15, TMPRSS15 and TNC, AREG, CEACAM5, EDA2R, GDF15 and TMPRSS15, AREG, COMP, FCRL1, TMPRSS15 and TNC, EDA2R, GDF15, PTX3, SERPINA1 and TMPRSS15, AREG, CEACAM5, COMP, NOTCH1 and PTX3, CEACAM5, COMP, EDA2R, GDF15 and SERPINA1, EDA2R, FCRL1, GDF15, SERPINA1 and TMPRSS15, AREG, CEACAM5, EDA2R, GDF15 and NOTCH1, CEACAM5, COMP, FCRL1, PTX3 and TNC, EDA2R, FCRL1, PTX3, SERPINA1 and TMPRSS15, EDA2R, FCRL1, GDF15, NOTCH1 and SERPINA1, AREG, CEACAM5, COMP, SERPINA1 and TMPRSS15, CEACAM5, COMP, EDA2R, NOTCH1 and TNC, AREG, CEACAM5, COMP, FCRL1 and TMPRSS15, GDF15, PTX3, SERPINA1, TMPRSS15 and TNC, CEACAM5, COMP, FCRL1, SERPINA1 and TMPRSS15, CEACAM5, EDA2R, NOTCH1, PTX3 and TNC, EDA2R, FCRL1, PTX3, TMPRSS15 and TNC, AREG, CEACAM5, COMP, EDA2R and NOTCH1, FCRL1, GDF15, SERPINA1, TMPRSS15 and TNC, AREG, CEACAM5, COMP, EDA2R and TNC, AREG, CEACAM5, FCRL1, TMPRSS15 and TNC, CEACAM5, EDA2R, FCRL1, NOTCH1 and TMPRSS15, AREG, COMP, GDF15, SERPINA1 and TNC, CEACAM5, EDA2R, SERPINA1, TMPRSS15 and TNC, AREG, CEACAM5, COMP, EDA2R and SERPINA1, CEACAM5, EDA2R, NOTCH1, SERPINA1 and TMPRSS15, AREG, COMP, EDA2R, GDF15 and TNC, AREG, CEACAM5, GDF15, PTX3 and TMPRSS15, COMP, EDA2R, FCRL1, NOTCH1 and TNC,COMP, EDA2R, NOTCH1, SERPINA1 and TNC, CEACAM5, EDA2R, NOTCH1, PTX3 and TMPRSS15, AREG, CEACAM5, NOTCH1, TMPRSS15 and TNC, EDA2R, NOTCH1, PTX3, SERPINA1 and TMPRSS15, AREG, COMP, EDA2R, GDF15 and SERPINA1, AREG, CEACAM5, COMP, PTX3 and TNC, AREG, GDF15, PTX3, SERPINA1 and TMPRSS15, AREG, CEACAM5, FCRL1, GDF15 and TMPRSS15, CEACAM5, COMP, EDA2R, NOTCH1 and TMPRSS15, COMP, NOTCH1, PTX3, TMPRSS15 and TNC, CEACAM5, COMP, NOTCH1, PTX3 and TNC, COMP, FCRL1, PTX3, SERPINA1 and TMPRSS15, COMP, EDA2R, PTX3, SERPINA1 and TNC, EDA2R, FCRL1, NOTCH1, SERPINA1 and TMPRSS15, AREG, CEACAM5, COMP, FCRL1 and PTX3, AREG, CEACAM5, COMP, NOTCH1 and TMPRSS15, EDA2R, NOTCH1, PTX3, TMPRSS15 and TNC, AREG, COMP, EDA2R, NOTCH1 and SERPINA1, CEACAM5, FCRL1, GDF15, SERPINA1 and TMPRSS15, EDA2R, FCRL1, GDF15, NOTCH1 and TNC, COMP, FCRL1, SERPINA1, TMPRSS15 and TNC, AREG, GDF15, NOTCH1, SERPINA1 and TNC, EDA2R, NOTCH1, SERPINA1, TMPRSS15 and TNC, CEACAM5, GDF15, PTX3, SERPINA1 and TMPRSS15, CEACAM5, EDA2R, FCRL1, SERPINA1 and TMPRSS15, AREG, CEACAM5, COMP, FCRL1 and TNC, AREG, CEACAM5, EDA2R, SERPINA1 and TMPRSS15, EDA2R, GDF15, SERPINA1, TMPRSS15 and TNC, EDA2R, GDF15, NOTCH1, SERPINA1 and TNC, CEACAM5, NOTCH1, PTX3, TMPRSS15 and TNCAREG, CEACAM5, PTX3, TMPRSS15 and TNC, AREG, EDA2R, FCRL1, GDF15 and NOTCH1, EDA2R, PTX3, SERPINA1, TMPRSS15 and TNC, AREG, COMP, NOTCH1, PTX3 and TMPRSS15, COMP, EDA2R, GDF15, SERPINA1 and TNC, EDA2R, FCRL1, NOTCH1, PTX3 and TNC, CEACAM5, COMP, PTX3, SERPINA1 and TNC, COMP, FCRL1, NOTCH1, PTX3 and TMPRSS15, CEACAM5, EDA2R, NOTCH1, PTX3 and SERPINA1, CEACAM5, NOTCH1, SERPINA1, TMPRSS15 and TNC, AREG, CEACAM5, EDA2R, NOTCH1 and PTX3, AREG, COMP, EDA2R, NOTCH1 and TNC, AREG, GDF15, SERPINA1, TMPRSS15 and TNC, AREG, FCRL1, GDF15, SERPINA1 and TMPRSS15, AREG, EDA2R, SERPINA1, TMPRSS15 and TNC, CEACAM5, EDA2R, FCRL1, GDF15 and NOTCH1, AREG, EDA2R, FCRL1, NOTCH1 and PTX3, AREG, CEACAM5, COMP, NOTCH1 and TNC, CEACAM5, FCRL1, PTX3, TMPRSS15 and TNC, CEACAM5, EDA2R, FCRL1, NOTCH1 and SERPINA1, CEACAM5, EDA2R, GDF15, SERPINA1 and TMPRSS15, CEACAM5, COMP, PTX3, SERPINA1 and TMPRSS15, AREG, FCRL1, PTX3, TMPRSS15 and TNC, AREG, COMP, FCRL1, PTX3 and TNC, CEACAM5, COMP, NOTCH1, PTX3 and TMPRSS15, CEACAM5, EDA2R, FCRL1, NOTCH1 and PTX3, AREG, EDA2R, GDF15, SERPINA1 and TMPRSS15, CEACAM5, COMP, NOTCH1, SERPINA1 and TNC, AREG, NOTCH1, PTX3, TMPRSS15 and TNC, AREG, COMP, FCRL1, NOTCH1 and TMPRSS15, CEACAM5, COMP, FCRL1, NOTCH1 and TMPRSS15,CEACAM5, FCRL1, NOTCH1, TMPRSS15 and TNC, AREG, COMP, SERPINA1, TMPRSS15 and TNC, COMP, FCRL1, NOTCH1, PTX3 and TNC, CEACAM5, FCRL1, NOTCH1, PTX3 and TMPRSS15, COMP, FCRL1, NOTCH1, TMPRSS15 and TNC, AREG, COMP, FCRL1, NOTCH1 and PTX3, AREG, FCRL1, NOTCH1, PTX3 and TMPRSS15, CEACAM5, COMP, FCRL1, NOTCH1 and PTX3, CEACAM5, COMP, FCRL1, PTX3 and SERPINA1, CEACAM5, COMP, FCRL1, SERPINA1 and TNC, AREG, CEACAM5, FCRL1, PTX3 and TMPRSS15, AREG, CEACAM5, SERPINA1, TMPRSS15 and TNC, AREG, COMP, FCRL1, PTX3 and SERPINA1, AREG, COMP, FCRL1, SERPINA1 and TMPRSS15, COMP, PTX3, SERPINA1, TMPRSS15 and TNC, AREG, CEACAM5, COMP, NOTCH1 and SERPINA1, CEACAM5, EDA2R, PTX3, SERPINA1 and TMPRSS15, AREG, EDA2R, PTX3, SERPINA1 and TMPRSS15, AREG, CEACAM5, EDA2R, NOTCH1 and SERPINA1, CEACAM5, COMP, FCRL1, NOTCH1 and TNC, AREG, CEACAM5, COMP, FCRL1 and SERPINA1, AREG, CEACAM5, COMP, FCRL1 and NOTCH1, AREG, EDA2R, GDF15, NOTCH1 and TNC, FCRL1, NOTCH1, PTX3, TMPRSS15 and TNC, CEACAM5, EDA2R, FCRL1, NOTCH1 and TNC, AREG, CEACAM5, PTX3, SERPINA1 and TMPRSS15, AREG, CEACAM5, COMP, PTX3 and SERPINA1, CEACAM5, COMP, NOTCH1, PTX3 and SERPINA1, AREG, CEACAM5, NOTCH1, PTX3 and TMPRSS15, CEACAM5, PTX3, SERPINA1, TMPRSS15 and TNC, AREG, EDA2R, NOTCH1, PTX3 and TNCEDA2R, FCRL1, NOTCH1, PTX3 and SERPINA1, AREG, CEACAM5, NOTCH1, PTX3 and SERPINA1, AREG, CEACAM5, FCRL1, NOTCH1 and TMPRSS15, FCRL1, NOTCH1, PTX3, SERPINA1 and TMPRSS15, AREG, CEACAM5, NOTCH1, SERPINA1 and TMPRSS15, FCRL1, PTX3, SERPINA1, TMPRSS15 and TNC, AREG, COMP, EDA2R, SERPINA1 and TNC, AREG, CEACAM5, GDF15, SERPINA1 and TMPRSS15, AREG, FCRL1, NOTCH1, TMPRSS15 and TNC, CEACAM5, NOTCH1, PTX3, SERPINA1 and TMPRSS15, COMP, FCRL1, PTX3, SERPINA1 and TNC, CEACAM5, COMP, NOTCH1, TMPRSS15 and TNC, CEACAM5, COMP, NOTCH1, SERPINA1 and TMPRSS15, AREG, CEACAM5, NOTCH1, PTX3 and TNC, CEACAM5, EDA2R, NOTCH1, SERPINA1 and TNC, AREG, CEACAM5, FCRL1, GDF15 and PTX3, CEACAM5, COMP, FCRL1, NOTCH1 and SERPINA1, CEACAM5, FCRL1, SERPINA1, TMPRSS15 and TNC, AREG, EDA2R, NOTCH1, PTX3 and SERPINA1, CEACAM5, FCRL1, PTX3, SERPINA1 and TMPRSS15, AREG, FCRL1, GDF15, PTX3 and TNC, AREG, COMP, NOTCH1, PTX3 and TNC, CEACAM5, FCRL1, NOTCH1, SERPINA1 and TMPRSS15, FCRL1, NOTCH1, SERPINA1, TMPRSS15 and TNC, AREG, COMP, PTX3, SERPINA1 and TMPRSS15, COMP, FCRL1, NOTCH1, PTX3 and SERPINA1, AREG, EDA2R, FCRL1, GDF15 and PTX3, AREG, FCRL1, SERPINA1, TMPRSS15 and TNC, AREG, CEACAM5, FCRL1, NOTCH1 and PTX3, CEACAM5, NOTCH1, PTX3, SERPINA1 and TNC,AREG, EDA2R, FCRL1, NOTCH1 and SERPINA1, NOTCH1, PTX3, SERPINA1, TMPRSS15 and TNC, AREG, CEACAM5, EDA2R, NOTCH1 and TNC, EDA2R, FCRL1, GDF15, PTX3 and TNC, CEACAM5, EDA2R, FCRL1, GDF15 and PTX3, CEACAM5, FCRL1, GDF15, PTX3 and TNC, COMP, NOTCH1, PTX3, SERPINA1 and TMPRSS15, AREG, CEACAM5, EDA2R, FCRL1 and NOTCH1, AREG, NOTCH1, PTX3, SERPINA1 and TMPRSS15, AREG, FCRL1, PTX3, SERPINA1 and TMPRSS15, AREG, CEACAM5, EDA2R, GDF15 and PTX3, AREG, COMP, NOTCH1, TMPRSS15 and TNC, AREG, PTX3, SERPINA1, TMPRSS15 and TNC, AREG, CEACAM5, FCRL1, SERPINA1 and TMPRSS15, AREG, NOTCH1, SERPINA1, TMPRSS15 and TNC, COMP, FCRL1, NOTCH1, SERPINA1 and TNC, AREG, CEACAM5, COMP, SERPINA1 and TNC, FCRL1, GDF15, PTX3, SERPINA1 and TNC, CEACAM5, EDA2R, GDF15, PTX3 and TNC, AREG, CEACAM5, NOTCH1, SERPINA1 and TNC, COMP, NOTCH1, PTX3, SERPINA1 and TNC, CEACAM5, GDF15, PTX3, SERPINA1 and TNC, AREG, COMP, FCRL1, NOTCH1 and TNC, EDA2R, FCRL1, GDF15, PTX3 and SERPINA1, AREG, COMP, NOTCH1, SERPINA1 and TMPRSS15, COMP, NOTCH1, SERPINA1, TMPRSS15 and TNC, EDA2R, FCRL1, NOTCH1, SERPINA1 and TNC, AREG, FCRL1, GDF15, PTX3 and SERPINA1, CEACAM5, FCRL1, NOTCH1, PTX3 and TNC, AREG, FCRL1, NOTCH1, PTX3 and TNC, AREG, EDA2R, FCRL1, PTX3 and SERPINA1,AREG, FCRL1, NOTCH1, PTX3 and SERPINA1, AREG, FCRL1, NOTCH1, SERPINA1 and TMPRSS15, CEACAM5, EDA2R, GDF15, PTX3 and SERPINA1, EDA2R, NOTCH1, PTX3, SERPINA1 and TNC, AREG, CEACAM5, EDA2R, FCRL1 and PTX3, AREG, COMP, FCRL1, NOTCH1 and SERPINA1, CEACAM5, FCRL1, GDF15, PTX3 and SERPINA1, AREG, EDA2R, FCRL1, NOTCH1 and TNC, EDA2R, FCRL1, PTX3, SERPINA1 and TNC, FCRL1, NOTCH1, PTX3, SERPINA1 and TNC, AREG, CEACAM5, GDF15, PTX3 and TNC, AREG, COMP, FCRL1, SERPINA1 and TNC, COMP, FCRL1, NOTCH1, SERPINA1 and TMPRSS15, CEACAM5, FCRL1, NOTCH1, PTX3 and SERPINA1, AREG, CEACAM5, GDF15, PTX3 and SERPINA1, AREG, COMP, NOTCH1, PTX3 and SERPINA1, AREG, CEACAM5, FCRL1, GDF15 and TNC, AREG, CEACAM5, FCRL1, NOTCH1 and TNC, AREG, EDA2R, FCRL1, PTX3 and TNC, AREG, COMP, PTX3, SERPINA1 and TNC, CEACAM5, EDA2R, FCRL1, PTX3 and TNC, CEACAM5, FCRL1, NOTCH1, SERPINA1 and TNC, AREG, COMP, NOTCH1, SERPINA1 and TNC, CEACAM5, FCRL1, PTX3, SERPINA1 and TNC, CEACAM5, EDA2R, FCRL1, PTX3 and SERPINA1, AREG, EDA2R, NOTCH1, SERPINA1 and TNC, AREG, FCRL1, NOTCH1, SERPINA1 and TNC, AREG, CEACAM5, FCRL1, NOTCH1 and SERPINA1, AREG, NOTCH1, PTX3, SERPINA1 and TNC, CEACAM5, FCRL1, GDF15, SERPINA1 and TNC, CEACAM5, EDA2R, FCRL1, GDF15 and TNC, AREG, CEACAM5, FCRL1, PTX3 and TNC,AREG, FCRL1, GDF15, SERPINA1 and TNC, AREG, EDA2R, GDF15, PTX3 and TNC, EDA2R, GDF15, PTX3, SERPINA1 and TNC, AREG, CEACAM5, EDA2R, FCRL1 and GDF15, AREG, GDF15, PTX3, SERPINA1 and TNC, AREG, EDA2R, FCRL1, GDF15 and SERPINA1, AREG, CEACAM5, FCRL1, GDF15 and SERPINA1, AREG, EDA2R, GDF15, PTX3 and SERPINA1, AREG, CEACAM5, FCRL1, PTX3 and SERPINA1, CEACAM5, EDA2R, PTX3, SERPINA1 and TNC, AREG, EDA2R, FCRL1, GDF15 and TNC, EDA2R, FCRL1, GDF15, SERPINA1 and TNC, AREG, CEACAM5, EDA2R, PTX3 and TNC, CEACAM5, EDA2R, GDF15, SERPINA1 and TNC, CEACAM5, EDA2R, FCRL1, SERPINA1 and TNC, CEACAM5, EDA2R, FCRL1, GDF15 and SERPINA1, AREG, FCRL1, PTX3, SERPINA1 and TNC, AREG, CEACAM5, EDA2R, PTX3 and SERPINA1, AREG, CEACAM5, EDA2R, GDF15 and TNC, AREG, CEACAM5, EDA2R, FCRL1 and SERPINA1, AREG, CEACAM5, EDA2R, FCRL1 and TNC, AREG, CEACAM5, GDF15, SERPINA1 and TNC, AREG, CEACAM5, EDA2R, GDF15 and SERPINA1, AREG, CEACAM5, PTX3, SERPINA1 and TNC, AREG, EDA2R, FCRL1, SERPINA1 and TNC, AREG, CEACAM5, FCRL1, SERPINA1 and TNC, AREG, CEACAM5, EDA2R, SERPINA1 and TNC, AREG, EDA2R, PTX3, SERPINA1 and TNC, or AREG, EDA2R, GDF15, SERPINA1 and TNC; further COMP, FCRL1, GDF15, NOTCH1 and PTX3.,

[0060] Preferably, A comprises a combination of 6 markers, and the combination of 6 markers is any six of B.

[0061] Preferably, the combination of 6 markers is d1) and d2):

[0062] d1) the combination of 5 markers (preferably any one of the above 63 combinations of 5 markers);

[0063] d2) any one of B;

[0064] The d2) is different from any one marker in the combination of 5 markers in d1).

[0065] Preferably, the 6 - marker combinations are: SPP1, PLXDC2, SOD3, IL4R, BAG3 and PROK1; AREG, CEACAM5, PTX3, CD48, CCL7 and IGFBP1; SPP1, PLXDC2, COMP, LMNB2, PROK1 and TCL1A; SPP1, LMNB2, FCRL1, SOD3, PLXDC2 and BAG3; SPP1, COMP, LMNB2, SOD3, TCL1A and PROK1; SPP1, LMNB2, FCRL1, SOD3, MEGF9 and PROK1; SPP1, LMNB2, SOD3, ADGRE5, TCL1A and PROK1; AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and ADAMTS8; SPP1, COMP, FCRL1, SOD3, LMNB2 and TCL1A; SPP1, LMNB2, FCRL1, SOD3, ADGRE1 and PLXDC1; SPP1, COMP, LMNB2, FCRL1, PLXDC2 and PROK1; AREG, CEACAM5, SOD3, RET, CCL7 and MMP12; TMPRSS15, PTX3, COMP, POF1B, PGA4 and ITM2A; SPP1, PLXDC2, COMP, IL4R, TCL1A and PROK1; CRTAC1, SPP1, TCL1A, SOD3, LMNB2 and ADGRE2; PTX3, GDF15, POF1B, THBS4, ADGRE1 and EXTL1; NOTCH1, COMP, GDF15, PTX3, PGA4 and CEACAM5; PTX3, POF1B, THBS4, ADGRE5, PGA4 and NPY; PTX3, LMNB2, SOD3, CNTN4, PGA4 and TCL1A; SPP1, LMNB2, FCRL1, SOD3, PLXDC1 and ITM2A; TMPRSS15, PTX3, GDF15, THBS4, ADGRE1 and IL4R; PTX3, COMP, HMCN2, POF1B, PGA4 and ADGRE1; SPP1, LMNB2, FCRL1, SOD3, ADGRE5 and C9; SPP1, PLXDC2, COMP, LMNB2, TCL1A and CLEC3B; SPP1, FCRL1, SOD3, ADGRE5, LMNB2 and CEACAM16; TMPRSS15, PTX3, GDF15, COMP, PGA4 and ITM2A; PTX3, GDF15, THBS4, CLEC3B, ADGRE1 and TNC; GDF15, SPP1, PLXDC2, COMP, PROK1 and LMNB2ADGRE1, GDF15, PTX3, THBS4, ADGRG2 and TNC, PTX3, GDF15, ENPP6, THBS4, ADGRE1 and AGR3, AREG, CEACAM5, PTX3, SPP1, PLXDC2 and SPON2, AREG, CEACAM5, RET, LPL, KRT19 and SPON2, PTX3, GDF15, RET, ADGRG2, BMP4 and ADGRE1, TMPRSS15, COMP, PTX3, PGA4, POF1B and NPY, PTX3, POF1B, FCRL1, SOD3, PGA4 and ITM2A, PTX3, POF1B, THBS4, FASLG, ITM2A and EXTL1, PTX3, POF1B, THBS4, EXTL1, PGA4 and ITM2A, SPP1, COMP, LMNB2, FCRL1, LPL and LBP, PTX3, GDF15, THBS4, EXTL1, ADGRE1 and ENPP6, SPP1, COMP, FCRL1, SOD3, CFP and LMNB2, PTX3, GDF15, THBS4, ADGRG2, ADGRE1 and IL4R, SPP1, COMP, LMNB2, FCRL1, TNC and CLEC3B, ADGRE1, KRT19, LMNB2, COMP, PTX3 and PGA4, PTX3, SPP1, ENPP6, COMP, TCL1A and ADGRE2, PTX3, GDF15, PLXDC2, THBS4, AGR3 and TNC, SPP1, ITGA11, FCRL1, SOD3, LMNB2 and PLXDC1, SPP1, COMP, LMNB2, FCRL1, PROK1 and SOD3, TMPRSS15, PTX3, GDF15, COMP, ADGRE1 and PGA4, SPP1, THBS4, LMNB2, ADGRE5, PROK1 and BAG3, SPP1, COMP, LMNB2, FCRL1, ADGRE1 and PTPRS, PTX3, ITGA11, POF1B, RET, SOD3 and PGA4, SPP1, COMP, FCRL1, ADGRE5, LPL and LMNB2, SPP1, COMP, LMNB2, FCRL1, SOD3 and CEACAM16, PTX3, GDF15, COMP, ADGRG2, ADGRE1 and THBS4, PTX3, COMP, POF1B, FCRL1, PGA4 and IL4R, PTX3, GDF15, THBS4, FASLG, TMPRSS15 and ITM2A, TMPRSS15, PTX3, POF1B, THBS4, PGA4 and CFP,PTX3, GDF15, THBS4, ADGRG2, BMP4 and PROK1, PTX3, GDF15, COMP, EXTL1, PGA4 and NOTCH1, ADGRE1, LMNB2, THBS4, TMPRSS15, GDF15 and TNC, SPP1, COMP, LMNB2, SOD3, FCRL1 and ASAH2, SPP1, COMP, FCRL1, ADGRE5, LMNB2 and TNC, SPP1, PLXDC2, COMP, LMNB2, FCRL1 and PLXDC1, SPP1, ADGRG2, FCRL1, SOD3, BAG3 and LMNB2, GSN, TMPRSS15, PGA4, PTX3, POF1B and SOD3, TMPRSS15, PTX3, THBS4, FASLG, MMP12 and ITM2A, TMPRSS15, PTX3, GDF15, THBS4, CCL7 and ADGRE1, COMP, FCRL1, PTX3, GDF15, NOTCH1 and PGA4, SPP1, THBS4, LMNB2, ADGRE5, CLEC3B and PROK1, PTX3, GDF15, THBS4, ADGRG2, PROK1 and TCL1A, SPP1, COMP, LMNB2, FCRL1, CLEC3B and BAG3, TMPRSS15, SPP1, FCRL1, SOD3, PLXDC1 and EDA2R, PTX3, GDF15, POF1B, THBS4, ADGRE5 and TNC, TMPRSS15, PTX3, THBS4, FASLG, GDF15 and AREG, SPP1, COMP, FCRL1, SOD3, TCL1A and LPL, PTX3, GDF15, THBS4, FASLG, ADGRE1 and POF1B, TMPRSS15, PTX3, GDF15, THBS4, FASLG and TNC, PTX3, GDF15, THBS4, EXTL1, ITM2A and TNC, SPP1, LMNB2, FCRL1, SOD3, COMP and TMPRSS15, SPP1, LMNB2, SOD3, ADGRE5, FCRL1 and NT5C1A, PTX3, GDF15, COMP, THBS4, ADGRE1 and ITGA2, SPP1, PLXDC2, FCRL1, SOD3, ESM1 and BAG3, TMPRSS15, PTX3, SPP1, THBS4, AREG and FASLG, SPP1, COMP, LMNB2, FASLG, FCRL1 and TCL1A, SPP1, PLXDC2, COMP, LMNB2, PROK1 and BAG3,AREG, CEACAM5, PTX3, CD48, CCL7 and IGSF3, SPP1, PLXDC2, COMP, LMNB2, PROK1 and DCC, SPP1, COMP, FCRL1, SOD3, LMNB2 and ADGRE1, AREG, CEACAM5, PTX3, CD48, CCL7 and NOTCH3, SPP1, LMNB2, FCRL1, SOD3, MEGF9 and CDH23, SPP1, COMP, LMNB2, FCRL1, PLXDC2 and ESM1, AREG, CEACAM5, PTX3, CD48, CCL7 and PLXDC2, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and EXTL1, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and EDA2R, SPP1, PLXDC2, COMP, LMNB2, PROK1 and FCER2, AREG, CEACAM5, SOD3, RET, CCL7 and ENPP6, SPP1, LMNB2, FCRL1, SOD3, AGR3 and PLXDC1, SPP1, COMP, LMNB2, SOD3, TCL1A and PLXDC2, SPP1, LMNB2, FCRL1, SOD3, ADGRE1 and TCL1A, SPP1, PLXDC2, COMP, LMNB2, PROK1 and THBS4, SPP1, PLXDC2, COMP, LMNB2, PROK1 and CCL7, SPP1, COMP, FCRL1, SOD3, LMNB2 and GCG, AREG, CEACAM5, SOD3, RET, CCL7 and EXTL1, SPP1, LMNB2, SOD3, ADGRE5, TCL1A and ADGRG2, SPP1, LMNB2, FCRL1, SOD3, MEGF9 and PLXDC1, SPP1, COMP, LMNB2, SOD3, TCL1A and ITM2A, PTX3, GDF15, POF1B, THBS4, ADGRE1 and PKD1, AREG, CEACAM5, SOD3, RET, CCL7 and ADAMTS8, TMPRSS15, PTX3, COMP, POF1B, PGA4 and ESM1, PTX3, LMNB2, SOD3, CNTN4, PGA4 and ADGRE1, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and SPON2, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and ADGRE5, PTX3, GDF15, POF1B, THBS4, ADGRE1 and CDH23SPP1, LMNB2, FCRL1, SOD3, PLXDC1 and TMPRSS15, PTX3, COMP, HMCN2, POF1B, PGA4 and PLXDC1, AREG, CEACAM5, SOD3, RET, CCL7 and GNAS, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and CLEC3B, CRTAC1, SPP1, TCL1A, SOD3, LMNB2 and ADGRE1, SPP1, COMP, LMNB2, SOD3, TCL1A and SELL, SPP1, PLXDC2, COMP, LMNB2, PROK1 and PLXDC1, AREG, CEACAM5, PTX3, CD48, CCL7 and POF1B, SPP1, COMP, LMNB2, FCRL1, PLXDC2 and TCL1A, AREG, CEACAM5, SOD3, RET, CCL7 and POF1B, PTX3, GDF15, POF1B, THBS4, ADGRE1 and TNC, SPP1, LMNB2, SOD3, ADGRE5, TCL1A and IL6, SPP1, FCRL1, SOD3, ADGRE5, LMNB2 and TCL1A, AREG, CEACAM5, PTX3, CD48, CCL7 and ITGAM, SPP1, PLXDC2, COMP, LMNB2, PROK1 and SOD3, SPP1, PLXDC2, COMP, LMNB2, PROK1 and IL4R, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and GNAS, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and PTPRS, SPP1, FCRL1, SOD3, ADGRE5, LMNB2 and PLXDC1, SPP1, COMP, FCRL1, SOD3, LMNB2 and TNC, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and ITGA2, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and SPP1, SPP1, LMNB2, FCRL1, SOD3, PLXDC1 and CNTN4, SPP1, COMP, FCRL1, SOD3, LMNB2 and C9, NOTCH1, COMP, GDF15, PTX3, PGA4 and ADGRE1, SPP1, PLXDC2, COMP, LMNB2, TCL1A and CNTN4, SPP1, COMP, FCRL1, CLEC3B, LMNB2 and TCL1A, AREG, CEACAM5, PTX3, CD48, CCL7 and ASAH2AREG, CEACAM5, SOD3, RET, CCL7 and ITGAM, AREG, CEACAM5, SOD3, RET, CCL7 and ITM2A, SPP1, FCRL1, SOD3, ADGRE5, LMNB2 and ITGA11, AREG, CEACAM5, RET, LPL, KRT19 and PTPRS, AREG, CEACAM5, SOD3, RET, CCL7 and IGSF3, SPP1, LMNB2, FCRL1, SOD3, PLXDC1 and PLXDC2, SPP1, PLXDC2, COMP, LMNB2, PROK1 and MEGF9, PTX3, POF1B, FCRL1, SOD3, PGA4 and PLXDC1, AREG, CEACAM5, PTX3, SPP1, PLXDC2 and TMPRSS15, AREG, CEACAM5, SOD3, RET, CCL7 and CFP, PTX3, POF1B, THBS4, EXTL1, PGA4 and ADGRE1, SPP1, LMNB2, FCRL1, SOD3, ITGB1 and PLXDC1, PTX3, POF1B, THBS4, ADGRE5, PGA4 and ITM2A, SPP1, COMP, LMNB2, SOD3, ADGRE1 and PROK1, TMPRSS15, PTX3, COMP, POF1B, PGA4 and CKAP4, TMPRSS15, PTX3, COMP, POF1B, PGA4 and ADGRE1, TMPRSS15, PTX3, COMP, POF1B, PGA4 and THBS4, SPP1, LMNB2, FCRL1, SOD3, ADGRE1 and BAG3, TMPRSS15, PTX3, COMP, POF1B, PGA4 and NPY, SPP1, LMNB2, SOD3, ADGRE5, PLXDC1 and PROK1, PTX3, GDF15, POF1B, THBS4, ADGRE1 and AREG, SPP1, COMP, LMNB2, SOD3, TCL1A and CEACAM16, SPP1, PLXDC2, COMP, LMNB2, PROK1 and MMP12, AREG, CEACAM5, SOD3, RET, CCL7 and DLK1, SPP1, COMP, LMNB2, SOD3, TCL1A and CNTN4, AREG, CEACAM5, PTX3, CD48, CCL7 and CDH23, SPP1, PLXDC2, COMP, LMNB2, PROK1 and ADGRE5, NOTCH1, COMP, GDF15, PTX3, PGA4 and ITM2A,PTX3, POF1B, THBS4, EXTL1, PGA4 and SOD3, SPP1, LMNB2, SOD3, ADGRE5, TCL1A and ITGA11, SPP1, COMP, FCRL1, SOD3, LMNB2 and NOS2, PTX3, GDF15, POF1B, THBS4, ADGRE1 and LMNB2, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and THBS4, PTX3, GDF15, THBS4, ADGRG2, ADGRE1 and AGR3, SPP1, PLXDC2, COMP, LMNB2, PROK1 and LPL, GDF15, SPP1, PLXDC2, COMP, PROK1 and ADAMTS8, SPP1, LMNB2, FCRL1, SOD3, ADGRE1 and CEACAM16, PTX3, GDF15, POF1B, THBS4, ADGRE1 and CFP, SPP1, COMP, LMNB2, SOD3, TCL1A and MEGF9, SPP1, PLXDC2, COMP, LMNB2, PROK1 and GNAS, SPP1, PLXDC2, COMP, LMNB2, PROK1 and AGR3, AREG, CEACAM5, SOD3, RET, CCL7 and PTPRS, TMPRSS15, PTX3, COMP, POF1B, PGA4 and IL4R, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and ESM1, SPP1, LMNB2, FCRL1, SOD3, AGR3 and PLXDC2, TMPRSS15, PTX3, COMP, POF1B, PGA4 and IGFBP1, AREG, CEACAM5, RET, LPL, KRT19 and IL4R, AREG, CEACAM5, SOD3, RET, CCL7 and IL4R, SPP1, LMNB2, FCRL1, SOD3, PLXDC1 and GCG, SPP1, COMP, FCRL1, SOD3, LMNB2 and PLXDC1, SPP1, COMP, LMNB2, FCRL1, PLXDC2 and TNC, PTX3, POF1B, THBS4, EXTL1, PGA4 and CLEC3B, SPP1, COMP, LMNB2, SOD3, ADGRE1 and TCL1A, TMPRSS15, PTX3, COMP, POF1B, PGA4 and GDF15, ADGRE1, GDF15, PTX3, THBS4, ADGRG2 and BMP4, PTX3, GDF15, THBS4, ADGRE5, ADGRE1 and TNC,PTX3, POF1B, THBS4, EXTL1, PGA4 and PCDH7, AREG, CEACAM5, PTX3, SPP1, PLXDC2 and FAP, PTX3, GDF15, THBS4, ADGRG2, ADGRE1 and BMP4, SPP1, LMNB2, SOD3, ADGRE5, PLXDC1 and AREG, PTX3, GDF15, THBS4, EXTL1, ADGRE1 and TNC, SPP1, LMNB2, FCRL1, SOD3, PLXDC1 and BAG3, AREG, CEACAM5, SOD3, RET, CCL7 and SPP1, SPP1, COMP, FCRL1, SOD3, LMNB2 and PLXDC2, SPP1, COMP, LMNB2, SOD3, TCL1A and CLEC3B, SPP1, COMP, LMNB2, SOD3, ADGRE1 and LPL, AREG, CEACAM5, PTX3, CD48, CCL7 and CLEC3B, SPP1, LMNB2, FCRL1, SOD3, PLXDC1 and CDH23, SPP1, PLXDC2, COMP, LMNB2, TCL1A and IGFBP1, PTX3, GDF15, RET, ADGRG2, BMP4 and FASLG, AREG, CEACAM5, PTX3, CD48, CCL7 and ENPP6, AREG, CEACAM5, PTX3, CD48, CCL7 and ITGB1, SPP1, COMP, LMNB2, SOD3, ADGRE1 and CFP, SPP1, PLXDC2, COMP, LMNB2, TCL1A and ADGRE5, PTX3, POF1B, FCRL1, SOD3, PGA4 and TMPRSS15, NOTCH1, COMP, GDF15, PTX3, PGA4 and FCER2, PTX3, COMP, HMCN2, POF1B, PGA4 and ITM2A, SPP1, LMNB2, FCRL1, SOD3, PLXDC1 and GNAS, PTX3, LMNB2, SOD3, CNTN4, PGA4 and RET, SPP1, COMP, LMNB2, FCRL1, LPL and PLXDC2, SPP1, PLXDC2, COMP, LMNB2, TCL1A and POF1B, AREG, CEACAM5, PTX3, SPP1, PLXDC2 and DCC, SPP1, COMP, FCRL1, SOD3, LMNB2 and FCER2, SPP1, COMP, FCRL1, SOD3, LMNB2 and SERPINA1, CRTAC1, SPP1, TCL1A, SOD3, LMNB2 and FCRL1,NOTCH1, COMP, GDF15, PTX3, PGA4 and DLK1, CRTAC1, SPP1, TCL1A, SOD3, LMNB2 and ITGB1, AREG, CEACAM5, SOD3, RET, CCL7 and THBS4, PTX3, POF1B, THBS4, ADGRE5, PGA4 and ENPP6, AREG, CEACAM5, PTX3, CD48, CCL7 and DLK1, CRTAC1, SPP1, TCL1A, SOD3, LMNB2 and COMP, SPP1, PLXDC2, COMP, LMNB2, PROK1 and POF1B, PTX3, GDF15, ENPP6, THBS4, ADGRE1 and BMP4, SPP1, LMNB2, SOD3, ADGRE5, PLXDC1 and TCL1A, SPP1, FCRL1, SOD3, ADGRE5, LMNB2 and AREG, PTX3, GDF15, POF1B, THBS4, ADGRE1 and PTPRS, SPP1, COMP, LMNB2, FCRL1, SOD3 and CDH23, TMPRSS15, PTX3, GDF15, THBS4, ADGRE1 and LMNB2, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and ANGPTL4, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and ENPP6, AREG, CEACAM5, PTX3, SPP1, PLXDC2 and CNTN4, SPP1, PLXDC2, COMP, LMNB2, PROK1 and PGA4, AREG, CEACAM5, SOD3, RET, CCL7 and ITGB1, SPP1, COMP, LMNB2, FCRL1, LPL and TCL1A, SPP1, LMNB2, SOD3, ADGRE5, TCL1A and CLEC3B, SPP1, PLXDC2, COMP, IL4R, TCL1A and DCC, AREG, CEACAM5, SOD3, RET, CCL7 and ESM1, PTX3, GDF15, COMP, ADGRG2, ADGRE1 and PGA4, SPP1, PLXDC2, COMP, LMNB2, PROK1 and NOS2, AREG, CEACAM5, SOD3, RET, CCL7 and C9, TMPRSS15, PTX3, GDF15, THBS4, ADGRE1 and PGA4, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and FCRL1, AREG, CEACAM5, SOD3, RET, CCL7 and EDA2RSPP1, LMNB2, FCRL1, SOD3, ADGRE5 and BAG3, NOTCH1, COMP, GDF15, PTX3, PGA4 and ADGRE2, AREG, CEACAM5, SOD3, RET, CCL7 and GCG, SPP1, COMP, LMNB2, SOD3, TCL1A and PLXDC1, SPP1, COMP, LMNB2, SOD3, TCL1A and ITGB1, PTX3, POF1B, THBS4, FASLG, ITM2A and PCDH7, TMPRSS15, COMP, PTX3, PGA4, POF1B and FASLG, AREG, CEACAM5, SOD3, RET, CCL7 and SPON2, SPP1, COMP, LMNB2, FCRL1, LPL and IFNL1, AREG, CEACAM5, PTX3, SPP1, PLXDC2 and ITGA2, AREG, CEACAM5, SOD3, RET, CCL7 and FAP, ADGRE1, GDF15, PTX3, THBS4, ADGRG2 and RET, SPP1, PLXDC2, COMP, LMNB2, PROK1 and TNC, SPP1, LMNB2, FCRL1, SOD3, MEGF9 and LPL, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and GRK5, AREG, CEACAM5, SOD3, RET, CCL7 and CDH23, SPP1, COMP, LMNB2, FCRL1, LPL and GSN, SPP1, PLXDC2, COMP, LMNB2, PROK1 and SERPINA1, TMPRSS15, COMP, PTX3, PGA4, POF1B and FCRL1, PTX3, POF1B, THBS4, EXTL1, PGA4 and PROK1, AREG, CEACAM5, PTX3, CD48, CCL7 and ADGRE1, AREG, CEACAM5, SOD3, RET, CCL7 and IFNL1, SPP1, PLXDC2, COMP, LMNB2, TCL1A and ADGRE1, SPP1, FCRL1, SOD3, ADGRE5, LMNB2 and CDH23, SPP1, COMP, LMNB2, SOD3, TCL1A and ADGRE5, SPP1, COMP, LMNB2, FCRL1, SOD3 and MEGF9, AREG, CEACAM5, PTX3, SPP1, PLXDC2 and C9, PTX3, GDF15, POF1B, THBS4, ADGRE1 and NPY, SPP1, PLXDC2, COMP, LMNB2, PROK1 and IGDCC4,CRTAC1, SPP1, TCL1A, SOD3, LMNB2 and PROK1, TMPRSS15, PTX3, GDF15, COMP, PGA4 and ENPP6, SPP1, COMP, LMNB2, FCRL1, LPL and CLEC3B, ADGRE1, GDF15, PTX3, THBS4, ADGRG2 and NOTCH3, SPP1, LMNB2, FCRL1, SOD3, PLXDC1 and CEACAM16, PTX3, GDF15, THBS4, CLEC3B, ADGRE1 and BMP4, TMPRSS15, PTX3, GDF15, THBS4, PGA4 and ITM2A, TMPRSS15, PTX3, GDF15, COMP, PGA4 and C9, TMPRSS15, COMP, PTX3, PGA4, POF1B and TNC, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and TNFRSF10B, PTX3, GDF15, POF1B, THBS4, ADGRE1 and ITGA11, PTX3, GDF15, THBS4, ADGRG2, ADGRE1 and TNC, AREG, CEACAM5, SOD3, RET, CCL7 and ADGRE5, PTX3, GDF15, POF1B, THBS4, ADGRE1 and LPL, SPP1, LMNB2, SOD3, ADGRE5, TCL1A and THBS4, PTX3, GDF15, POF1B, THBS4, ADGRE1 and ITM2A, PTX3, GDF15, THBS4, EXTL1, ADGRE1 and ITM2A, SPP1, FCRL1, SOD3, ADGRE5, LMNB2 and PROK1, PTX3, LMNB2, SOD3, CNTN4, PGA4 and MEGF9, SPP1, LMNB2, FCRL1, SOD3, MEGF9 and PGA4, PTX3, GDF15, THBS4, ADGRG2, ADGRE1 and TCL1A, SPP1, COMP, LMNB2, FCRL1, ADGRE1 and TCL1A, PTX3, COMP, POF1B, FCRL1, PGA4 and TMPRSS15, NOTCH1, COMP, GDF15, PTX3, PGA4 and AGR3, PTX3, GDF15, ENPP6, THBS4, ADGRE1 and AREG, SPP1, PLXDC2, COMP, LMNB2, PROK1 and PCDH7, PTX3, GDF15, POF1B, THBS4, ADGRE1 and ITGA2, SPP1, COMP, LMNB2, SOD3, TCL1A and FCER2,SPP1, PLXDC2, COMP, LMNB2, PROK1 and IL6, SPP1, THBS4, LMNB2, ADGRE5, PROK1 and PLXDC2, SPP1, LMNB2, FCRL1, SOD3, PLXDC1 and IL4R, SPP1, PLXDC2, COMP, LMNB2, PROK1 and PTPRS, CRTAC1, SPP1, TCL1A, SOD3, LMNB2 and DLK1, PTX3, GDF15, ENPP6, THBS4, ADGRE1 and ITGA11, AREG, CEACAM5, PTX3, CD48, CCL7 and ADAMTS8, AREG, CEACAM5, SOD3, RET, CCL7 and BAG3, SPP1, COMP, FCRL1, SOD3, LMNB2 and ITGA2, PTX3, GDF15, COMP, ADGRG2, ADGRE1 and TCL1A, PTX3, POF1B, THBS4, ADGRE5, PGA4 and GSN, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and DCC, AREG, CEACAM5, PTX3, CD48, CCL7 and AGR3, AREG, CEACAM5, PTX3, CD48, CCL7 and GDF15, PTX3, GDF15, THBS4, ADGRG2, ADGRE1 and ADGRE5, ADGRE1, GDF15, PTX3, THBS4, ADGRG2 and TCL1A, SPP1, PLXDC2, COMP, LMNB2, PROK1 and ITGA2, TMPRSS15, COMP, PTX3, PGA4, POF1B and ITM2A, SPP1, LMNB2, FCRL1, SOD3, ADGRE5 and MEGF9, PTX3, GDF15, POF1B, THBS4, ADGRE1 and GSN, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and BAG3, AREG, CEACAM5, SOD3, RET, CCL7 and SERPINA1, PTX3, GDF15, POF1B, THBS4, ADGRE1 and ADGRE5, SPP1, COMP, FCRL1, SOD3, LMNB2 and LPL, SPP1, COMP, FCRL1, CLEC3B, LMNB2 and ADGRE1, SPP1, PLXDC2, COMP, LMNB2, TCL1A and CFP, SPP1, LMNB2, SOD3, ADGRE5, TCL1A and ITM2A, TMPRSS15, PTX3, POF1B, THBS4, PGA4 and SOD3,NOTCH1, COMP, GDF15, PTX3, PGA4 and ADAMTS8, AREG, CEACAM5, RET, LPL, KRT19 and C9, AREG, CEACAM5, RET, LPL, KRT19 and ESM1, AREG, CEACAM5, SOD3, RET, CCL7 and TNFRSF10B, PTX3, GDF15, THBS4, CLEC3B, ADGRE1 and TCL1A, SPP1, FCRL1, SOD3, ADGRE5, LMNB2 and GCG, SPP1, COMP, FCRL1, SOD3, LMNB2 and ITIH3, PTX3, GDF15, POF1B, THBS4, ADGRE1 and BMP4, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and IFNL1, AREG, CEACAM5, SOD3, RET, CCL7 and IGFBP1, SPP1, COMP, LMNB2, SOD3, FCRL1 and ITM2A, TMPRSS15, PTX3, GDF15, COMP, PGA4 and BMP4, SPP1, PLXDC2, COMP, LMNB2, PROK1 and ADAMTS8, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and RET, TMPRSS15, PTX3, GDF15, THBS4, PGA4 and CLEC3B, ADGRE1, LMNB2, THBS4, TMPRSS15, GDF15 and CLEC3B, SPP1, COMP, FCRL1, CLEC3B, LMNB2 and FCER2, SPP1, PLXDC2, COMP, LMNB2, PROK1 and TNFRSF10B, AREG, CEACAM5, PTX3, CD48, CCL7 and IFNL1, SPP1, PLXDC2, COMP, IL4R, TCL1A and LMNB2, PTX3, GDF15, THBS4, EXTL1, ADGRE1 and AGR3, SPP1, COMP, LMNB2, SOD3, TCL1A and AREG, AREG, CEACAM5, PTX3, CD48, CCL7 and MMP12, AREG, CEACAM5, SOD3, RET, CCL7 and DCC, PTX3, GDF15, THBS4, CLEC3B, ADGRE1 and POF1B, SPP1, COMP, LMNB2, SOD3, TCL1A and ASAH2, SPP1, COMP, LMNB2, FCRL1, LPL and PROK1, SPP1, PLXDC2, COMP, LMNB2, TCL1A and DLK1SPP1, PLXDC2, COMP, LMNB2, PROK1 and FGF21, SPP1, PLXDC2, SOD3, IL4R, BAG3 and LMNB2, SPP1, COMP, FCRL1, SOD3, LMNB2 and GRK5, AREG, CEACAM5, RET, LPL, KRT19 and TMPRSS15, SPP1, COMP, FCRL1, CLEC3B, LMNB2 and SOD3, PTX3, GDF15, ENPP6, THBS4, ADGRE1 and TNC, AREG, CEACAM5, PTX3, CD48, CCL7 and FAP, PTX3, COMP, POF1B, FCRL1, PGA4 and CLEC3B, SPP1, LMNB2, SOD3, ADGRE5, TCL1A and IFNL1, SPP1, COMP, LMNB2, FCRL1, PLXDC2 and CLEC3B, NOTCH1, COMP, GDF15, PTX3, PGA4 and TCL1A, TMPRSS15, PTX3, GDF15, COMP, PGA4 and FCRL1, SPP1, FCRL1, SOD3, ADGRE5, LMNB2 and ADGRG2, SPP1, LMNB2, FCRL1, SOD3, PLXDC1 and AREG, SPP1, LMNB2, FCRL1, SOD3, TCL1A and PROK1, PTX3, GDF15, COMP, ADGRG2, ADGRE1 and DCC, PTX3, GDF15, THBS4, EXTL1, ADGRE1 and BMP4, SPP1, PLXDC2, COMP, LMNB2, PROK1 and PKD1, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and FAP, AREG, CEACAM5, PTX3, CD48, CCL7 and PTPRS, PTX3, GDF15, COMP, ADGRG2, ADGRE1 and RET, SPP1, COMP, LMNB2, FCRL1, LPL and PTPRS, TMPRSS15, PTX3, COMP, POF1B, PGA4 and FASLG, SPP1, THBS4, LMNB2, ADGRE5, PROK1 and SOD3, GSN, TMPRSS15, PGA4, PTX3, POF1B and COMP, SPP1, LMNB2, SOD3, ADGRE5, TCL1A and PGA4, TMPRSS15, PTX3, COMP, POF1B, PGA4 and IFNL1, SPP1, PLXDC2, COMP, LMNB2, TCL1A and NT5C1A, SPP1, PLXDC2, COMP, LMNB2, TCL1A and CNTN1CRTAC1, SPP1, TCL1A, SOD3, LMNB2 and ADGRE5, PTX3, LMNB2, SOD3, CNTN4, PGA4 and ITM2A, PTX3, COMP, HMCN2, POF1B, PGA4 and NOTCH1, SPP1, LMNB2, FCRL1, SOD3, ITGB1 and COMP, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and AGR3, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and SOD3, AREG, CEACAM5, RET, LPL, KRT19 and PLXDC2, NOTCH1, COMP, GDF15, PTX3, PGA4 and PCDH7, GDF15, SPP1, PLXDC2, COMP, PROK1 and FCER2, AREG, CEACAM5, PTX3, SPP1, PLXDC2 and ADGRE5, PTX3, POF1B, FCRL1, SOD3, PGA4 and EXTL1, SPP1, COMP, FCRL1, CLEC3B, LMNB2 and PROK1, PTX3, POF1B, THBS4, EXTL1, PGA4 and BAG3, SPP1, COMP, LMNB2, FCRL1, ADGRE1 and LPL, CRTAC1, SPP1, TCL1A, SOD3, LMNB2 and NOTCH1, SPP1, LMNB2, FCRL1, SOD3, ADGRE5 and ITIH3, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and GDF15, PTX3, COMP, POF1B, FCRL1, PGA4 and ITM2A, TMPRSS15, PTX3, COMP, POF1B, PGA4 and NT5C1A, SPP1, PLXDC2, COMP, LMNB2, TCL1A and TNC, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and PTX3, TMPRSS15, PTX3, GDF15, THBS4, PGA4 and COMP, SPP1, PLXDC2, COMP, LMNB2, TCL1A and VSIG4, SPP1, COMP, LMNB2, SOD3, TCL1A and TNC, PTX3, COMP, POF1B, FCRL1, PGA4 and PLXDC1, SPP1, LMNB2, SOD3, ADGRE5, TCL1A and ADGRE1, PTX3, GDF15, THBS4, ADGRG2, ADGRE1 and AREG, SPP1, LMNB2, SOD3, ADGRE5, PLXDC1 and FASLG,NOTCH1, COMP, GDF15, PTX3, PGA4 and PKD1, PTX3, GDF15, POF1B, THBS4, ADGRE1 and CEACAM16, TMPRSS15, PTX3, GDF15, THBS4, ADGRE1 and GNAS, SPP1, LMNB2, FCRL1, SOD3, PLXDC1 and TCL1A, SPP1, PLXDC2, COMP, LMNB2, PROK1 and ASAH2, SPP1, PLXDC2, COMP, IL4R, TCL1A and DLK1, SPP1, FCRL1, SOD3, ADGRE5, LMNB2 and PGA4, SPP1, COMP, FCRL1, ADGRE5, LMNB2 and PROK1, AREG, CEACAM5, RET, LPL, KRT19 and ENPP6, PTX3, LMNB2, SOD3, CNTN4, PGA4 and BMP4, SPP1, PLXDC2, COMP, LMNB2, PROK1 and IGSF3, TMPRSS15, PTX3, GDF15, THBS4, ADGRE1 and PLXDC1, PTX3, GDF15, THBS4, ADGRG2, ADGRE1 and CLEC3B, SPP1, FCRL1, SOD3, ADGRE5, LMNB2 and CLEC3B, SPP1, LMNB2, FCRL1, SOD3, MEGF9 and ITGA11, SPP1, PLXDC2, COMP, LMNB2, PROK1 and ITGB1, AREG, CEACAM5, SOD3, RET, CCL7 and NTRK2, SPP1, LMNB2, FCRL1, SOD3, PLXDC1 and PROK1, SPP1, COMP, FCRL1, CLEC3B, LMNB2 and PGA4, SPP1, COMP, LMNB2, FCRL1, SOD3 and AREG, PTX3, COMP, HMCN2, POF1B, PGA4 and FASLG, PTX3, LMNB2, SOD3, CNTN4, PGA4 and TNC, SPP1, COMP, LMNB2, FCRL1, PLXDC2 and NOS2, SPP1, PLXDC2, COMP, LMNB2, TCL1A and ADGRG2, SPP1, PLXDC2, COMP, LMNB2, PROK1 and NT5C1A, SPP1, LMNB2, SOD3, ADGRE5, TCL1A and FAP, ADGRE1, GDF15, PTX3, THBS4, ADGRG2 and RBFOX3, SPP1, COMP, LMNB2, SOD3, FCRL1 and VSIG4,PTX3, COMP, HMCN2, POF1B, PGA4 and LMNB2, PTX3, POF1B, FCRL1, SOD3, PGA4 and ADGRE5, AREG, CEACAM5, PTX3, CD48, CCL7 and TMPRSS15, SPP1, LMNB2, SOD3, ADGRE5, TCL1A and CNTN4, PTX3, GDF15, THBS4, ADGRG2, ADGRE1 and FASLG, SPP1, COMP, LMNB2, SOD3, FCRL1 and ADGRG2, SPP1, ITGA11, FCRL1, SOD3, LMNB2 and PLXDC2, SPP1, PLXDC2, COMP, LMNB2, PROK1 and BMP4, TMPRSS15, PTX3, COMP, POF1B, PGA4 and CCL7, SPP1, LMNB2, FCRL1, SOD3, PLXDC1 and GRK5, SPP1, COMP, FCRL1, CLEC3B, LMNB2 and NOS2, SPP1, LMNB2, SOD3, ADGRE5, PLXDC1 and GRK5, AREG, CEACAM5, SOD3, RET, CCL7 and TMPRSS15, SPP1, COMP, LMNB2, FCRL1, PROK1 and ADGRG2, SPP1, COMP, FCRL1, SOD3, LMNB2 and CCL7, AREG, CEACAM5, SOD3, RET, CCL7 and ITGA11, TMPRSS15, PTX3, POF1B, THBS4, PGA4 and ITM2A, TMPRSS15, PTX3, COMP, POF1B, PGA4 and TNFRSF10B, AREG, CEACAM5, RET, LPL, KRT19 and ADGRE1, SPP1, LMNB2, SOD3, ADGRE5, TCL1A and BAG3, SPP1, ITGA11, FCRL1, SOD3, LMNB2 and TCL1A, TMPRSS15, PTX3, GDF15, THBS4, FGF21 and ADGRE1, SPP1, COMP, LMNB2, SOD3, TCL1A and GRK5, PTX3, POF1B, THBS4, EXTL1, PGA4 and PTPRS, SPP1, LMNB2, FCRL1, SOD3, PLXDC1 and PGA4, SPP1, COMP, FCRL1, CLEC3B, LMNB2 and CEACAM16, SPP1, COMP, FCRL1, CLEC3B, LMNB2 and AGR3, PTX3, GDF15, POF1B, THBS4, ADGRE1 and IL6SPP1, LMNB2, SOD3, ADGRE5, TCL1A and TNC, SPP1, COMP, FCRL1, ADGRE5, LMNB2 and PLXDC1, PTX3, POF1B, FCRL1, SOD3, PGA4 and NPY, PTX3, POF1B, THBS4, EXTL1, PGA4 and LPL, SPP1, COMP, FCRL1, SOD3, LMNB2 and BAG3, TMPRSS15, SPP1, FCRL1, SOD3, PLXDC1 and CKAP4, TMPRSS15, PTX3, POF1B, THBS4, PGA4 and ITGA11, TMPRSS15, PTX3, GDF15, COMP, PGA4 and MMP12, NOTCH1, COMP, GDF15, PTX3, PGA4 and BMP4, SPP1, COMP, LMNB2, SOD3, TCL1A and DLK1, NOTCH1, COMP, GDF15, PTX3, PGA4 and PLXDC1, SPP1, COMP, LMNB2, FCRL1, SOD3 and PKD1, SPP1, COMP, FCRL1, SOD3, LMNB2 and PGA4, TMPRSS15, PTX3, COMP, POF1B, PGA4 and CDH23, PTX3, GDF15, THBS4, ADGRG2, ADGRE1 and ITM2A, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and CFP, AREG, CEACAM5, PTX3, CD48, CCL7 and ITGA2, AREG, CEACAM5, RET, LPL, KRT19 and PLXDC1, PTX3, COMP, HMCN2, POF1B, PGA4 and LPL, SPP1, COMP, FCRL1, SOD3, LMNB2 and IFNL1, SPP1, PLXDC2, COMP, LMNB2, TCL1A and IL6, ADGRE1, GDF15, PTX3, THBS4, ADGRG2 and IL4R, TMPRSS15, COMP, PTX3, PGA4, POF1B and GDF15, SPP1, FCRL1, SOD3, ADGRE5, LMNB2 and LPL, TMPRSS15, COMP, PTX3, PGA4, POF1B and LMNB2, SPP1, THBS4, LMNB2, ADGRE5, CLEC3B and FCRL1, TMPRSS15, PTX3, COMP, POF1B, PGA4 and PROK1, ADGRE1, GDF15, PTX3, THBS4, ADGRG2 and ADGRE2, NOTCH1, COMP, GDF15, PTX3, PGA4 and EXTL1,SPP1, COMP, LMNB2, FCRL1, SOD3 and AGR3, PTX3, GDF15, THBS4, ADGRG2, ADGRE1 and DCC, GDF15, SPP1, PLXDC2, COMP, PROK1 and BAG3, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and C9, AREG, CEACAM5, SOD3, RET, CCL7 and PLXDC2, PTX3, GDF15, COMP, ADGRG2, ADGRE1 and ADGRE2, SPP1, PLXDC2, COMP, LMNB2, PROK1 and CLEC3B, TMPRSS15, SPP1, FCRL1, SOD3, PLXDC1 and PGA4, AREG, CEACAM5, PTX3, CD48, CCL7 and TNFRSF10B, AREG, CEACAM5, SOD3, RET, CCL7 and NOTCH3, TMPRSS15, PTX3, GDF15, THBS4, ADGRE1 and POF1B, SPP1, PLXDC2, COMP, LMNB2, TCL1A and ITGA11, PTX3, SPP1, ENPP6, COMP, TCL1A and ADGRE5, PTX3, POF1B, FCRL1, SOD3, PGA4 and ADGRE2, PTX3, ITGA11, POF1B, RET, SOD3 and TNC, PTX3, GDF15, THBS4, CLEC3B, ADGRE1 and LMNB2, SPP1, PLXDC2, SOD3, IL4R, BAG3 and CEACAM16, SPP1, COMP, LMNB2, FCRL1, ADGRE1 and MMP12, NOTCH1, COMP, GDF15, PTX3, PGA4 and POF1B, SPP1, LMNB2, SOD3, ADGRE5, PLXDC1 and SELL, TMPRSS15, COMP, PTX3, PGA4, POF1B and CLEC3B, TMPRSS15, PTX3, COMP, POF1B, PGA4 and SOD3, SPP1, LMNB2, SOD3, ADGRE5, TCL1A and FASLG, PTX3, GDF15, POF1B, THBS4, ADGRE1 and SPON2, PTX3, ITGA11, POF1B, RET, SOD3 and LMNB2, SPP1, LMNB2, FCRL1, SOD3, TCL1A and ITGA2, SPP1, PLXDC2, COMP, LMNB2, TCL1A and FASLG, PTX3, GDF15, THBS4, ADGRG2, ADGRE1 and IL6,PTX3, POF1B, THBS4, EXTL1, PGA4 and IFNL1, SPP1, LMNB2, FCRL1, SOD3, PLXDC1 and ITIH3, PTX3, GDF15, THBS4, ADGRG2, PROK1 and ADGRE2, AREG, CEACAM5, SOD3, RET, CCL7 and ANGPTL4, PTX3, COMP, HMCN2, POF1B, PGA4 and NPY, PTX3, GDF15, THBS4, ADGRG2, ADGRE1 and COMP, SPP1, PLXDC2, COMP, LMNB2, PROK1 and ESM1, TMPRSS15, COMP, PTX3, PGA4, POF1B and PCDH7, SPP1, LMNB2, FCRL1, SOD3, TCL1A and CNTN4, SPP1, COMP, FCRL1, ADGRE5, LMNB2 and SOD3, SPP1, LMNB2, FCRL1, SOD3, ADGRE1 and ITGA2, ADGRE1, LMNB2, THBS4, TMPRSS15, GDF15 and CFP, PTX3, GDF15, PLXDC2, THBS4, AGR3 and ITM2A, SPP1, COMP, FCRL1, SOD3, LMNB2 and NPY, PTX3, COMP, POF1B, FCRL1, PGA4 and PCDH7, PTX3, POF1B, FCRL1, SOD3, PGA4 and PCDH7, SPP1, PLXDC2, COMP, LMNB2, TCL1A and GDF15, TMPRSS15, PTX3, GDF15, COMP, PGA4 and PKD1, SPP1, PLXDC2, COMP, IL4R, TCL1A and CKAP4, TMPRSS15, PTX3, COMP, POF1B, PGA4 and FGF21, SPP1, LMNB2, FCRL1, SOD3, PLXDC1 and GSN, SPP1, LMNB2, FCRL1, SOD3, PLXDC1 and TNC, SPP1, PLXDC2, COMP, LMNB2, TCL1A and LPL, SPP1, LMNB2, FCRL1, SOD3, ADGRE5 and PLXDC2, SPP1, PLXDC2, COMP, IL4R, TCL1A and PGA4, SPP1, COMP, LMNB2, FCRL1, SOD3 and GNAS, PTX3, GDF15, ENPP6, THBS4, ADGRE1 and POF1B, SPP1, PLXDC2, COMP, IL4R, TCL1A and THBS4, TMPRSS15, PTX3, COMP, POF1B, PGA4 and MMP12,TMPRSS15, PTX3, GDF15, COMP, PGA4 and GNAS, SPP1, COMP, LMNB2, SOD3, TCL1A and PTX3, TMPRSS15, PTX3, COMP, POF1B, PGA4 and CFP, AREG, CEACAM5, RET, LPL, KRT19 and ITGA2, SPP1, COMP, LMNB2, SOD3, TCL1A and C9, PTX3, POF1B, THBS4, EXTL1, PGA4 and GSN, AREG, CEACAM5, PTX3, CD48, CCL7 and CNTN4, SPP1, COMP, FCRL1, SOD3, LMNB2 and ENPP6, NOTCH1, COMP, GDF15, PTX3, PGA4 and FCRL1, SPP1, COMP, LMNB2, FCRL1, PLXDC2 and SERPINA1, AREG, CEACAM5, PTX3, CD48, CCL7 and C9, AREG, CEACAM5, PTX3, CD48, CCL7 and PLXDC1, AREG, CEACAM5, SOD3, RET, CCL7 and PTX3, ADGRE1, GDF15, PTX3, THBS4, ADGRG2 and NOS2, SPP1, PLXDC2, COMP, LMNB2, FCRL1 and ADGRE1, SPP1, LMNB2, FCRL1, SOD3, ADGRE5 and TNC, PTX3, POF1B, THBS4, EXTL1, PGA4 and TMPRSS15, AREG, CEACAM5, RET, LPL, KRT19 and IFNL1, TMPRSS15, COMP, PTX3, PGA4, POF1B and DLK1, SPP1, COMP, LMNB2, SOD3, ADGRE1 and PLXDC1, PTX3, COMP, POF1B, FCRL1, PGA4 and MEGF9, SPP1, PLXDC2, COMP, LMNB2, TCL1A and BAG3, SPP1, COMP, FCRL1, ADGRE5, LMNB2 and PLXDC2, SPP1, COMP, LMNB2, FCRL1, PLXDC2 and IL4R, SPP1, COMP, FCRL1, SOD3, LMNB2 and ESM1, PTX3, GDF15, THBS4, ADGRE5, ADGRE1 and CFP, SPP1, LMNB2, FCRL1, SOD3, ADGRE1 and ITGA11, TMPRSS15, PTX3, COMP, POF1B, PGA4 and GRK5, SPP1, LMNB2, SOD3, ADGRE5, PLXDC1 and CLEC3BSPP1, LMNB2, FCRL1, SOD3, COMP and EXTL1, SPP1, COMP, FCRL1, CLEC3B, LMNB2 and CFP, SPP1, LMNB2, FCRL1, SOD3, TCL1A and THBS4, SPP1, COMP, LMNB2, FCRL1, SOD3 and PCDH7, SPP1, COMP, FCRL1, CLEC3B, LMNB2 and IFNL1, SPP1, LMNB2, SOD3, ADGRE5, FCRL1 and NOS2, SPP1, LMNB2, SOD3, ADGRE5, TCL1A and ENPP6, AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and ITGA11, AREG, CEACAM5, RET, LPL, KRT19 and EXTL1, SPP1, LMNB2, SOD3, ADGRE5, PLXDC1 and ITM2A, PTX3, POF1B, THBS4, ADGRE5, PGA4 and TNC, PTX3, GDF15, THBS4, ADGRG2, ADGRE1 and ADAMTS8, TMPRSS15, PTX3, COMP, POF1B, PGA4 and ENPP6, SPP1, COMP, LMNB2, SOD3, FCRL1 and DLK1, SPP1, PLXDC2, COMP, LMNB2, PROK1 and ENPP6, TMPRSS15, COMP, PTX3, PGA4, POF1B and PROK1, PTX3, GDF15, POF1B, THBS4, ADGRE1 and IL4R, TMPRSS15, PTX3, GDF15, THBS4, FASLG and GNAS, SPP1, PLXDC2, COMP, LMNB2, PROK1 and CNTN5, AREG, CEACAM5, RET, LPL, KRT19 and COMP, NOTCH1, COMP, GDF15, PTX3, PGA4 and ASAH2, PTX3, GDF15, RET, ADGRG2, BMP4 and AGR3, TMPRSS15, PTX3, POF1B, THBS4, PGA4 and ADGRE1, TMPRSS15, PTX3, COMP, POF1B, PGA4 and ASAH2, SPP1, LMNB2, FCRL1, SOD3, PLXDC2 and ESM1, TMPRSS15, PTX3, GDF15, COMP, PGA4 and FGF21, PTX3, GDF15, RET, ADGRG2, BMP4 and PROK1, SPP1, PLXDC2, SOD3, IL4R, BAG3 and ESM1,SPP1, COMP, LMNB2, SOD3, TCL1A and ADGRG2, TMPRSS15, PTX3, POF1B, THBS4, PGA4 and BMP4, SPP1, COMP, LMNB2, FCRL1, LPL and GNAS, AREG, CEACAM5, PTX3, CD48, CCL7 and FCRL1, AREG, CEACAM5, SOD3, RET, CCL7 and ITGA2, SPP1, LMNB2, SOD3, ADGRE5, FCRL1 and ITM2A, SPP1, LMNB2, FCRL1, SOD3, ADGRE1 and TMPRSS15, SPP1, LMNB2, SOD3, ADGRE5, TCL1A and LBP, SPP1, COMP, FCRL1, CLEC3B, LMNB2 and ITIH3, SPP1, COMP, LMNB2, FCRL1, PLXDC2 and GCG, SPP1, LMNB2, FCRL1, SOD3, PLXDC2 and GCG, AREG, CEACAM5, SOD3, RET, CCL7 and GRK5, CRTAC1, SPP1, TCL1A, SOD3, LMNB2 and CD48, TMPRSS15, COMP, PTX3, PGA4, POF1B and CNTN5, SPP1, LMNB2, FCRL1, SOD3, TCL1A and ITM2A, PTX3, GDF15, POF1B, THBS4, ADGRE1 and BAG3, PTX3, POF1B, THBS4, FASLG, ITM2A and ADGRG2, PTX3, LMNB2, SOD3, CNTN4, PGA4 and ESM1, SPP1, COMP, LMNB2, FCRL1, LPL and ITM2A, AREG, CEACAM5, PTX3, CD48, CCL7 and BMP4, AREG, CEACAM5, PTX3, CD48, CCL7 and EDA2R, PTX3, COMP, HMCN2, POF1B, PGA4 and CNTN4, CRTAC1, SPP1, TCL1A, SOD3, LMNB2 and FASLG, TMPRSS15, COMP, PTX3, PGA4, POF1B and AREG, PTX3, LMNB2, SOD3, CNTN4, PGA4 and GRK5, SPP1, THBS4, LMNB2, ADGRE5, PROK1 and ENPP6, or PTX3, GDF15, THBS4, ADGRG2, PROK1 and BMP4.,

[0066] Preferably, the 6 - marker combinations are: SPP1, PLXDC2, SOD3, IL4R, BAG3 and PROK1; AREG, CEACAM5, PTX3, CD48, CCL7 and IGFBP1; SPP1, PLXDC2, COMP, LMNB2, PROK1 and TCL1A; SPP1, LMNB2, FCRL1, SOD3, PLXDC2 and BAG3; SPP1, COMP, LMNB2, SOD3, TCL1A and PROK1; SPP1, LMNB2, FCRL1, SOD3, MEGF9 and PROK1; SPP1, LMNB2, SOD3, ADGRE5, TCL1A and PROK1; AREG, CEACAM5, PLXDC2, COMP, ADGRE2 and ADAMTS8; SPP1, COMP, FCRL1, SOD3, LMNB2 and TCL1A; SPP1, LMNB2, FCRL1, SOD3, ADGRE1 and PLXDC1; SPP1, COMP, LMNB2, FCRL1, PLXDC2 and PROK1; AREG, CEACAM5, SOD3, RET, CCL7 and MMP12; TMPRSS15, PTX3, COMP, POF1B, PGA4 and ITM2A; SPP1, PLXDC2, COMP, IL4R, TCL1A and PROK1; CRTAC1, SPP1, TCL1A, SOD3, LMNB2 and ADGRE2; PTX3, GDF15, POF1B, THBS4, ADGRE1 and EXTL1; NOTCH1, COMP, GDF15, PTX3, PGA4 and CEACAM5; PTX3, POF1B, THBS4, ADGRE5, PGA4 and NPY; PTX3, LMNB2, SOD3, CNTN4, PGA4 and TCL1A; SPP1, LMNB2, FCRL1, SOD3, PLXDC1 and ITM2A; TMPRSS15, PTX3, GDF15, THBS4, ADGRE1 and IL4R; PTX3, COMP, HMCN2, POF1B, PGA4 and ADGRE1; SPP1, LMNB2, FCRL1, SOD3, ADGRE5 and C9; SPP1, PLXDC2, COMP, LMNB2, TCL1A and CLEC3B; SPP1, FCRL1, SOD3, ADGRE5, LMNB2 and CEACAM16; TMPRSS15, PTX3, GDF15, COMP, PGA4 and ITM2A; PTX3, GDF15, THBS4, CLEC3B, ADGRE1 and TNC; GDF15, SPP1, PLXDC2, COMP, PROK1 and LMNB2ADGRE1, GDF15, PTX3, THBS4, ADGRG2 and TNC, PTX3, GDF15, ENPP6, THBS4, ADGRE1 and AGR3, AREG, CEACAM5, PTX3, SPP1, PLXDC2 and SPON2, AREG, CEACAM5, RET, LPL, KRT19 and SPON2, PTX3, GDF15, RET, ADGRG2, BMP4 and ADGRE1, TMPRSS15, COMP, PTX3, PGA4, POF1B and NPY, PTX3, POF1B, FCRL1, SOD3, PGA4 and ITM2A, PTX3, POF1B, THBS4, FASLG, ITM2A and EXTL1, PTX3, POF1B, THBS4, EXTL1, PGA4 and ITM2A, SPP1, COMP, LMNB2, FCRL1, LPL and LBP, PTX3, GDF15, THBS4, EXTL1, ADGRE1 and ENPP6, SPP1, COMP, FCRL1, SOD3, CFP and LMNB2, PTX3, GDF15, THBS4, ADGRG2, ADGRE1 and IL4R, SPP1, COMP, LMNB2, FCRL1, TNC and CLEC3B, ADGRE1, KRT19, LMNB2, COMP, PTX3 and PGA4, PTX3, SPP1, ENPP6, COMP, TCL1A and ADGRE2, PTX3, GDF15, PLXDC2, THBS4, AGR3 and TNC, SPP1, ITGA11, FCRL1, SOD3, LMNB2 and PLXDC1, SPP1, COMP, LMNB2, FCRL1, PROK1 and SOD3, TMPRSS15, PTX3, GDF15, COMP, ADGRE1 and PGA4, SPP1, THBS4, LMNB2, ADGRE5, PROK1 and BAG3, SPP1, COMP, LMNB2, FCRL1, ADGRE1 and PTPRS, PTX3, ITGA11, POF1B, RET, SOD3 and PGA4, SPP1, COMP, FCRL1, ADGRE5, LPL and LMNB2, SPP1, COMP, LMNB2, FCRL1, SOD3 and CEACAM16, PTX3, GDF15, COMP, ADGRG2, ADGRE1 and THBS4, PTX3, COMP, POF1B, FCRL1, PGA4 and IL4R, PTX3, GDF15, THBS4, FASLG, TMPRSS15 and ITM2A, TMPRSS15, PTX3, POF1B, THBS4, PGA4 and CFP,PTX3, GDF15, THBS4, ADGRG2, BMP4 and PROK1, PTX3, GDF15, COMP, EXTL1, PGA4 and NOTCH1, ADGRE1, LMNB2, THBS4, TMPRSS15, GDF15 and TNC, SPP1, COMP, LMNB2, SOD3, FCRL1 and ASAH2, SPP1, COMP, FCRL1, ADGRE5, LMNB2 and TNC, SPP1, PLXDC2, COMP, LMNB2, FCRL1 and PLXDC1, SPP1, ADGRG2, FCRL1, SOD3, BAG3 and LMNB2, GSN, TMPRSS15, PGA4, PTX3, POF1B and SOD3, TMPRSS15, PTX3, THBS4, FASLG, MMP12 and ITM2A, TMPRSS15, PTX3, GDF15, THBS4, CCL7 and ADGRE1, COMP, FCRL1, PTX3, GDF15, NOTCH1 and PGA4, SPP1, THBS4, LMNB2, ADGRE5, CLEC3B and PROK1, PTX3, GDF15, THBS4, ADGRG2, PROK1 and TCL1A, SPP1, COMP, LMNB2, FCRL1, CLEC3B and BAG3, TMPRSS15, SPP1, FCRL1, SOD3, PLXDC1 and EDA2R, PTX3, GDF15, POF1B, THBS4, ADGRE5 and TNC, TMPRSS15, PTX3, THBS4, FASLG, GDF15 and AREG, SPP1, COMP, FCRL1, SOD3, TCL1A and LPL, PTX3, GDF15, THBS4, FASLG, ADGRE1 and POF1B, TMPRSS15, PTX3, GDF15, THBS4, FASLG and TNC, PTX3, GDF15, THBS4, EXTL1, ITM2A and TNC, SPP1, LMNB2, FCRL1, SOD3, COMP and TMPRSS15, SPP1, LMNB2, SOD3, ADGRE5, FCRL1 and NT5C1A, PTX3, GDF15, COMP, THBS4, ADGRE1 and ITGA2, SPP1, PLXDC2, FCRL1, SOD3, ESM1 and BAG3, TMPRSS15, PTX3, SPP1, THBS4, AREG and FASLG, or SPP1, COMP, LMNB2, FASLG, FCRL1 and TCL1A; that is, any one of the above 84 6 - markers combinations.,

[0067] Preferably, the 6 - marker combination is any six of those in E.

[0068] Preferably, the 6 - marker combinations are: CEACAM5, COMP, PTX3, TNC, NOTCH1, and GDF15; CEACAM5, COMP, PTX3, NOTCH1, GDF15, and EDA2R; TMPRSS15, CEACAM5, COMP, PTX3, NOTCH1, and GDF15; TMPRSS15, CEACAM5, COMP, PTX3, TNC, and GDF15; CEACAM5, COMP, PTX3, NOTCH1, SERPINA1, and GDF15; COMP, PTX3, AREG, NOTCH1, GDF15, and EDA2R; COMP, FCRL1, PTX3, AREG, NOTCH1, and GDF15; TMPRSS15, COMP, PTX3, NOTCH1, GDF15, and EDA2R; TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, and GDF15; COMP, FCRL1, PTX3, NOTCH1, GDF15, and EDA2R; TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, and EDA2R; TMPRSS15, COMP, PTX3, TNC, NOTCH1, and GDF15; TMPRSS15, COMP, FCRL1, PTX3, TNC, and GDF15; COMP, PTX3, NOTCH1, SERPINA1, GDF15, and EDA2R; TMPRSS15, CEACAM5, PTX3, TNC, NOTCH1, and GDF15; COMP, PTX3, TNC, NOTCH1, SERPINA1, and GDF15; CEACAM5, COMP, PTX3, AREG, NOTCH1, and GDF15; COMP, PTX3, TNC, NOTCH1, GDF15, and EDA2R; TMPRSS15, COMP, PTX3, NOTCH1, SERPINA1, and GDF15; TMPRSS15, COMP, PTX3, AREG, TNC, and EDA2R; TMPRSS15, COMP, FCRL1, PTX3, GDF15, and EDA2R; TMPRSS15, COMP, PTX3, AREG, GDF15, and EDA2R; COMP, FCRL1, PTX3, TNC, NOTCH1, and GDF15; TMPRSS15, CEACAM5, COMP, PTX3, TNC, and EDA2R; TMPRSS15, COMP, FCRL1, PTX3, NOTCH1, and GDF15; COMP, PTX3, AREG, TNC, NOTCH1, and GDF15COMP, FCRL1, NOTCH1, SERPINA1, GDF15 and EDA2R, COMP, FCRL1, PTX3, NOTCH1, SERPINA1 and GDF15, COMP, FCRL1, AREG, TNC, NOTCH1 and GDF15, TMPRSS15, COMP, FCRL1, TNC, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, NOTCH1 and GDF15, TMPRSS15, COMP, FCRL1, PTX3, AREG and EDA2R, CEACAM5, COMP, TNC, NOTCH1, GDF15 and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, AREG and GDF15, TMPRSS15, COMP, FCRL1, TNC, NOTCH1 and GDF15, TMPRSS15, CEACAM5, COMP, PTX3, AREG and EDA2R, CEACAM5, COMP, TNC, NOTCH1, SERPINA1 and GDF15, CEACAM5, COMP, FCRL1, PTX3, GDF15 and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, SERPINA1 and GDF15, CEACAM5, COMP, FCRL1, PTX3, AREG and EDA2R, CEACAM5, COMP, PTX3, TNC, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, GDF15 and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, NOTCH1 and EDA2R, CEACAM5, COMP, FCRL1, TNC, NOTCH1 and GDF15, TMPRSS15, COMP, FCRL1, PTX3, SERPINA1 and EDA2R, TMPRSS15, COMP, FCRL1, AREG, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, AREG, TNC and EDA2R, TMPRSS15, COMP, PTX3, TNC, GDF15 and EDA2R, TMPRSS15, COMP, AREG, TNC, GDF15 and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, TNC and EDA2R, CEACAM5, COMP, FCRL1, PTX3, TNC and GDF15, TMPRSS15, CEACAM5, COMP, PTX3, SERPINA1 and GDF15, TMPRSS15, FCRL1, PTX3, TNC, NOTCH1 and GDF15,TMPRSS15, CEACAM5, COMP, PTX3, AREG and GDF15, TMPRSS15, COMP, FCRL1, TNC, SERPINA1 and EDA2R, COMP, FCRL1, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, TNC and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, SERPINA1 and EDA2R, TMPRSS15, COMP, PTX3, AREG, NOTCH1 and EDA2R, CEACAM5, COMP, PTX3, AREG, TNC and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, TNC and EDA2R, COMP, PTX3, AREG, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, AREG, TNC and GDF15, COMP, FCRL1, PTX3, AREG, NOTCH1 and EDA2R, CEACAM5, COMP, FCRL1, NOTCH1, SERPINA1 and GDF15, TMPRSS15, COMP, FCRL1, NOTCH1, SERPINA1 and GDF15, COMP, FCRL1, PTX3, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, FCRL1, PTX3, NOTCH1, GDF15 and EDA2R, COMP, FCRL1, PTX3, TNC, SERPINA1 and GDF15, TMPRSS15, COMP, FCRL1, AREG, SERPINA1 and EDA2R, TMPRSS15, COMP, FCRL1, TNC, SERPINA1 and GDF15, COMP, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, CEACAM5, COMP, PTX3, AREG, NOTCH1 and EDA2R, TMPRSS15, COMP, AREG, TNC, NOTCH1 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG and EDA2R, TMPRSS15, COMP, FCRL1, AREG, TNC and EDA2R, CEACAM5, COMP, FCRL1, AREG, NOTCH1 and GDF15, TMPRSS15, COMP, PTX3, TNC, SERPINA1 and GDF15,TMPRSS15, CEACAM5, COMP, AREG, NOTCH1 and GDF15, TMPRSS15, COMP, AREG, NOTCH1, SERPINA1 and GDF15, CEACAM5, COMP, FCRL1, PTX3, AREG and GDF15, CEACAM5, COMP, PTX3, AREG, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, TNC, NOTCH1 and GDF15, TMPRSS15, COMP, PTX3, AREG, TNC and GDF15, CEACAM5, COMP, AREG, TNC, NOTCH1 and GDF15, COMP, FCRL1, PTX3, AREG, GDF15 and EDA2R, TMPRSS15, PTX3, TNC, NOTCH1, GDF15 and EDA2R, CEACAM5, PTX3, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, COMP, TNC, SERPINA1, GDF15 and EDA2R, COMP, FCRL1, AREG, NOTCH1, SERPINA1 and GDF15, COMP, FCRL1, PTX3, AREG, TNC and GDF15, TMPRSS15, COMP, PTX3, AREG, NOTCH1 and GDF15, TMPRSS15, COMP, FCRL1, TNC, NOTCH1 and EDA2R, TMPRSS15, FCRL1, PTX3, NOTCH1, SERPINA1 and GDF15, CEACAM5, COMP, PTX3, TNC, NOTCH1 and EDA2R, TMPRSS15, COMP, FCRL1, AREG, TNC and GDF15, TMPRSS15, COMP, PTX3, TNC, NOTCH1 and EDA2R, TMPRSS15, CEACAM5, COMP, TNC, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, SERPINA1 and GDF15, TMPRSS15, PTX3, AREG, TNC, NOTCH1 and GDF15, CEACAM5, COMP, FCRL1, AREG, SERPINA1 and EDA2R, CEACAM5, COMP, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, COMP, TNC, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, PTX3, AREG, NOTCH1 and GDF15TMPRSS15, FCRL1, PTX3, AREG, NOTCH1 and GDF15, TMPRSS15, PTX3, AREG, NOTCH1, GDF15 and EDA2R, TMPRSS15, COMP, PTX3, SERPINA1, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, NOTCH1 and EDA2R, TMPRSS15, COMP, FCRL1, AREG, NOTCH1 and GDF15, CEACAM5, PTX3, AREG, TNC, NOTCH1 and GDF15, TMPRSS15, COMP, FCRL1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG and GDF15, CEACAM5, COMP, FCRL1, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, GDF15 and EDA2R, CEACAM5, COMP, PTX3, NOTCH1, SERPINA1 and EDA2R, COMP, FCRL1, PTX3, TNC, NOTCH1 and EDA2R, CEACAM5, COMP, FCRL1, TNC, SERPINA1 and EDA2R, TMPRSS15, COMP, FCRL1, NOTCH1, GDF15 and EDA2R, CEACAM5, PTX3, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, COMP, FCRL1, AREG, NOTCH1 and EDA2R, TMPRSS15, AREG, TNC, NOTCH1, GDF15 and EDA2R, TMPRSS15, COMP, AREG, NOTCH1, GDF15 and EDA2R, CEACAM5, COMP, PTX3, TNC, SERPINA1 and GDF15, COMP, FCRL1, PTX3, TNC, GDF15 and EDA2R, COMP, FCRL1, TNC, NOTCH1, GDF15 and EDA2R, COMP, FCRL1, PTX3, AREG, TNC and EDA2R, TMPRSS15, CEACAM5, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, PTX3, TNC, NOTCH1, SERPINA1 and GDF15, COMP, FCRL1, AREG, NOTCH1, GDF15 and EDA2R, CEACAM5, PTX3, TNC, NOTCH1, GDF15 and EDA2R,TMPRSS15, COMP, AREG, TNC, SERPINA1 and EDA2R, CEACAM5, COMP, FCRL1, NOTCH1, SERPINA1 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, TNC and EDA2R, TMPRSS15, COMP, PTX3, AREG, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, AREG, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, TNC, NOTCH1 and GDF15, COMP, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, NOTCH1 and GDF15, TMPRSS15, CEACAM5, PTX3, NOTCH1, GDF15 and EDA2R, TMPRSS15, COMP, AREG, TNC, NOTCH1 and GDF15, COMP, PTX3, AREG, TNC, GDF15 and EDA2R, COMP, PTX3, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, TNC, SERPINA1 and GDF15, TMPRSS15, COMP, NOTCH1, SERPINA1, GDF15 and EDA2R, COMP, FCRL1, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, SERPINA1 and EDA2R, COMP, PTX3, AREG, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, COMP, PTX3, AREG, SERPINA1 and EDA2R, TMPRSS15, COMP, FCRL1, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, TNC, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, AREG, SERPINA1 and EDA2R, CEACAM5, FCRL1, PTX3, TNC, NOTCH1 and GDF15, TMPRSS15, FCRL1, PTX3, SERPINA1, GDF15 and EDA2R, CEACAM5, COMP, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, GDF15 and EDA2R,CEACAM5, PTX3, AREG, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, NOTCH1, GDF15 and EDA2R, COMP, FCRL1, PTX3, TNC, SERPINA1 and EDA2R, COMP, FCRL1, PTX3, SERPINA1, GDF15 and EDA2R, TMPRSS15, COMP, FCRL1, AREG, SERPINA1 and GDF15, CEACAM5, COMP, PTX3, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, PTX3, TNC, GDF15 and EDA2R, TMPRSS15, COMP, PTX3, NOTCH1, SERPINA1 and EDA2R, FCRL1, PTX3, AREG, TNC, NOTCH1 and GDF15, CEACAM5, FCRL1, PTX3, NOTCH1, SERPINA1 and GDF15, TMPRSS15, COMP, PTX3, TNC, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, TNC, NOTCH1 and EDA2R, TMPRSS15, COMP, TNC, NOTCH1, SERPINA1 and GDF15, FCRL1, PTX3, AREG, NOTCH1, GDF15 and EDA2R, TMPRSS15, COMP, AREG, SERPINA1, GDF15 and EDA2R, CEACAM5, FCRL1, PTX3, AREG, NOTCH1 and GDF15, TMPRSS15, CEACAM5, COMP, AREG, SERPINA1 and GDF15, TMPRSS15, COMP, AREG, TNC, SERPINA1 and GDF15, TMPRSS15, PTX3, AREG, NOTCH1, SERPINA1 and GDF15, COMP, FCRL1, AREG, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, AREG, TNC, NOTCH1 and GDF15, TMPRSS15, FCRL1, AREG, TNC, GDF15 and EDA2R, CEACAM5, COMP, PTX3, AREG, SERPINA1 and GDF15, TMPRSS15, PTX3, NOTCH1, SERPINA1, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, AREG, NOTCH1 and EDA2R,TMPRSS15, CEACAM5, COMP, FCRL1, NOTCH1 and GDF15, CEACAM5, FCRL1, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, FCRL1, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, COMP, AREG, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, FCRL1, PTX3, AREG, GDF15 and EDA2R, COMP, FCRL1, AREG, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, SERPINA1 and GDF15, TMPRSS15, AREG, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, PTX3, NOTCH1 and EDA2R, COMP, AREG, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, PTX3, AREG, TNC and EDA2R, TMPRSS15, FCRL1, PTX3, TNC, NOTCH1 and EDA2R, TMPRSS15, PTX3, AREG, TNC, GDF15 and EDA2R, FCRL1, PTX3, TNC, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, AREG, NOTCH1 and EDA2R, TMPRSS15, CEACAM5, COMP, SERPINA1, GDF15 and EDA2R, COMP, PTX3, AREG, TNC, NOTCH1 and EDA2R, COMP, FCRL1, PTX3, AREG, SERPINA1 and GDF15, COMP, FCRL1, AREG, TNC, GDF15 and EDA2R, CEACAM5, COMP, PTX3, TNC, SERPINA1 and EDA2R, COMP, AREG, TNC, NOTCH1, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, AREG, TNC and EDA2R, TMPRSS15, FCRL1, PTX3, TNC, GDF15 and EDA2R, CEACAM5, COMP, AREG, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, PTX3, NOTCH1, SERPINA1 and GDF15,TMPRSS15, CEACAM5, AREG, NOTCH1, GDF15 and EDA2R, COMP, PTX3, AREG, SERPINA1, GDF15 and EDA2R, TMPRSS15, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, COMP, FCRL1, AREG, TNC, SERPINA1 and GDF15, PTX3, AREG, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, FCRL1, TNC, NOTCH1, GDF15 and EDA2R, CEACAM5, COMP, PTX3, AREG, SERPINA1 and EDA2R, TMPRSS15, FCRL1, AREG, TNC, NOTCH1 and GDF15, FCRL1, PTX3, TNC, NOTCH1, SERPINA1 and GDF15, CEACAM5, COMP, FCRL1, TNC, SERPINA1 and GDF15, TMPRSS15, COMP, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, FCRL1, PTX3, AREG, NOTCH1 and EDA2R, CEACAM5, COMP, AREG, NOTCH1, SERPINA1 and EDA2R, COMP, PTX3, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, PTX3, AREG, GDF15 and EDA2R, COMP, FCRL1, AREG, TNC, NOTCH1 and EDA2R, CEACAM5, COMP, PTX3, AREG, TNC and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG and EDA2R, TMPRSS15, FCRL1, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, FCRL1, PTX3, TNC, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3 and TNC, TMPRSS15, CEACAM5, COMP, FCRL1, NOTCH1 and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, TNC and NOTCH1, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3 and AREG, FCRL1, PTX3, NOTCH1, SERPINA1, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, SERPINA1, GDF15 and EDA2R,PTX3, AREG, TNC, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, TNC, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, AREG and TNC, TMPRSS15, FCRL1, AREG, NOTCH1, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, AREG, TNC and GDF15, CEACAM5, COMP, AREG, NOTCH1, SERPINA1 and GDF15, CEACAM5, COMP, FCRL1, TNC, NOTCH1 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG and TNC, TMPRSS15, PTX3, AREG, TNC, NOTCH1 and EDA2R, CEACAM5, PTX3, AREG, NOTCH1, GDF15 and EDA2R, FCRL1, PTX3, AREG, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, FCRL1, PTX3, TNC and GDF15, TMPRSS15, CEACAM5, FCRL1, TNC, GDF15 and EDA2R, CEACAM5, FCRL1, PTX3, NOTCH1, GDF15 and EDA2R, COMP, FCRL1, PTX3, AREG, SERPINA1 and EDA2R, CEACAM5, FCRL1, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, AREG, TNC, NOTCH1 and EDA2R, TMPRSS15, FCRL1, AREG, NOTCH1, SERPINA1 and GDF15, TMPRSS15, FCRL1, PTX3, AREG, TNC and EDA2R, TMPRSS15, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, PTX3, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, AREG, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, TNC, GDF15 and EDA2R, PTX3, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, AREG, TNC and SERPINA1,CEACAM5, AREG, TNC, NOTCH1, GDF15 and EDA2R, COMP, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, FCRL1, PTX3, AREG, TNC and GDF15, CEACAM5, COMP, AREG, TNC, GDF15 and EDA2R, TMPRSS15, CEACAM5, PTX3, TNC, NOTCH1 and EDA2R, TMPRSS15, CEACAM5, NOTCH1, SERPINA1, GDF15 and EDA2R, CEACAM5, FCRL1, AREG, TNC, NOTCH1 and GDF15, TMPRSS15, CEACAM5, FCRL1, AREG, TNC and EDA2R, CEACAM5, COMP, FCRL1, AREG, SERPINA1 and GDF15, CEACAM5, COMP, AREG, TNC, SERPINA1 and GDF15, TMPRSS15, FCRL1, AREG, TNC, NOTCH1 and EDA2R, COMP, FCRL1, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, FCRL1, AREG, TNC, SERPINA1 and EDA2R, CEACAM5, COMP, AREG, TNC, NOTCH1 and EDA2R, TMPRSS15, CEACAM5, PTX3, AREG, NOTCH1 and EDA2R, TMPRSS15, CEACAM5, AREG, TNC, GDF15 and EDA2R, COMP, FCRL1, AREG, TNC, SERPINA1 and EDA2R, TMPRSS15, PTX3, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, NOTCH1 and EDA2R, TMPRSS15, PTX3, AREG, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, TNC and SERPINA1, CEACAM5, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, PTX3, AREG, TNC, SERPINA1 and EDA2R, CEACAM5, FCRL1, PTX3, TNC, NOTCH1 and EDA2R, TMPRSS15, CEACAM5, TNC, NOTCH1, SERPINA1 and EDA2R, CEACAM5, AREG, TNC, NOTCH1, SERPINA1 and GDF15,TMPRSS15, CEACAM5, COMP, FCRL1, TNC and SERPINA1, TMPRSS15, CEACAM5, FCRL1, AREG, NOTCH1 and GDF15, CEACAM5, COMP, AREG, SERPINA1, GDF15 and EDA2R, COMP, PTX3, AREG, TNC, SERPINA1 and GDF15, TMPRSS15, CEACAM5, FCRL1, PTX3, SERPINA1 and GDF15, TMPRSS15, CEACAM5, FCRL1, PTX3, TNC and EDA2R, TMPRSS15, CEACAM5, FCRL1, TNC, NOTCH1 and EDA2R, TMPRSS15, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, AREG and NOTCH1, TMPRSS15, FCRL1, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, PTX3, TNC, SERPINA1 and GDF15, TMPRSS15, CEACAM5, AREG, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG and GDF15, COMP, PTX3, AREG, TNC, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG and SERPINA1, TMPRSS15, CEACAM5, FCRL1, AREG, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, AREG, TNC and NOTCH1, FCRL1, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, AREG and TNC, CEACAM5, COMP, FCRL1, PTX3, AREG and NOTCH1, TMPRSS15, CEACAM5, FCRL1, AREG, TNC and NOTCH1, TMPRSS15, FCRL1, AREG, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, SERPINA1 and EDA2R, CEACAM5, COMP, FCRL1, TNC, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, COMP, NOTCH1, SERPINA1 and EDA2R,TMPRSS15, COMP, FCRL1, PTX3, AREG, and TNC, TMPRSS15, FCRL1, AREG, NOTCH1, SERPINA1, and EDA2R, CEACAM5, PTX3, TNC, NOTCH1, SERPINA1, and EDA2R, CEACAM5, FCRL1, AREG, NOTCH1, SERPINA1, and GDF15, TMPRSS15, PTX3, TNC, SERPINA1, GDF15, and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, TNC, and NOTCH1, CEACAM5, FCRL1, TNC, NOTCH1, GDF15, and EDA2R, CEACAM5, AREG, NOTCH1, SERPINA1, GDF15, and EDA2R, CEACAM5, COMP, TNC, SERPINA1, GDF15, and EDA2R, FCRL1, AREG, TNC, NOTCH1, SERPINA1, and GDF15, TMPRSS15, FCRL1, TNC, NOTCH1, SERPINA1, and EDA2R, TMPRSS15, CEACAM5, PTX3, NOTCH1, SERPINA1, and EDA2R, TMPRSS15, CEACAM5, PTX3, AREG, TNC, and GDF15, TMPRSS15, CEACAM5, FCRL1, NOTCH1, SERPINA1, and EDA2R, TMPRSS15, FCRL1, PTX3, TNC, SERPINA1, and EDA2R, TMPRSS15, FCRL1, PTX3, AREG, SERPINA1, and EDA2R, CEACAM5, FCRL1, PTX3, NOTCH1, SERPINA1, and EDA2R, TMPRSS15, CEACAM5, FCRL1, NOTCH1, SERPINA1, and GDF15, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, and TNC, CEACAM5, AREG, TNC, NOTCH1, SERPINA1, and EDA2R, TMPRSS15, CEACAM5, TNC, SERPINA1, GDF15, and EDA2R, TMPRSS15, FCRL1, PTX3, AREG, SERPINA1, and GDF15, TMPRSS15, CEACAM5, FCRL1, AREG, NOTCH1, and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, AREG, and SERPINA1, TMPRSS15, CEACAM5, FCRL1, PTX3, TNC, and NOTCH1,TMPRSS15, PTX3, AREG, TNC, SERPINA1 and GDF15, TMPRSS15, CEACAM5, FCRL1, TNC, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, FCRL1, AREG, SERPINA1 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, TNC and NOTCH1, CEACAM5, PTX3, AREG, TNC, NOTCH1 and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, AREG and NOTCH1, TMPRSS15, CEACAM5, COMP, FCRL1, TNC and NOTCH1, TMPRSS15, CEACAM5, FCRL1, SERPINA1, GDF15 and EDA2R, CEACAM5, COMP, PTX3, TNC, NOTCH1 and SERPINA1, CEACAM5, COMP, AREG, TNC, NOTCH1 and SERPINA1, CEACAM5, COMP, PTX3, AREG, NOTCH1 and SERPINA1, TMPRSS15, PTX3, AREG, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3 and NOTCH1, TMPRSS15, COMP, FCRL1, PTX3, TNC and SERPINA1, TMPRSS15, CEACAM5, PTX3, AREG, TNC and NOTCH1, TMPRSS15, CEACAM5, AREG, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, AREG, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, PTX3, TNC, SERPINA1 and EDA2R, TMPRSS15, COMP, AREG, TNC, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, FCRL1, AREG, TNC and GDF15, CEACAM5, COMP, PTX3, AREG, TNC and NOTCH1, TMPRSS15, COMP, FCRL1, AREG, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, COMP, PTX3, NOTCH1 and SERPINA1, CEACAM5, COMP, FCRL1, PTX3, NOTCH1 and SERPINA1, CEACAM5, COMP, AREG, TNC, SERPINA1 and EDA2R,TMPRSS15, CEACAM5, PTX3, SERPINA1, GDF15 and EDA2R, TMPRSS15, FCRL1, PTX3, NOTCH1, SERPINA1 and EDA2R, FCRL1, AREG, TNC, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, AREG, TNC, SERPINA1 and EDA2R, TMPRSS15, COMP, FCRL1, AREG, TNC and NOTCH1, FCRL1, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, FCRL1, AREG, TNC, SERPINA1 and GDF15, FCRL1, PTX3, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, AREG and SERPINA1, CEACAM5, PTX3, AREG, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, AREG, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, PTX3, AREG, SERPINA1 and GDF15, TMPRSS15, CEACAM5, FCRL1, TNC, SERPINA1 and GDF15, CEACAM5, FCRL1, PTX3, AREG, NOTCH1 and EDA2R, CEACAM5, COMP, FCRL1, AREG, TNC and NOTCH1, TMPRSS15, CEACAM5, COMP, TNC, NOTCH1 and SERPINA1, COMP, AREG, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, AREG, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3 and SERPINA1, TMPRSS15, COMP, PTX3, AREG, TNC and NOTCH1, CEACAM5, COMP, PTX3, AREG, TNC, SERPINA1, CEACAM5, COMP, FCRL1, PTX3, TNC and SERPINA1, TMPRSS15, CEACAM5, PTX3, TNC, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, PTX3, AREG, SERPINA1 and EDA2R, CEACAM5, FCRL1, AREG, NOTCH1, GDF15 and EDA2R,TMPRSS15, CEACAM5, AREG, TNC, SERPINA1 and GDF15, TMPRSS15, CEACAM5, AREG, TNC, NOTCH1 and SERPINA1, TMPRSS15, COMP, FCRL1, AREG, TNC and SERPINA1, TMPRSS15, COMP, PTX3, AREG, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, PTX3, AREG, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, COMP, FCRL1, NOTCH1 and SERPINA1, TMPRSS15, COMP, PTX3, AREG, TNC and SERPINA1, CEACAM5, FCRL1, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, NOTCH1 and SERPINA1, TMPRSS15, FCRL1, PTX3, AREG, TNC and NOTCH1, TMPRSS15, CEACAM5, FCRL1, AREG, SERPINA1 and GDF15, FCRL1, PTX3, AREG, TNC, NOTCH1 and EDA2R, CEACAM5, COMP, FCRL1, AREG, TNC and SERPINA1, AREG, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG and SERPINA1, COMP, FCRL1, PTX3, AREG, TNC and NOTCH1, TMPRSS15, COMP, FCRL1, TNC, NOTCH1 and SERPINA1, COMP, PTX3, AREG, TNC, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, FCRL1, PTX3, TNC and SERPINA1, TMPRSS15, CEACAM5, PTX3, AREG, TNC and SERPINA1, TMPRSS15, CEACAM5, COMP, FCRL1, AREG and NOTCH1, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG and NOTCH1, CEACAM5, FCRL1, AREG, NOTCH1, SERPINA1 and EDA2R, FCRL1, PTX3, AREG, NOTCH1, SERPINA1 and EDA2R, CEACAM5, FCRL1, AREG, TNC, NOTCH1 and EDA2RTMPRSS15, CEACAM5, FCRL1, TNC, NOTCH1 and SERPINA1, COMP, FCRL1, PTX3, AREG, NOTCH1 and SERPINA1, CEACAM5, COMP, FCRL1, PTX3, AREG and SERPINA1, CEACAM5, COMP, FCRL1, AREG, NOTCH1 and SERPINA1, COMP, FCRL1, AREG, TNC, NOTCH1 and SERPINA1, CEACAM5, FCRL1, PTX3, TNC, GDF15 and EDA2R, CEACAM5, FCRL1, PTX3, AREG, NOTCH1 and SERPINA1, CEACAM5, FCRL1, PTX3, AREG, TNC and NOTCH1, TMPRSS15, FCRL1, PTX3, AREG, TNC and SERPINA1, TMPRSS15, CEACAM5, FCRL1, PTX3, NOTCH1 and SERPINA1, COMP, FCRL1, PTX3, TNC, NOTCH1 and SERPINA1, COMP, FCRL1, PTX3, AREG, TNC and SERPINA1, CEACAM5, FCRL1, PTX3, TNC, SERPINA1 and GDF15, TMPRSS15, FCRL1, PTX3, AREG, NOTCH1 and SERPINA1, CEACAM5, FCRL1, PTX3, SERPINA1, GDF15 and EDA2R, TMPRSS15, FCRL1, PTX3, TNC, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, FCRL1, AREG, TNC and SERPINA1, CEACAM5, FCRL1, PTX3, AREG, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, AREG, NOTCH1 and SERPINA1, TMPRSS15, FCRL1, AREG, TNC, NOTCH1 and SERPINA1, CEACAM5, FCRL1, PTX3, AREG, TNC and GDF15, TMPRSS15, COMP, PTX3, TNC, NOTCH1 and SERPINA1, CEACAM5, PTX3, AREG, TNC, NOTCH1 and SERPINA1, TMPRSS15, PTX3, AREG, TNC, NOTCH1 and SERPINA1, CEACAM5, FCRL1, PTX3, TNC, NOTCH1 and SERPINA1,CEACAM5, FCRL1, AREG, TNC, NOTCH1 and SERPINA1, PTX3, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, FCRL1, PTX3, AREG, SERPINA1, GDF15 and EDA2R, CEACAM5, FCRL1, PTX3, AREG, SERPINA1 and GDF15, FCRL1, PTX3, TNC, SERPINA1, GDF15 and EDA2R, FCRL1, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, FCRL1, PTX3, AREG, TNC, NOTCH1 and SERPINA1, CEACAM5, FCRL1, PTX3, AREG, SERPINA1 and EDA2R, FCRL1, PTX3, AREG, TNC, SERPINA1 and GDF15, CEACAM5, FCRL1, PTX3, TNC, SERPINA1 and EDA2R, FCRL1, PTX3, AREG, TNC, GDF15 and EDA2R, CEACAM5, FCRL1, PTX3, AREG, TNC and EDA2R, CEACAM5, PTX3, AREG, TNC, GDF15 and EDA2R, CEACAM5, PTX3, TNC, SERPINA1, GDF15 and EDA2R, CEACAM5, PTX3, AREG, TNC, SERPINA1 and GDF15, CEACAM5, FCRL1, AREG, TNC, SERPINA1 and EDA2R, FCRL1, PTX3, AREG, TNC, SERPINA1 and EDA2R, CEACAM5, FCRL1, PTX3, AREG, TNC and SERPINA1, CEACAM5, PTX3, AREG, SERPINA1, GDF15 and EDA2R, CEACAM5, FCRL1, AREG, TNC, SERPINA1 and GDF15, CEACAM5, FCRL1, TNC, SERPINA1, GDF15 and EDA2R, CEACAM5, FCRL1, AREG, TNC, GDF15 and EDA2R, CEACAM5, PTX3, AREG, TNC, SERPINA1 and EDA2R, FCRL1, AREG, TNC, SERPINA1, GDF15 and EDA2R, PTX3, AREG, TNC, SERPINA1, GDF15 and EDA2R, CEACAM5, FCRL1, AREG, SERPINA1, GDF15 and EDA2R, or CEACAM5, AREG, TNC, SERPINA1, GDF15 and EDA2R.,

[0069] Preferably, A comprises a combination of 7 markers, and the combination of 7 markers is any seven of B.

[0070] Preferably, the combination of 7 markers is e1) and e2):

[0071] e1) the combination of 6 markers (preferably any one of the above 84 combinations of 6 markers);

[0072] e2) any one of B;

[0073] The e2) is different from any one marker in the combination of 6 markers in e1).

[0074] Preferably, the 7 - marker combinations are: SPP1, PLXDC2, COMP, LMNB2, TCL1A, PROK1 and ADGRG2; SPP1, COMP, LMNB2, SOD3, TCL1A, PROK1 and ADGRG2; SPP1, PLXDC2, COMP, LMNB2, PROK1, TCL1A and ADGRG2; SPP1, LMNB2, FCRL1, SOD3, PLXDC2, BAG3 and PROK1; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A and SOD3; SPP1, PLXDC2, COMP, LMNB2, PROK1, TCL1A and POF1B; SPP1, PLXDC2, COMP, LMNB2, TCL1A, PROK1 and POF1B; SPP1, PLXDC2, COMP, LMNB2, TCL1A, PROK1 and THBS4; PTX3, POF1B, FCRL1, SOD3, PGA4, ITM2A and PCDH7; PTX3, GDF15, ENPP6, THBS4, ADGRE1, AGR3 and TNC; SPP1, PLXDC2, COMP, LMNB2, PROK1, BAG3 and AREG; SPP1, PLXDC2, COMP, LMNB2, PROK1, TCL1A and SOD3; SPP1, PLXDC2, COMP, LMNB2, PROK1, TCL1A and BAG3; SPP1, PLXDC2, COMP, LMNB2, PROK1, TCL1A and FCER2; SPP1, PLXDC2, COMP, LMNB2, TCL1A, PROK1 and BAG3; SPP1, PLXDC2, COMP, LMNB2, TCL1A, PROK1 and CNTN4; SPP1, PLXDC2, COMP, LMNB2, TCL1A, PROK1 and ITGA11; SPP1, PLXDC2, COMP, LMNB2, PROK1, BAG3 and ITM2A; SPP1, LMNB2, SOD3, ADGRE5, TCL1A, ADGRG2 and PROK1; SPP1, PLXDC2, COMP, LMNB2, TCL1A, SOD3 and PROK1; SPP1, PLXDC2, SOD3, IL4R, BAG3, PROK1 and LMNB2; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A and PCDH7; SPP1, COMP, LMNB2, SOD3, ADGRE1, FCRL1 and TCL1A; SPP1, PLXDC2, COMP, LMNB2, TCL1A, PROK1 and SOD3SPP1, PLXDC2, COMP, LMNB2, TCL1A, PROK1 and IL6, SPP1, PLXDC2, COMP, LMNB2, PROK1, TCL1A and IL4R, SPP1, PLXDC2, COMP, LMNB2, PROK1, TCL1A and FGF21, SPP1, COMP, LMNB2, SOD3, FCRL1, TCL1A and LPL, SPP1, PLXDC2, COMP, LMNB2, TCL1A, IL4R and PROK1, PTX3, POF1B, FCRL1, SOD3, PGA4, ITM2A and EXTL1, SPP1, PLXDC2, COMP, LMNB2, TCL1A, PROK1 and IL4R, PTX3, POF1B, THBS4, ADGRE5, PGA4, ITM2A and PTPRS, SPP1, LMNB2, FCRL1, SOD3, PLXDC1, CDH23 and ADGRE5, SPP1, COMP, FCRL1, SOD3, TCL1A, LMNB2 and ADGRE1, SPP1, PLXDC2, COMP, LMNB2, TCL1A, IGFBP1 and PROK1, SPP1, PLXDC2, COMP, LMNB2, PROK1, TCL1A and CNTN1, PTX3, POF1B, FCRL1, SOD3, PGA4, ITM2A and PLXDC1, SPP1, PLXDC2, COMP, LMNB2, TCL1A, CLEC3B and PROK1, SPP1, PLXDC2, COMP, LMNB2, TCL1A, PROK1 and PTPRS, or PTX3, POF1B, THBS4, EXTL1, PGA4, SOD3 and ITM2A; that is, any one of the above 40 7 - markers combinations.,

[0075] Preferably, the 7 - markers combination is any seven of those in E.

[0076] Preferably, the 7 - markers combination is: CEACAM5, COMP, PTX3, TNC, NOTCH1, GDF15 and EDA2R; TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, NOTCH1 and GDF15; CEACAM5, COMP, PTX3, AREG, TNC, NOTCH1 and GDF15; CEACAM5, COMP, PTX3, AREG, NOTCH1, GDF15 and EDA2R; TMPRSS15, COMP, FCRL1, PTX3, AREG, TNC and EDA2R; COMP, FCRL1, PTX3, TNC, NOTCH1, GDF15 and EDA2R; CEACAM5, COMP, FCRL1, PTX3, AREG, NOTCH1 and GDF15; COMP, PTX3, AREG, TNC, NOTCH1, GDF15 and EDA2R; CEACAM5, COMP, FCRL1, PTX3, NOTCH1, GDF15 and EDA2R; TMPRSS15, COMP, FCRL1, PTX3, SERPINA1, GDF15 and EDA2R; TMPRSS15, COMP, FCRL1, PTX3, AREG, GDF15 and EDA2R; CEACAM5, COMP, FCRL1, PTX3, NOTCH1, SERPINA1 and GDF15; CEACAM5, COMP, PTX3, TNC, NOTCH1, SERPINA1 and GDF15; TMPRSS15, CEACAM5, COMP, PTX3, NOTCH1, GDF15 and EDA2R; TMPRSS15, CEACAM5, COMP, PTX3, AREG, NOTCH1 and GDF15; CEACAM5, COMP, FCRL1, PTX3, TNC, NOTCH1 and GDF15; TMPRSS15, COMP, PTX3, TNC, NOTCH1, GDF15 and EDA2R; TMPRSS15, COMP, FCRL1, PTX3, NOTCH1, GDF15 and EDA2R; TMPRSS15, CEACAM5, COMP, PTX3, AREG, TNC and GDF15; TMPRSS15, CEACAM5, COMP, PTX3, TNC, NOTCH1 and GDF15; COMP, PTX3, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R; TMPRSS15, COMP, FCRL1, PTX3, TNC, GDF15 and EDA2R; COMP, FCRL1, PTX3, AREG, NOTCH1, GDF15 and EDA2R,TMPRSS15, COMP, PTX3, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, COMP, PTX3, AREG, TNC, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, TNC and GDF15, TMPRSS15, COMP, FCRL1, PTX3, NOTCH1, SERPINA1 and GDF15, TMPRSS15, COMP, FCRL1, PTX3, AREG, NOTCH1 and GDF15, TMPRSS15, COMP, FCRL1, PTX3, TNC, NOTCH1 and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, GDF15 and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, TNC, SERPINA1 and EDA2R, COMP, PTX3, AREG, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, COMP, FCRL1, PTX3, AREG, NOTCH1 and EDA2R, TMPRSS15, COMP, PTX3, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, TNC and EDA2R, TMPRSS15, COMP, PTX3, AREG, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, AREG, TNC, NOTCH1 and GDF15, TMPRSS15, COMP, FCRL1, AREG, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, AREG and EDA2R, CEACAM5, COMP, PTX3, AREG, NOTCH1, SERPINA1 and GDF15, COMP, FCRL1, PTX3, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, AREG, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, AREG, TNC and EDA2R, COMP, FCRL1, PTX3, AREG, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, PTX3, TNC, GDF15 and EDA2R,COMP, FCRL1, PTX3, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, AREG, TNC and GDF15, TMPRSS15, COMP, FCRL1, PTX3, AREG, TNC and GDF15, TMPRSS15, CEACAM5, COMP, PTX3, AREG, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, AREG and GDF15, CEACAM5, COMP, FCRL1, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, COMP, FCRL1, PTX3, TNC, NOTCH1 and EDA2R, TMPRSS15, CEACAM5, COMP, AREG, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, AREG, NOTCH1 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, AREG, NOTCH1 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG, SERPINA1 and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, AREG, SERPINA1 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, TNC, GDF15 and EDA2R, COMP, FCRL1, PTX3, AREG, TNC, NOTCH1 and GDF15, TMPRSS15, COMP, PTX3, AREG, TNC, NOTCH1 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG, TNC and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, NOTCH1, SERPINA1 and GDF15, TMPRSS15, COMP, FCRL1, PTX3, NOTCH1, SERPINA1 and EDA2R, CEACAM5, COMP, PTX3, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, COMP, PTX3, AREG, TNC, NOTCH1 and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, NOTCH1, SERPINA1 and GDF15, TMPRSS15, COMP, PTX3, TNC, SERPINA1, GDF15 and EDA2R,TMPRSS15, COMP, FCRL1, AREG, TNC, NOTCH1 and EDA2R, TMPRSS15, CEACAM5, PTX3, TNC, NOTCH1, GDF15 and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, TNC, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, NOTCH1 and EDA2R, COMP, FCRL1, PTX3, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, TNC, SERPINA1 and GDF15, TMPRSS15, COMP, FCRL1, AREG, SERPINA1, GDF15 and EDA2R, TMPRSS15, PTX3, AREG, TNC, NOTCH1, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, NOTCH1, SERPINA1, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, AREG, GDF15 and EDA2R, COMP, PTX3, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, COMP, AREG, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, AREG, TNC, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, AREG, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, TNC, SERPINA1 and EDA2R, TMPRSS15, COMP, FCRL1, TNC, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, SERPINA1 and GDF15, TMPRSS15, COMP, FCRL1, PTX3, AREG, SERPINA1 and GDF15, TMPRSS15, FCRL1, PTX3, TNC, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, TNC, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, TNC, NOTCH1 and EDA2R,TMPRSS15, CEACAM5, COMP, FCRL1, TNC, SERPINA1 and GDF15, COMP, FCRL1, PTX3, AREG, TNC, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, AREG, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, COMP, FCRL1, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, TNC, NOTCH1, GDF15 and EDA2R, COMP, FCRL1, AREG, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, COMP, FCRL1, AREG, TNC, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, AREG, TNC, SERPINA1 and GDF15, CEACAM5, COMP, FCRL1, AREG, TNC, NOTCH1 and GDF15, TMPRSS15, COMP, FCRL1, AREG, TNC, GDF15 and EDA2R, TMPRSS15, COMP, PTX3, AREG, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, SERPINA1 and EDA2R, TMPRSS15, COMP, FCRL1, AREG, TNC, NOTCH1 and GDF15, TMPRSS15, CEACAM5, COMP, PTX3, TNC, NOTCH1 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, TNC, NOTCH1 and GDF15, TMPRSS15, CEACAM5, FCRL1, PTX3, TNC, NOTCH1 and GDF15, COMP, FCRL1, PTX3, AREG, TNC, NOTCH1 and EDA2R, CEACAM5, COMP, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, COMP, FCRL1, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, AREG, TNC, NOTCH1 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, AREG, TNC and EDA2R, CEACAM5, COMP, FCRL1, AREG, NOTCH1, GDF15 and EDA2R,COMP, FCRL1, PTX3, AREG, SERPINA1, GDF15 and EDA2R, COMP, FCRL1, PTX3, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, AREG, TNC, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG, SERPINA1 and GDF15, CEACAM5, COMP, FCRL1, TNC, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, COMP, FCRL1, TNC, SERPINA1, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, AREG, SERPINA1 and GDF15, CEACAM5, COMP, FCRL1, PTX3, AREG, TNC and GDF15, CEACAM5, COMP, FCRL1, PTX3, TNC, SERPINA1 and GDF15, TMPRSS15, CEACAM5, PTX3, AREG, TNC, NOTCH1 and GDF15, TMPRSS15, COMP, FCRL1, AREG, NOTCH1, SERPINA1 and EDA2R, CEACAM5, COMP, AREG, TNC, NOTCH1, GDF15 and EDA2R, TMPRSS15, PTX3, AREG, TNC, NOTCH1, SERPINA1 and GDF15, CEACAM5, COMP, FCRL1, PTX3, AREG, SERPINA1 and EDA2R, TMPRSS15, COMP, PTX3, AREG, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG, NOTCH1 and EDA2R, TMPRSS15, FCRL1, PTX3, AREG, NOTCH1, GDF15 and EDA2R, TMPRSS15, COMP, FCRL1, AREG, TNC, SERPINA1 and GDF15, TMPRSS15, FCRL1, PTX3, NOTCH1, SERPINA1, GDF15 and EDA2R, CEACAM5, COMP, AREG, TNC, NOTCH1, SERPINA1 and GDF15,TMPRSS15, CEACAM5, COMP, FCRL1, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, TNC, NOTCH1 and EDA2R, TMPRSS15, COMP, AREG, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, COMP, AREG, TNC, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, PTX3, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, AREG, TNC, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, AREG, NOTCH1, SERPINA1 and GDF15, TMPRSS15, FCRL1, PTX3, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, COMP, PTX3, AREG, TNC, SERPINA1 and GDF15, CEACAM5, COMP, PTX3, TNC, NOTCH1, SERPINA1 and EDA2R, CEACAM5, COMP, PTX3, AREG, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, NOTCH1, SERPINA1 and GDF15, COMP, FCRL1, AREG, TNC, NOTCH1, GDF15 and EDA2R, COMP, FCRL1, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, TNC, NOTCH1, SERPINA1 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, SERPINA1, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, COMP, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, PTX3, SERPINA1, GDF15 and EDA2R,TMPRSS15, CEACAM5, COMP, AREG, NOTCH1, SERPINA1 and EDA2R, CEACAM5, COMP, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG, GDF15 and EDA2R, CEACAM5, COMP, PTX3, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, NOTCH1 and GDF15, COMP, FCRL1, PTX3, AREG, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, COMP, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, PTX3, TNC, NOTCH1, SERPINA1 and GDF15, CEACAM5, COMP, FCRL1, AREG, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, PTX3, TNC, SERPINA1 and EDA2R, CEACAM5, COMP, FCRL1, AREG, TNC, SERPINA1 and EDA2R, CEACAM5, PTX3, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, COMP, FCRL1, TNC, NOTCH1, SERPINA1 and EDA2R, FCRL1, PTX3, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, COMP, AREG, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, TNC, NOTCH1, GDF15 and EDA2R, CEACAM5, COMP, PTX3, AREG, TNC, NOTCH1 and EDA2R, TMPRSS15, FCRL1, AREG, TNC, NOTCH1, SERPINA1 and GDF15, CEACAM5, FCRL1, PTX3, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG, NOTCH1 and GDF15,TMPRSS15, FCRL1, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R; TMPRSS15, FCRL1, PTX3, AREG, TNC, GDF15 and EDA2R; CEACAM5, COMP, AREG, TNC, NOTCH1, SERPINA1 and EDA2R; TMPRSS15, COMP, FCRL1, AREG, NOTCH1, SERPINA1 and GDF15; TMPRSS15, CEACAM5, AREG, TNC, NOTCH1, SERPINA1 and GDF15; TMPRSS15, COMP, PTX3, TNC, NOTCH1, SERPINA1 and EDA2R; CEACAM5, COMP, PTX3, AREG, TNC, GDF15 and EDA2R; COMP, FCRL1, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R; CEACAM5, COMP, FCRL1, TNC, SERPINA1, GDF15 and EDA2R; CEACAM5, COMP, FCRL1, AREG, TNC, NOTCH1 and EDA2R; TMPRSS15, FCRL1, PTX3, AREG, TNC, NOTCH1 and GDF15; TMPRSS15, COMP, PTX3, AREG, TNC, SERPINA1 and EDA2R; TMPRSS15, CEACAM5, COMP, TNC, SERPINA1, GDF15 and EDA2R; TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, NOTCH1 and EDA2R; FCRL1, PTX3, AREG, TNC, NOTCH1, GDF15 and EDA2R; TMPRSS15, CEACAM5, FCRL1, NOTCH1, SERPINA1, GDF15 and EDA2R; TMPRSS15, CEACAM5, PTX3, NOTCH1, SERPINA1, GDF15 and EDA2R; TMPRSS15, CEACAM5, COMP, PTX3, AREG, TNC and SERPINA1; TMPRSS15, PTX3, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R; COMP, PTX3, AREG, TNC, SERPINA1, GDF15 and EDA2R; TMPRSS15, CEACAM5, COMP, NOTCH1, SERPINA1, GDF15 and EDA2R; TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, AREG and TNCTMPRSS15, CEACAM5, COMP, PTX3, AREG, TNC and NOTCH1, TMPRSS15, CEACAM5, FCRL1, AREG, TNC, NOTCH1 and GDF15, COMP, FCRL1, PTX3, AREG, TNC, SERPINA1 and GDF15, TMPRSS15, CEACAM5, PTX3, AREG, NOTCH1, SERPINA1 and GDF15, CEACAM5, FCRL1, PTX3, TNC, NOTCH1, SERPINA1 and GDF15, CEACAM5, COMP, PTX3, AREG, TNC, SERPINA1 and GDF15, TMPRSS15, FCRL1, AREG, TNC, NOTCH1, GDF15 and EDA2R, TMPRSS15, COMP, PTX3, AREG, NOTCH1, SERPINA1 and EDA2R, CEACAM5, FCRL1, PTX3, AREG, TNC, NOTCH1, GDF15, CEACAM5, COMP, PTX3, AREG, SERPINA1, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, TNC, SERPINA1 and EDA2R, TMPRSS15, FCRL1, PTX3, AREG, NOTCH1, SERPINA1 and GDF15, FCRL1, PTX3, AREG, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, PTX3, NOTCH1, SERPINA1 and EDA2R, CEACAM5, PTX3, AREG, TNC, NOTCH1, GDF15 and EDA2R, FCRL1, PTX3, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, GDF15 and EDA2R, CEACAM5, PTX3, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, FCRL1, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, PTX3, AREG, TNC, NOTCH1 and EDA2R, TMPRSS15, COMP, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, PTX3, AREG, TNC, GDF15 and EDA2R,CEACAM5, FCRL1, PTX3, TNC, NOTCH1, GDF15 and EDA2R, COMP, FCRL1, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, CEACAM5, COMP, FCRL1, AREG, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, TNC, GDF15 and EDA2R, COMP, FCRL1, PTX3, AREG, TNC, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, PTX3, AREG, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG, TNC and SERPINA1, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, TNC and GDF15, CEACAM5, COMP, PTX3, AREG, TNC, SERPINA1 and EDA2R, CEACAM5, FCRL1, PTX3, AREG, NOTCH1, SERPINA1 and GDF15, PTX3, AREG, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, TNC, NOTCH1 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, TNC and EDA2R, CEACAM5, FCRL1, PTX3, AREG, NOTCH1, GDF15 and EDA2R, COMP, FCRL1, AREG, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, AREG, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, PTX3, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, AREG and SERPINA1, TMPRSS15, CEACAM5, FCRL1, PTX3, TNC, SERPINA1 and GDF15, CEACAM5, PTX3, AREG, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, FCRL1, PTX3, AREG, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, AREG and NOTCH1,TMPRSS15, CEACAM5, COMP, AREG, SERPINA1, GDF15 and EDA2R, TMPRSS15, FCRL1, PTX3, AREG, TNC, NOTCH1 and EDA2R, CEACAM5, COMP, FCRL1, AREG, TNC, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, AREG, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, AREG, TNC, NOTCH1 and EDA2R, TMPRSS15, PTX3, AREG, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, TNC and SERPINA1, TMPRSS15, CEACAM5, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, COMP, PTX3, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, FCRL1, PTX3, AREG, NOTCH1, SERPINA1 and EDA2R, CEACAM5, COMP, FCRL1, AREG, TNC, SERPINA1 and GDF15, TMPRSS15, FCRL1, PTX3, AREG, TNC, SERPINA1 and GDF15, TMPRSS15, FCRL1, PTX3, AREG, TNC, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, FCRL1, AREG, TNC, GDF15 and EDA2R, TMPRSS15, FCRL1, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, AREG, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, SERPINA1, GDF15 and EDA2R, CEACAM5, FCRL1, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, CEACAM5, FCRL1, AREG, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, TNC and NOTCH1, TMPRSS15, CEACAM5, COMP, AREG, TNC, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, FCRL1, PTX3, TNC, SERPINA1 and EDA2R,TMPRSS15, CEACAM5, PTX3, TNC, SERPINA1, GDF15 and EDA2R; TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, SERPINA1 and GDF15; CEACAM5, FCRL1, AREG, TNC, NOTCH1, GDF15 and EDA2R; TMPRSS15, CEACAM5, FCRL1, PTX3, NOTCH1, SERPINA1 and EDA2R; TMPRSS15, FCRL1, PTX3, TNC, SERPINA1, GDF15 and EDA2R; TMPRSS15, CEACAM5, COMP, FCRL1, AREG, TNC and NOTCH1; TMPRSS15, CEACAM5, FCRL1, AREG, NOTCH1, SERPINA1 and GDF15; TMPRSS15, CEACAM5, FCRL1, TNC, NOTCH1, SERPINA1 and EDA2R; TMPRSS15, CEACAM5, AREG, TNC, NOTCH1, SERPINA1 and EDA2R; TMPRSS15, CEACAM5, PTX3, AREG, NOTCH1, SERPINA1 and EDA2R; TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, NOTCH1 and SERPINA1; TMPRSS15, CEACAM5, PTX3, TNC, NOTCH1, SERPINA1 and EDA2R; CEACAM5, COMP, FCRL1, PTX3, AREG, TNC and NOTCH1; TMPRSS15, CEACAM5, FCRL1, AREG, TNC, SERPINA1 and EDA2R; TMPRSS15, CEACAM5, FCRL1, TNC, SERPINA1, GDF15 and EDA2R; TMPRSS15, CEACAM5, FCRL1, AREG, TNC, SERPINA1 and GDF15; CEACAM5, COMP, AREG, TNC, SERPINA1, GDF15 and EDA2R; TMPRSS15, FCRL1, PTX3, TNC, NOTCH1, SERPINA1 and EDA2R; TMPRSS15, CEACAM5, PTX3, AREG, SERPINA1, GDF15 and EDA2R; TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, SERPINA1 and EDA2R; TMPRSS15, COMP, FCRL1, PTX3, AREG, TNC and SERPINA1TMPRSS15, FCRL1, AREG, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, PTX3, AREG, TNC, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, TNC and NOTCH1, CEACAM5, COMP, FCRL1, PTX3, AREG, TNC and SERPINA1, TMPRSS15, CEACAM5, COMP, PTX3, AREG, NOTCH1 and SERPINA1, CEACAM5, FCRL1, PTX3, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, PTX3, AREG, TNC, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, PTX3, AREG, TNC, SERPINA1 and GDF15, FCRL1, PTX3, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, AREG, TNC and NOTCH1, CEACAM5, AREG, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG, NOTCH1 and SERPINA1, CEACAM5, PTX3, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, CEACAM5, COMP, PTX3, AREG, TNC, NOTCH1 and SERPINA1, FCRL1, AREG, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, CEACAM5, FCRL1, PTX3, AREG, TNC, NOTCH1 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, TNC, NOTCH1 and SERPINA1, CEACAM5, COMP, FCRL1, PTX3, AREG, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, FCRL1, AREG, NOTCH1, SERPINA1 and EDA2R, CEACAM5, FCRL1, PTX3, AREG, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, COMP, FCRL1, AREG, TNC, NOTCH1 and SERPINA1, CEACAM5, COMP, FCRL1, PTX3, TNC, NOTCH1 and SERPINA1,TMPRSS15, CEACAM5, FCRL1, PTX3, TNC, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, FCRL1, AREG, SERPINA1, GDF15 and EDA2R, CEACAM5, FCRL1, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, TNC, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, COMP, PTX3, TNC, NOTCH1 and SERPINA1, COMP, FCRL1, PTX3, AREG, TNC, NOTCH1 and SERPINA1, TMPRSS15, COMP, FCRL1, PTX3, AREG, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, FCRL1, AREG, TNC, NOTCH1 and SERPINA1, CEACAM5, COMP, FCRL1, AREG, TNC, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, TNC and SERPINA1, TMPRSS15, COMP, PTX3, AREG, TNC, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, NOTCH1 and SERPINA1, CEACAM5, FCRL1, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, FCRL1, PTX3, AREG, TNC, NOTCH1 and SERPINA1, CEACAM5, FCRL1, PTX3, AREG, TNC, NOTCH1 and SERPINA1, CEACAM5, FCRL1, PTX3, AREG, SERPINA1, GDF15 and EDA2R, CEACAM5, FCRL1, PTX3, AREG, TNC, SERPINA1 and GDF15, CEACAM5, FCRL1, PTX3, AREG, TNC, SERPINA1 and EDA2R, FCRL1, PTX3, AREG, TNC, SERPINA1, GDF15 and EDA2R, CEACAM5, FCRL1, PTX3, TNC, SERPINA1, GDF15 and EDA2R, CEACAM5, FCRL1, PTX3, AREG, TNC, GDF15 and EDA2R, CEACAM5, PTX3, AREG, TNC, SERPINA1, GDF15 and EDA2R,or CEACAM5, FCRL1, AREG, TNC, SERPINA1, GDF15 and EDA2R.,

[0077] Preferably, the A comprises a combination of 8 markers, and the combination of 8 markers is any eight of the B.

[0078] Preferably, the combination of 8 markers is f1) and f2):

[0079] f1) the combination of 7 markers (preferably any one of the above 40 combinations of 7 markers);

[0080] f2) any one of the B;

[0081] The f2) is different from any one marker in the combination of 7 markers in f1).

[0082] Preferably, the 8 - markers combination is: PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PROK1 and PCDH7; PTX3, POF1B, THBS4, EXTL1, PGA4, ADGRE1, SOD3 and ITM2A; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, SOD3 and PCDH7; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7 and COMP; PTX3, POF1B, THBS4, EXTL1, PGA4, SOD3, ITM2A and PCDH7; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7 and SOD3; PTX3, POF1B, THBS4, EXTL1, PGA4, ADGRE1, ITM2A and BAG3; PTX3, POF1B, THBS4, EXTL1, PGA4, ADGRE1, ITM2A and PCDH7; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PROK1 and ADGRE1; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7 and ADGRE1; PTX3, POF1B, THBS4, EXTL1, PGA4, ADGRE1, ITM2A and SOD3; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7 and AREG; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7 and ADGRE5; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PROK1 and BAG3; PTX3, POF1B, THBS4, EXTL1, PGA4, ADGRE1, ITM2A and COMP; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7 and HMCN2; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, SOD3 and PROK1; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PROK1 and COMP; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PROK1 and NT5C1A; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7 and LBP; PTX3, POF1B, THBS4, EXTL1, PGA4, SOD3, ITM2A and ADGRE1PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7, and SPON2; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7, and CDH23; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PROK1, and PTPRS; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PROK1, and FCER2; PTX3, POF1B, THBS4, EXTL1, PGA4, ADGRE1, ITM2A, and CCL7; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7, and TNC; PTX3, POF1B, THBS4, ADGRE5, PGA4, ITM2A, FCER2, and TNC; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7, and CKAP4; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7, and FCER2; PTX3, POF1B, THBS4, EXTL1, PGA4, SOD3, ITM2A, and PROK1; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7, and CEACAM5; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7, and IFNL1; PTX3, POF1B, THBS4, EXTL1, PGA4, ADGRE1, ITM2A, and TNC; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7, and BAG3; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7, and NOS2; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7, and C9; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7, and IL4R; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PROK1, and SOD3; PTX3, POF1B, THBS4, EXTL1, PGA4, ADGRE1, ITM2A, and IGFBP1; PTX3, POF1B, THBS4, ADGRE5, PGA4, ITM2A, NPY, and CEACAM16; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7, and CCL7PTX3, POF1B, THBS4, ADGRE5, PGA4, ITM2A, FCER2 and BAG3, PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PROK1 and TNC, PTX3, POF1B, THBS4, ADGRE5, PGA4, ITM2A, NPY and PTPRS, PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7 and NPY, PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PROK1 and NPY, PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PROK1 and AGR3, PTX3, POF1B, THBS4, EXTL1, PGA4, PCDH7 and CEACAM16, PTX3, POF1B, THBS4, ADGRE5, PGA4, ITM2A, NPY and TNC, PTX3, POF1B, THBS4, EXTL1, PGA4, PCDH7 and PROK1, SPP1, LMNB2, SOD3, ADGRE5, PLXDC1, PROK1, LBP and FASLG, PTX3, POF1B, THBS4, ADGRE5, PGA4, ITM2A, FCER2 and IGFBP1, PTX3, POF1B, THBS4, ADGRE5, PGA4, ITM2A, NPY and PCDH7, PTX3, POF1B, THBS4, EXTL1, PGA4, PCDH7 and NT5C1A, PTX3, POF1B, THBS4, EXTL1, PGA4, PCDH7 and IGFBP1, PTX3, POF1B, THBS4, FASLG, ITM2A, EXTL1, TNC and PROK1, PTX3, POF1B, THBS4, EXTL1, PGA4, ADGRE1, ITM2A and NPY, PTX3, POF1B, THBS4, EXTL1, PGA4, ADGRE1, ITM2A and TNFRSF10B, PTX3, POF1B, THBS4, ADGRE5, PGA4, ITM2A, PTPRS and ADGRE1, PTX3, POF1B, THBS4, EXTL1, PGA4, SOD3, PROK1 and ITM2A, PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7 and ITGB7, PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PROK1 and C9,PTX3, POF1B, THBS4, ADGRE5, PGA4, ITM2A, NPY and ADGRE1, PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, AGR3 and PCDH7, PTX3, POF1B, THBS4, EXTL1, PGA4, ADGRE1, ITM2A and LPL, PTX3, POF1B, THBS4, EXTL1, PGA4, ADGRE1, ITM2A and NOS2, PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7 and AGR3, PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PROK1 and DLK1, PTX3, POF1B, THBS4, EXTL1, PGA4, ADGRE1, ITM2A and TMPRSS15, PTX3, POF1B, THBS4, EXTL1, PGA4, ADGRE1, ITM2A and CEACAM16, PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7 and TNFRSF10B, PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, SOD3 and ADGRE1, or PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7 and GCG.,

[0083] Preferably, the combination of the 8 markers is any eight of those in E.

[0084] Preferably, the 8 - marker combinations are: TMPRSS15, COMP, FCRL1, PTX3, TNC, NOTCH1, GDF15 and EDA2R; CEACAM5, COMP, FCRL1, PTX3, TNC, NOTCH1, GDF15 and EDA2R; TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, NOTCH1, GDF15 and EDA2R; TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, AREG, TNC and EDA2R; TMPRSS15, CEACAM5, COMP, PTX3, AREG, TNC, GDF15 and EDA2R; TMPRSS15, COMP, FCRL1, PTX3, AREG, TNC, GDF15 and EDA2R; CEACAM5, COMP, FCRL1, PTX3, AREG, NOTCH1, GDF15 and EDA2R; TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, TNC, GDF15 and EDA2R; TMPRSS15, CEACAM5, COMP, PTX3, TNC, NOTCH1, GDF15 and EDA2R; COMP, FCRL1, PTX3, AREG, TNC, NOTCH1, GDF15 and EDA2R; CEACAM5, COMP, FCRL1, PTX3, NOTCH1, SERPINA1, GDF15 and EDA2R; TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, TNC, NOTCH1 and GDF15; TMPRSS15, COMP, FCRL1, PTX3, AREG, NOTCH1, GDF15 and EDA2R; TMPRSS15, CEACAM5, COMP, FCRL1, TNC, NOTCH1, SERPINA1 and GDF15; TMPRSS15, COMP, FCRL1, PTX3, AREG, TNC, SERPINA1 and EDA2R; CEACAM5, COMP, FCRL1, PTX3, AREG, TNC, NOTCH1 and GDF15; TMPRSS15, CEACAM5, COMP, PTX3, AREG, TNC, NOTCH1 and GDF15; TMPRSS15, CEACAM5, COMP, PTX3, AREG, TNC, NOTCH1 and EDA2R; CEACAM5, COMP, PTX3, AREG, TNC, NOTCH1, GDF15 and EDA2R; CEACAM5, COMP, PTX3, AREG, TNC, NOTCH1, GDF15 and EDA2RCEACAM5, COMP, FCRL1, PTX3, AREG, NOTCH1, and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, AREG, NOTCH1, and GDF15, TMPRSS15, COMP, FCRL1, AREG, TNC, NOTCH1, GDF15, and EDA2R, CEACAM5, COMP, FCRL1, PTX3, TNC, NOTCH1, SERPINA1, and GDF15, TMPRSS15, CEACAM5, COMP, PTX3, AREG, NOTCH1, GDF15, and EDA2R, CEACAM5, COMP, PTX3, TNC, NOTCH1, SERPINA1, GDF15, and EDA2R, TMPRSS15, CEACAM5, COMP, AREG, TNC, NOTCH1, GDF15, and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, TNC, NOTCH1, SERPINA1, and GDF15, TMPRSS15, COMP, PTX3, AREG, TNC, NOTCH1, GDF15, and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, NOTCH1, SERPINA1, GDF15, and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, AREG, TNC, NOTCH1, and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, TNC, NOTCH1, and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, AREG, TNC, NOTCH1, and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, TNC, NOTCH1, GDF15, and EDA2R, COMP, FCRL1, PTX3, AREG, NOTCH1, SERPINA1, GDF15, and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, AREG, TNC, and GDF15, COMP, PTX3, AREG, TNC, NOTCH1, SERPINA1, GDF15, and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, TNC, SERPINA1, GDF15, and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG, NOTCH1, GDF15, and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, AREG, GDF15, and EDA2R,TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, TNC, SERPINA1 and EDA2R, TMPRSS15, COMP, FCRL1, AREG, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, AREG, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, NOTCH1, SERPINA1, GDF15 and EDA2R, COMP, FCRL1, PTX3, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, AREG, SERPINA1, GDF15 and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, PTX3, AREG, NOTCH1, SERPINA1 and GDF15, TMPRSS15, COMP, FCRL1, PTX3, AREG, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, COMP, PTX3, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG, TNC, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, AREG, NOTCH1 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, NOTCH1, SERPINA1 and GDF15, TMPRSS15, COMP, PTX3, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, AREG, TNC, NOTCH1, SERPINA1 and GDF15, CEACAM5, COMP, FCRL1, PTX3, AREG, TNC, NOTCH1 and EDA2R, CEACAM5, COMP, PTX3, AREG, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, TNC, SERPINA1 and GDF15,TMPRSS15, CEACAM5, COMP, PTX3, AREG, TNC, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, AREG, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, PTX3, AREG, TNC, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG, TNC, NOTCH1 and EDA2R, CEACAM5, COMP, FCRL1, AREG, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, AREG, SERPINA1 and GDF15, TMPRSS15, COMP, PTX3, AREG, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, PTX3, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, COMP, FCRL1, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, TNC, NOTCH1, GDF15 and EDA2R, CEACAM5, COMP, PTX3, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, AREG, TNC, SERPINA1 and GDF15, COMP, FCRL1, PTX3, AREG, TNC, NOTCH1, SERPINA1 and GDF15, COMP, FCRL1, PTX3, AREG, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, AREG, TNC, NOTCH1, SERPINA1 and EDA2R,TMPRSS15, COMP, FCRL1, PTX3, TNC, NOTCH1, SERPINA1 and EDA2R, CEACAM5, COMP, FCRL1, AREG, TNC, NOTCH1, GDF15 and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, AREG, TNC, SERPINA1 and GDF15, TMPRSS15, COMP, FCRL1, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG, TNC, GDF15 and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, AREG, NOTCH1, SERPINA1 and GDF15, TMPRSS15, COMP, FCRL1, AREG, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, AREG, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, AREG, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, PTX3, AREG, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, CEACAM5, COMP, AREG, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG, TNC, NOTCH1 and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, NOTCH1, SERPINA1 and EDA2R, CEACAM5, COMP, FCRL1, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, COMP, PTX3, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, CEACAM5, COMP, PTX3, AREG, TNC, NOTCH1, SERPINA1 and EDA2R,TMPRSS15, COMP, PTX3, AREG, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, NOTCH1, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, TNC, SERPINA1, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, COMP, AREG, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG, NOTCH1, SERPINA1 and GDF15, CEACAM5, COMP, FCRL1, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, COMP, FCRL1, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG, TNC, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, PTX3, AREG, TNC, NOTCH1, SERPINA1 and GDF15, CEACAM5, COMP, FCRL1, PTX3, AREG, SERPINA1, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, FCRL1, PTX3, AREG, TNC, NOTCH1, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, AREG, TNC, SERPINA1 and GDF15, CEACAM5, FCRL1, PTX3, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, AREG, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, TNC, NOTCH1, SERPINA1 and EDA2R,CEACAM5, COMP, FCRL1, PTX3, AREG, NOTCH1, SERPINA1 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, AREG, TNC, GDF15 and EDA2R, TMPRSS15, FCRL1, PTX3, AREG, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, TNC, NOTCH1 and GDF15, TMPRSS15, CEACAM5, PTX3, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, AREG, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, FCRL1, PTX3, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, AREG, TNC, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, FCRL1, AREG, TNC, NOTCH1, GDF15 and EDA2R, COMP, FCRL1, AREG, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, AREG, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, TNC, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, AREG, TNC, NOTCH1, SERPINA1 and GDF15, CEACAM5, COMP, PTX3, AREG, TNC, SERPINA1, GDF15 and EDA2R, CEACAM5, FCRL1, PTX3, AREG, TNC, NOTCH1, GDF15 and EDA2R, TMPRSS15, FCRL1, AREG, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, TNC, SERPINA1, GDF15 and EDA2R, COMP, FCRL1, PTX3, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, FCRL1, PTX3, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R,TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, AREG, TNC and NOTCH1, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, FCRL1, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, CEACAM5, FCRL1, PTX3, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, AREG, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, FCRL1, PTX3, AREG, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, FCRL1, PTX3, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, FCRL1, PTX3, AREG, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, CEACAM5, PTX3, AREG, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, NOTCH1, SERPINA1 and EDA2R, CEACAM5, FCRL1, PTX3, AREG, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, PTX3, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, FCRL1, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, AREG, TNC, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, AREG, TNC and SERPINA1, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, TNC, NOTCH1 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG, TNC, NOTCH1 and SERPINA1,TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, TNC, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, FCRL1, AREG, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, TNC, SERPINA1 and GDF15, CEACAM5, FCRL1, PTX3, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, TNC, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, AREG, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, TNC, NOTCH1 and SERPINA1, TMPRSS15, CEACAM5, PTX3, AREG, TNC, SERPINA1, GDF15 and EDA2R, CEACAM5, FCRL1, AREG, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, TMPRSS15, COMP, FCRL1, PTX3, AREG, TNC, NOTCH1 and SERPINA1, CEACAM5, COMP, FCRL1, PTX3, AREG, TNC, NOTCH1 and SERPINA1, or CEACAM5, FCRL1, PTX3, AREG, TNC, SERPINA1, GDF15 and EDA2R.,

[0085] Preferably, A further comprises at least one of K, the union of K and A is B, and K and A have no intersection (for example: if A comprises FCRL1, then K is B without FCRL1).

[0086] Preferably, the test sample of the product is selected from at least one of the body fluids, tissues, cells, and excreta of the subject to be tested; further preferably, it is body fluid.

[0087] Preferably, the body fluid comprises at least one of blood, lymph, pleural effusion, cerebrospinal fluid, synovial fluid, ascites, saliva, lymph, and internal fluid; further preferably, it is blood.

[0088] Preferably, the tissue comprises intestinal mucosal tissue.

[0089] Preferably, the blood comprises at least one of serum, plasma, dried blood spot, and whole blood; further preferably, it is serum.

[0090] Preferably, the excrement contains at least one of urine, feces, tears, and sweat.

[0091] Preferably, the test sample is selected from the serum of the subject to be tested.

[0092] Preferably, the subject to be tested includes mammals, such as humans, non-human primates (such as orangutans, apes), rodents (such as rats, mice, guinea pigs), pets (such as cats, dogs), and livestock (such as horses, cows, sheep, pigs, rabbits).

[0093] Preferably, the subject to be tested includes humans.

[0094] Preferably, the substance for detecting the biomarker includes the substance for quantitatively detecting the biomarker.

[0095] Preferably, the substance for detecting the biomarker includes the substance for detecting the biomarker at the gene level and / or protein level.

[0096] Preferably, the substance includes the substance for one or more of the following detection techniques or methods: immunohistochemistry, Western blotting, Northern blotting, PCR, biochip method, nucleic acid sequencing, amino acid sequencing, high performance liquid chromatography, capillary gel electrophoresis, near-infrared spectroscopy, mass spectrometry, surface plasmon resonance technology, immuno-PCR technology, biotin-avidin technology.

[0097] Preferably, the immunohistochemistry includes at least one of enzyme-linked immunosorbent assay, immunofluorescence, radioimmunoassay, immunoprecipitation, immunochemiluminescence, colloidal gold immunoassay, fluorescence immunochromatography, complement fixation assay, flow cytometry fluorescence resolution, single molecule detection technology; further preferably enzyme-linked immunosorbent assay; and even more preferably sandwich ELISA.

[0098] Preferably, the substance for detecting the biomarker is selected from one or more of: a substance specific to the biomarker, a probe specific to the biomarker, a gene chip, a protein chip, and a PCR primer.

[0099] Preferably, the substance specific to the biomarker includes any one of h1) to h4):

[0100] h1) An antibody that specifically binds to the biomarker;

[0101] h2) A ligand protein or polypeptide that specifically binds to the biomarker;

[0102] h3) A non-protein compound that specifically recognizes the biomarker;

[0103] h4) A nucleic acid aptamer that specifically recognizes the biomarker.

[0104] Preferably, the antibody comprises at least one of a polyclonal antibody, a monoclonal antibody, a single-chain antibody, a functional antibody fragment, an antibody Fab region, a nanobody, a chimeric antibody, and a multispecific antibody.

[0105] Preferably, the product comprises at least one of a reagent, a kit, a test strip, a chip, a device, and a system.

[0106] Preferably, the product further comprises a substance for detecting other markers for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer. For example, the markers may be SNORD15B and SNORA5C disclosed in CN114959028A, ring finger protein 32 disclosed in CN109852698A, RANBP1 disclosed in CN111848773A, etc.

[0107] Preferably, the product further comprises an auxiliary reagent for detecting gene expression levels, and the auxiliary reagent for detecting gene expression levels includes at least one of a reaction reagent for visualizing an amplicon corresponding to a primer, an RNA extraction reagent, a reverse transcription reagent, a cDNA amplification reagent, a standard for preparing a standard curve, and a positive control.

[0108] Preferably, the product further comprises an auxiliary reagent for detecting protein expression levels, and the auxiliary reagent for detecting protein expression levels includes at least one of a chromogenic agent, a blocking solution, an antibody diluent, a washing buffer, a chromogenic termination solution, a standard for preparing a standard curve, and a positive control.

[0109] Preferably, the colorectal cancer includes early-stage colorectal cancer (stage I and stage II) and / or advanced-stage colorectal cancer (stage III and stage IV).

[0110] Preferably, the staging is for differentiating early-stage colorectal cancer (stage I and stage II) from advanced-stage colorectal cancer (stage III and stage IV).

[0111] In the second aspect of the present invention, there is provided a marker combination, which comprises at least two of those described in B in the first aspect of the present invention, and can be 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, 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, or 90 kinds of those in B.

[0112] Preferably, the marker combination comprises:

[0113] k1) FCRL1; and

[0114] k2) at least one of those in B;

[0115] Any one marker in k2) is different from k1).

[0116] Preferably, the marker combination comprises:

[0117] j1) AREG; and

[0118] j2) at least one of those in B;

[0119] Any one marker in j2) is different from j1).

[0120] Preferably, the marker combination comprises any 2, 3, 4, 5, 6, 7, or 8 kinds of those in B.

[0121] Preferably, the marker combination comprises a 2 - markers combination, a 3 - markers combination, a 4 - markers combination, a 5 - markers combination, a 6 - markers combination, a 7 - markers combination, or an 8 - markers combination in the first aspect of the present invention.

[0122] Preferably, the marker combination further comprises markers for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of other colorectal cancers. For example, the markers can be SNORD15B and SNORA5C disclosed in CN114959028A, ring finger protein 32 disclosed in CN109852698A, RANBP1 disclosed in CN111848773A, etc.

[0123] Preferably, the marker combination is used for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer.

[0124] Preferably, the marker combination is derived from at least one of the body fluid, tissue, cell, and excrement of the subject to be tested; further preferably, it is body fluid.

[0125] Preferably, the subject to be tested, body fluid, tissue, cell, or excrement is the subject to be tested, body fluid, tissue, cell, or excrement in the first aspect of the present invention.

[0126] Preferably, the colorectal cancer includes early-stage colorectal cancer (stage I and stage II) and / or advanced-stage colorectal cancer (stage III and stage IV).

[0127] Preferably, the staging is to distinguish early-stage colorectal cancer (stage I and stage II) from advanced-stage colorectal cancer (stage III and stage IV).

[0128] In the third aspect of the present invention, there is provided a product comprising a substance for detecting the marker combination in the second aspect of the present invention.

[0129] Preferably, the product is used for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer.

[0130] Preferably, the substance for detecting the marker combination includes a substance for quantitatively detecting the marker combination.

[0131] Preferably, the substance for detecting the marker combination includes a substance for detecting the marker combination at the gene level and / or protein level.

[0132] Preferably, the substance includes a substance for one or more detection techniques or methods selected from the following group: immunohistochemistry, Western blotting, Northern blotting, PCR, biochip method, nucleic acid sequencing method, amino acid sequencing method, high performance liquid chromatography, capillary gel electrophoresis, near-infrared spectroscopy, mass spectrometry, surface plasmon resonance technology, immun-PCR technology, biotin-avidin technology.

[0133] Preferably, the immunohistochemistry method includes at least one of enzyme-linked immunosorbent assay, immunofluorescence assay, radioimmunoassay, immunoprecipitation, immunochemiluminescence assay, colloidal gold immunotechnology, fluorescence immunochromatography technology, complement fixation analysis, flow cytometry fluorescence resolution, single molecule detection technology; further preferably enzyme-linked immunosorbent assay; more preferably sandwich ELISA.

[0134] Preferably, the substances of the detection marker combination are selected from one or more of: substances specific to the marker, probes specific to the marker, gene chips, protein chips, PCR primers.

[0135] Preferably, the substance specific to the marker includes any one of h1) to h4):

[0136] h1) An antibody that specifically binds to the marker;

[0137] h2) A ligand protein or polypeptide that specifically binds to the marker;

[0138] h3) A non-protein compound that specifically recognizes the marker;

[0139] h4) An aptamer that specifically recognizes the marker.

[0140] Preferably, the antibody includes at least one of polyclonal antibody, monoclonal antibody, single-chain antibody, functional antibody fragment, Fab region of antibody, nanobody, chimeric antibody, multispecific antibody.

[0141] Preferably, the product includes at least one of reagent, kit, test strip, chip, device, system.

[0142] Preferably, the product further includes substances for detecting other markers used for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer. For example, the markers can be SNORD15B and SNORA5C disclosed in CN114959028A, ring finger protein 32 disclosed in CN109852698A, RANBP1 disclosed in CN111848773A, etc.

[0143] Preferably, the product further includes a reagent for assisting in detecting gene expression levels. The reagent for assisting in detecting gene expression levels includes at least one of reaction reagents for visualizing the amplicon corresponding to the primer, RNA extraction reagent, reverse transcription reagent, cDNA amplification reagent, standard product for preparing the standard curve, and positive control product.

[0144] Preferably, the product further comprises an auxiliary detection reagent for protein expression level, and the auxiliary detection reagent for protein expression level comprises at least one of a chromogenic agent, a blocking solution, an antibody diluent, a washing buffer, a chromogenic termination solution, a standard product for preparing a standard curve, and a positive control product.

[0145] Preferably, the colorectal cancer includes early-stage colorectal cancer (stage I and stage II) and / or advanced-stage colorectal cancer (stage III and stage IV).

[0146] Preferably, the staging is for differentiating early-stage colorectal cancer (stage I and stage II) from advanced-stage colorectal cancer (stage III and stage IV).

[0147] In a fourth aspect of the present invention, there is provided a method for constructing a model, and the method comprises the step of using the biomarker in the first aspect of the present invention for model construction.

[0148] Preferably, the method comprises the step of using the biomarker combination in the second aspect of the present invention for model construction.

[0149] Preferably, the model is used for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer.

[0150] Preferably, the algorithm for constructing the model comprises at least one of logistic regression, linear discriminant analysis, linear discriminant analysis of characteristic genes, support vector machine, random forest (RandomRorest), recursive partitioning tree, XGBoost, Shrunken Centroids, StepAIC, Kth-Nearest Neighbor, Boosting, neural network, Bayesian network, and hidden Markov model; and further comprises at least one of random forest (RandomRorest) and XGBoost.

[0151] Preferably, the colorectal cancer includes early-stage colorectal cancer (stage I and stage II) and / or advanced-stage colorectal cancer (stage III and stage IV).

[0152] Preferably, the staging is for differentiating early-stage colorectal cancer (stage I and stage II) from advanced-stage colorectal cancer (stage III and stage IV).

[0153] In a fifth aspect of the present invention, there is provided a device or system, comprising:

[0154] A detection module: for detecting the content, activity, and / or expression level of the biomarker in the first aspect of the present invention in a test sample; and

[0155] Analysis module: configured to input the data obtained by the detection module into a model constructed according to the construction method of the fourth aspect of the present invention for analysis.

[0156] Preferably, the device or system is used for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer.

[0157] Preferably, the detection module is configured to detect the content, activity, and / or expression level of the biomarker combination of the second aspect of the present invention in a test sample.

[0158] Preferably, the test sample is the test sample of the first aspect of the present invention.

[0159] Preferably, the device or system further comprises: an output module, configured to output information according to the analysis result obtained by the analysis module.

[0160] Preferably, the colorectal cancer includes early-stage colorectal cancer (stage I and stage II) and / or advanced-stage colorectal cancer (stage III and stage IV).

[0161] Preferably, the staging is to distinguish early-stage colorectal cancer (stage I and stage II) from advanced-stage colorectal cancer (stage III and stage IV).

[0162] In a sixth aspect of the present invention, there is provided a computer device, which includes a memory and a processor, the memory stores a program, and when the processor executes the program, any one of the following methods i1) - i2) is implemented:

[0163] i1) The construction method of the model of the fourth aspect of the present invention;

[0164] i2)

[0165] S1: Obtain the content, activity, and / or expression level of the biomarker in the test sample of the first aspect of the present invention; and

[0166] S2: Input the data obtained in S1 into a model constructed according to the construction method of the fourth aspect of the present invention for analysis.

[0167] Preferably, in i2), S1 is to obtain the content, activity, and / or expression level of the biomarker combination of the second aspect of the present invention in the test sample.

[0168] Preferably, the test sample is the test sample of the first aspect of the present invention.

[0169] Preferably, i2) further includes the following step: output information according to the obtained analysis result.

[0170] The seventh aspect of the present invention provides a computer-readable storage medium, which includes a stored computer program; wherein, when the computer program runs, it controls the computer-readable storage medium to implement any one of the methods i1) to i2) in the sixth aspect of the present invention.

[0171] The eighth aspect of the present invention provides a method for constructing a colorectal cancer model, by adjusting the content, expression level, and / or activity of the biomarker in the first aspect of the present invention in the model:

[0172] When the content, expression level, and / or activity of the biomarker in a test subject with colorectal cancer is increased relative to a test subject without colorectal cancer (preferably a healthy test subject), increase the content, expression level, and / or activity of the biomarker in the model;

[0173] When the content, expression level, and / or activity of the biomarker in a test subject with colorectal cancer is decreased relative to a test subject without colorectal cancer (preferably a healthy test subject), decrease the content, expression level, and / or activity of the biomarker in the model.

[0174] Preferably, the model is an animal model.

[0175] Preferably, the animal is a rat, a mouse, or a guinea pig.

[0176] Preferably, the colorectal cancer includes early-stage colorectal cancer (stage I and stage II) and / or advanced-stage colorectal cancer (stage III and stage IV).

[0177] The ninth aspect of the present invention provides a method for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer, which includes the step of detecting the content, expression level, and / or activity of the biomarker in the first aspect of the present invention in a test sample.

[0178] Preferably, the method includes the step of detecting the content, expression level, and / or activity of the biomarker combination in the second aspect of the present invention in a test sample.

[0179] Preferably, the test sample is the test sample in the first aspect of the present invention.

[0180] Preferably, use the product in the first aspect of the present invention to detect the content, expression level, and / or activity of the biomarker in the first aspect of the present invention in a test sample.

[0181] Preferably, use the product in the third aspect of the present invention to detect the content, expression level, and / or activity of the biomarker combination in the second aspect of the present invention in a test sample.

[0182] Preferably, the method further comprises the following steps: inputting data on the content, expression level, and / or activity of the biomarker in the first aspect of the present invention or the combination of biomarkers in the second aspect of the present invention in the test sample obtained into a model constructed according to the construction method in the fourth aspect of the present invention for analysis.

[0183] Preferably, the method further comprises the following steps: outputting information according to the obtained analysis result.

[0184] Preferably, the colorectal cancer includes early-stage colorectal cancer (stage I and stage II) and / or advanced-stage colorectal cancer (stage III and stage IV).

[0185] Preferably, the staging is to distinguish early-stage colorectal cancer (stage I and stage II) from advanced-stage colorectal cancer (stage III and stage IV).

[0186] The beneficial effects of the present invention are:

[0187] The present invention for the first time discloses one or more of ADAMTS8, ADGRE1, ADGRE2, ADGRE5, ADGRG2, AGR3, ANGPTL4, AREG, ASAH2, BAG3, BMP4, C9, CCL7, CD48, CDH23, CEACAM16, CEACAM5, CFP, CKAP4, CLEC3B, CNTN1, CNTN4, CNTN5, COMP, CRTAC1, DCC, DLK1, EDA2R, ENPP6, ESM1, EXTL1, FAP, FASLG, FCER2, FCRL1, FGF21, GCG, GDF15, GNAS, GRK5, GSN, HMCN2, IFNL1, IGDCC4, IGFBP1, IGSF3, IL4R, IL6, ITGA11, ITGA2, ITGAM, ITGB1, ITGB7, ITIH3, ITM2A, KRT19, LBP, LMNB2, LPL, MEGF9, MMP12, NOTCH1, NOTCH3, NOS2, NPY, NT5C1A, NTRK2, PCDH7, PGA4, PKD1, PLXDC1, PLXDC2, POF1B, PROK1, PTPRS, PTX3, RBFOX3, RET, SELL, SERPINA1, SOD3, SPON2, SPP1, TCL1A, THBS4, TMPRSS15, TNC, TNFRSF10B, TNFRSF11A, VSIG4 as markers for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer. By detecting the content, expression level, and / or activity of the above markers, early screening, diagnosis, severity evaluation, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer can be achieved. BRIEF DESCRIPTION OF THE DRAWINGS

[0188] Figure 1 It is a result graph of the comparison of AUC of the RandomForest model and the XGBboost model for some single markers.

[0189] Figure 2 It is an ROC curve graph of some combinations of 2 markers (TMPRSS15 and GDF15; SPP1 and ADGRE5).

[0190] Figure 3 It is a result graph of the comparison of AUC of the RandomForest model and the XGBboost model for some combinations of 2 markers.

[0191] Figure 4It is the ROC curve graph of partial 3 - markers combinations (SPP1, COMP, and FCRL1; TMPRSS15, SPP1, and SOD3; AREG, CEACAM5, and PLXDC2).

[0192] Figure 5 It is the result graph of the AUC comparison between the RandomForest model and the XGBboost model for partial 3 - markers combinations.

[0193] Figure 6 It is the ROC curve graph of partial 4 - markers combinations (SPP1, COMP, FCRL1, and LMNB2; ADGRE1, GDF15, PTX3, and THBS4).

[0194] Figure 7 It is the result graph of the AUC comparison between the RandomForest model and the XGBboost model for partial 4 - markers combinations.

[0195] Figure 8 It is the ROC curve graph of partial 5 - markers combinations (AREG, CEACAM5, PTX3, SPP1, and PLXDC2; TMPRSS15, COMP, PTX3, PGA4, and POF1B; SPP1, PLXDC2, SOD3, IL4R, and BAG3; NOTCH1, COMP, GDF15, PTX3, and PGA4).

[0196] Figure 9 It is the result graph of the AUC comparison between the RandomForest model and the XGBboost model for partial 5 - markers combinations.

[0197] Figure 10 It is the ROC curve graph of partial 6 - markers combinations (SPP1, PLXDC2, SOD3, IL4R, BAG3, and PROK1; AREG, CEACAM5, PTX3, CD48, CCL7, and IGFBP1; NOTCH1, COMP, GDF15, PTX3, PGA4, and CEACAM5).

[0198] Figure 11 It is the result graph of the AUC comparison between the RandomForest model and the XGBboost model for partial 6 - markers combinations.

[0199] Figure 12It is the ROC curve graph of part of the 7 - markers combinations (SPP1, COMP, LMNB2, PLXDC2, TCL1A, PROK1, and ADGRG2; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, and SOD3).

[0200] Figure 13 It is the result graph of the AUC comparison between the RandomForest model and the XGBboost model of part of the 7 - markers combinations.

[0201] Figure 14 It is the ROC curve graph of part of the 8 - markers combinations (PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PROK1, and PCDH7; SPP1, LMNB2, SOD3, ADGRE5, PLXDC1, PROK1, LBP, and FASLG).

[0202] Figure 15 It is the result graph of the AUC comparison between the RandomForest model and the XGBboost model of part of the 8 - markers combinations. Detailed implementation manners

[0203] The content of the present invention will be further described in detail through specific embodiments below.

[0204] It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention.

[0205] For the experimental methods without specific conditions noted in the following embodiments, they are usually in accordance with conventional conditions or the conditions recommended by the manufacturer. For the materials, reagents, etc. used in this embodiment, unless otherwise specified, they are reagents and materials obtained from commercial channels.

[0206] The information of the proteins involved in the following embodiments is shown in Table 1.

[0207] Table 1 Protein information

[0208]

[0209]

[0210]

[0211]

[0212]

[0213] Notes to Table 1: Ensembl ID is the gene search ID included in the Ensembl database; Uniprot ID is the protein search ID included in the Swiss-Prot sub-library of the UniProt protein database.

[0214] Example 1 Diagnostic markers for colorectal cancer

[0215] 1. Clinical Sample Collection

[0216] This embodiment collected 139 patients diagnosed with colorectal cancer in the hospital and 40 healthy people as controls, collected fresh blood samples before surgery in the hospital, and detected the protein expression level in the blood by the protein detection proximity extension technology PEA (Proximity Extension Assay) platform as a marker for modeling prediction. According to the clinical progression of the patient's disease, the patient group was divided into two groups: 139 cases in the colorectal cancer group, including 60 cases in the early stage (stage I and stage II), 79 cases in the late stage (stage III and stage IV), and 40 cases in the healthy group. All the colorectal cancers in the group were new diseases, and there were no other serious diseases and cancers. They had not received surgery or other treatments at the time of sampling. The age range of the colorectal cancer group in the experimental group was 28 to 83 years old, with an average age of 57.6 years old, and a male-female ratio of 85:54; the age range in the control group (healthy people) was 22 to 77 years old, with an average age of 51.5, and a male-female ratio of 9:31.

[0217] Sample inclusion criteria:

[0218] Inclusion criteria for the experimental group: (1) patients with confirmed preoperative colon or rectal cancer; (2) aged 18 to 80 years, regardless of gender; (3) no history of malignant tumors in other parts of the body; (4) no previous anti-tumor treatment before resection; (5) no history of blood transfusion in the past three years.

[0219] Sample exclusion criteria: (1) patients diagnosed with colorectal cancer who have completed surgical treatment or received radiotherapy, chemotherapy, and targeted drug treatment; (2) patients with other non-colorectal cancer tumors or other tumors with colorectal metastasis.

[0220] Clinical manifestations: 1) Experimental group: pathological examination showed the presence of cancer cells, and some patients had bloody stools, colorectal cramps, anemia, weakness and fatigue; 2) Control group: healthy people, without symptoms such as intestinal discomfort.

[0221] In this embodiment, the experimental group and the control group were patients who visited the Sixth Affiliated Hospital of Sun Yat-sen University from January 2021 to January 2023, and were recruited into the group strictly in accordance with the above inclusion criteria. A total of 139 patients diagnosed with colorectal cancer and 40 healthy individuals were recruited. Informed consent was obtained from the families of all subjects for all specimen collections, and the study was approved by the Institutional Review Board of the Sixth Affiliated Hospital of Sun Yat-sen University.

[0222] 2. Blood sample processing

[0223] 5 mL of peripheral venous blood from the enrolled patients and the healthy control group was collected using an EDTA anticoagulant purple-top tube, centrifuged for 10 minutes, the upper plasma was taken, and it was stored upright in a -80°C refrigerator.

[0224] 3. Protein detection

[0225] In this embodiment, the inventors performed plasma proteome detection on 179 plasma samples using the Proximity Extension Assay (PEA) platform. Specifically, in the detection, 3072 protein-specific antibodies were each separately labeled with unique PEA oligonucleotide probes. Each antibody was labeled with two independent and complementary sequences. These conjugated antibodies were mixed into eight independent 384-well plates, and each 384-well plate included 3 protein replicates for inter-plate quality control. During the detection process, 179 samples were randomly distributed on 3 different 96-well plates and incubated overnight at +4°C with the antibodies labeled with PEA probes. After the immunoreaction, an extension and pre-amplification mixture was added to the incubated samples at room temperature for PCR amplification. Then, before adding the individual sample index sequences, the PCR amplification products were mixed and then subjected to a second PCR amplification. After the samples were mixed, the generated library was purified by magnetic beads and quality-controlled on a Bioanalyzer. Finally, sequencing was performed using the Illumina NovaSeq 6000 instrument, with two S1 flow cells and a read length of 2 × 50 bases. The counts of known barcode sequences were then converted into normalized protein expression units (NPX) through a QC and normalization process, and a total of 2884 proteins were quantified.

[0226] 4. Construction of a colorectal cancer protein biomarker screening model

[0227] The inventors used the XGBoost machine learning method to evaluate potential proteins that could distinguish colorectal cancer from healthy individuals. To avoid bias in machine learning modeling due to sample selection, the Bootstrap method was used for 100 random modelings. In each modeling, 70% (125 cases) of the 139 colorectal cancer samples and 40 healthy controls were selected as the training set, and the remaining 30% (54 cases) were used as the test set.

[0228] (1) The independent colorectal cancer prediction ability of each protein was evaluated by AUC (area under the curve), sensitivity, and specificity. The mean value and confidence interval were calculated 100 times, and the proteins were ranked according to their prediction efficacy. Proteins with an AUC greater than 0.7 were selected.

[0229] (2) An XGBoost machine learning algorithm without restricting the number of proteins was used to build a model. Models with high classification accuracy were selected, and the weights and frequencies of each protein in the model were statistically analyzed to identify four key proteins, GDF15, PTX3, SPP1, and TMPRSS15, for constructing the prediction model.

[0230] (3) Among 2,884 proteins, the combination of each protein with one of GDF15, PTX3, SPP1, or TMPRSS15 was evaluated using the XGBoost machine learning method. AUC, sensitivity, and specificity were evaluated, and protein combinations with an AUC greater than 0.87 were selected.

[0231] After the above three steps, take the union of the proteins obtained in each step to get 90 markers: ADAMTS8, ADGRE1, ADGRE2, ADGRE5, ADGRG2, AGR3, ANGPTL4, AREG, ASAH2, BAG3, BMP4, C9, CCL7, CD48, CDH23, CEACAM16, CEACAM5, CFP, CKAP4, CLEC3B, CNTN1, CNTN4, CNTN5, COMP, CRTAC1, DCC, DLK1, EDA2R, ENPP6, ESM1, EXTL1, FAP, FASLG, FCER2, FCRL1, FGF21, GCG, GDF15, GNAS, GRK5, GSN, HMCN2, IFNL1, IGDCC4, IGFBP1, IGSF3, IL4R, IL6, ITGA11, ITGA2, ITGAM, ITGB1, ITGB7, ITIH3, ITM2A, KRT19, LBP, LMNB2, LPL, MEGF9, MMP12, NOTCH1, NOTCH3, NOS2, NPY, NT5C1A, NTRK2, PCDH7, PGA4, PKD1, PLXDC1, PLXDC2, POF1B, PROK1, PTPRS, PTX3, RBFOX3, RET, SELL, SERPINA1, SOD3, SPON2, SPP1, TCL1A, THBS4, TMPRSS15, TNC, TNFRSF10B, TNFRSF11A, VSIG4; all 90 proteins have significant differences, as shown in Table 2 specifically (where in Table 2: p.adj is the corrected P value of the t-test difference, Mean_CRC is the average expression value of this protein after normalization in colorectal cancer, Mean_Healthy is the average expression value of this protein after normalization in the healthy control population, logFC is the difference multiple of the average expression values in the two groups of samples (when logFC is greater than 0, it indicates that this protein is highly expressed in colorectal cancer patients; when logFC is less than 0, it indicates that this protein is lowly expressed in colorectal cancer patients), the same below); the AUC range of the 90 significantly different proteins is: 0.6107 - 0.8546. Among them, the AUC of 61 proteins for prediction efficacy is greater than 0.7, as shown in Table 3 specifically (where in Table 3, Mean_AUC represents the average AUC of 100 training classifications of this protein combination in the XGBoost machine learning model, sd_AUC is the standard deviation of the AUC of 100 training classifications, Median_AUC is the median value of the AUC of 100 training classifications, the same below). It can be seen that the above 90 markers can be used for the diagnosis of colorectal cancer.

[0232] Table 2 Ninety proteins with significant differences in the training set

[0233]

[0234]

[0235]

[0236] Table 3. 61 proteins with AUC greater than 0.7 in the prediction efficacy of the test set

[0237]

[0238]

[0239]

[0240] Furthermore, in order to verify the accuracy and stability of the selected markers above, the inventor used the machine learning method of RandoForest to perform modeling prediction analysis on the above 10 markers with better performance. The modeling method is as follows: randomly select 70% (125 cases) of 139 colorectal cancer samples and 40 healthy controls as the training set, and the remaining 30% (54 cases) as the test set. Conduct 100 times of model training, and then statistically compare the average value of the AUC of the 100 times of models with that of XGBboost. The results are as Figure 1 shown: The AUC consistency between the RandomForest model and the XGBboost model is very good: the average AUC of the 100 random models is basically equivalent, and the standard deviation SD (black line) of the AUC of the 100 random models is also very close, that is, the stability is also very close; indicating the replaceability of the model algorithm in the implementation column scheme.

[0241] Among the above 90 protein markers, the combination marker examples are as follows, respectively using but not limited to combinations of 2, 3, 4, 5, 6, 7, and 8 proteins. Use the XGBoost machine learning method to evaluate the AUC, sensitivity, and specificity of each combination, and use the Random Forest machine learning method to further verify the combinations with excellent effects, specifically as follows:

[0242] 2-marker combinations: Among 90 markers, all proteins are arranged and combined, resulting in a total of 90 * 89 / 2 = 4005 combinations. The range of the predicted efficacy AUC values is 0.653 - 0.92, that is, the above 4005 2-marker combinations can be used for the diagnosis of colorectal cancer; among them, any two combinations of the 30 markers ADGRE5, ADGRG2, AREG, CEACAM5, CLEC3B, CNTN5, COMP, EDA2R, ENPP6, EXTL1, FASLG, FCRL1, GDF15, HMCN2, ITGA11, ITGA2, ITGAM, ITGB7, KRT19, LMNB2, PLXDC1, PLXDC2, POF1B, PTX3, RET, SELL, SOD3, SPP1, THBS4, TMPRSS15, a total of 435 combinations, the range of the predicted efficacy AUC values is 0.79 - 0.92, and among them, the AUC of 427 combinations is greater than 0.8, as shown in Table 4. This group of proteins has relatively high and stable predicted AUC. For example: TMPRSS15 and GDF15; TMPRSS15 and SPP1; TMPRSS15 and KRT19, etc.; The ROC curves of some 2-marker combinations (TMPRSS15 and GDF15; SPP1 and ADGRE5) are as Figure 2 shown.

[0243] Among the 2-marker permutations and combinations of 90 markers (that is, excluding the above 435 marker combinations from the above 4005 marker combinations), there are also some 2-marker combinations with good protein complementarity, and their AUC is greater than 0.85, as shown in Table 5 specifically. The range of the predicted efficacy AUC values is 0.85 - 0.92. The 2-marker combinations shown in Table 5 can be used for the diagnosis of colorectal cancer.

[0244] At the same time, some of the 2-marker combinations shown in Table 6 (combinations of any two of the 11 protein markers AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1) were verified individually, and the results are shown in Table 6. The range of the predicted efficacy AUC values is 0.7458 - 0.8486. The 2-marker combinations shown in Table 6 can be used for the diagnosis of colorectal cancer.

[0245] The comparison results of the AUC of the RandomRorest model and the XGBboost model are as Figure 3As shown: The AUC consistency between the RandomRorest model and the XGBboost model is very good. The average AUC of 100 random models is basically equivalent, and the standard deviation SD (black line) of the AUC of 100 random models is also very close, that is, the stability is also very close, indicating the replaceability of the model algorithms in the implementation column scheme.

[0246] Table 4 Combinations of 2 markers with a predicted efficacy AUC greater than or equal to 0.8 in the test set (combinations of any two of the 30 proteins)

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259] Table 5 Combinations of 2 markers with a partial predicted efficacy AUC greater than or equal to 0.85 in the test set (excluding the above 435 marker combinations from the above 4005 marker combinations)

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269] Table 6. Some combinations of 2 markers with a predicted efficacy AUC greater than or equal to 0.74 in the test set (partial 2 - marker combinations from the combinations of any two of the 11 protein markers: AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1)

[0270] gene Mean_AUC sd_AUC Median_AUC NOTCH1_TMPRSS15 0.8486 0.0503 0.8574 PTX3_TNC 0.8469 0.0512 0.8508 COMP_SERPINA1 0.8459 0.0522 0.8498 NOTCH1_CEACAM5 0.8448 0.0486 0.8479 COMP_TNC 0.8422 0.0579 0.8430 FCRL1_SERPINA1 0.8369 0.0536 0.8368 NOTCH1_SERPINA1 0.8361 0.0517 0.8392 CEACAM5_SERPINA1 0.8310 0.0622 0.8322 PTX3_SERPINA1 0.8248 0.0475 0.8216 NOTCH1_AREG 0.8240 0.0525 0.8274 NOTCH1_FCRL1 0.8209 0.0604 0.8298 FCRL1_TNC 0.8018 0.0611 0.8032 CEACAM5_TNC 0.7995 0.0610 0.8060 NOTCH1_TNC 0.7736 0.0742 0.7817 NOTCH1_COMP 0.7878 0.0591 0.7991 AREG_TNC 0.7458 0.0628 0.7442 SERPINA1_TNC 0.7531 0.0569 0.7591 SERPINA1_AREG 0.7489 0.0582 0.7551

[0271] 3 - marker combinations: 90 markers are arranged and combined into 90 * 89 * 88 / 6 = 117480 combinations. For example: SPP1, COMP, and FCRL1; TMPRSS15, SPP1, and SOD3; PTX3, GDF15, and THBS4, etc. The range of the predicted efficacy AUC values of these 117480 3 - marker combinations is 0.66 - 0.9543 (since there are too many combinations, the AUC values of the 3 - marker combinations are not listed one by one, only the range of the AUC values of the 117480 3 - marker combinations is given to show the diagnostic effect of the above 117480 3 - marker combinations), and the average AUC is 0.8388. Among them, the range of the predicted efficacy AUC values of the 3 - marker combinations in Table 7 is 0.92 - 0.9543, the range of sensitivity is 0.6856 - 0.9374, and the range of specificity is 0.716 - 0.9842; among them, some 3 - marker combinations with an AUC greater than or equal to 0.92 are shown in Table 7 (where, in Table 7, Mean_AUC represents the average AUC of 100 training classifications of the protein combination in the XGBoost machine learning model, sd_AUC is the standard deviation of the AUC of 100 training classifications, Median_AUC is the median value of the AUC of 100 training classifications, specificity is the average specificity of 100 training classifications, sensitivity is the average sensitivity of 100 training classifications, accuracy is the average accuracy rate of 100 training classifications, ppv is the positive predictive value, and npv is the negative predictive value, the same below), and the ROC curves of some 3 - marker combinations (SPP1, COMP, and FCRL1; TMPRSS15, SPP1, and SOD3; AREG, CEACAM5, and PLXDC2) are as Figure 4As shown. It can be seen that the above 117,480 3 - markers combinations can be used for the diagnosis of colorectal cancer.

[0272] At the same time, some of the 3 - markers combinations shown in Table 8 (combinations of any three of the 11 protein markers: AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1) were verified separately. The results are shown in Table 8, and the range of the AUC values of the prediction efficacy is 0.7458 - 0.8486. The 3 - markers combinations shown in Table 8 can be used for the diagnosis of colorectal cancer.

[0273] The comparison results of the AUC of the RandomForest model and the XGBboost model are as Figure 5 shown: The AUC consistency of the RandomForest model and the XGBboost model is very good: The average AUC of 100 random models is basically the same, and the standard deviation SD (black line) of the AUC of 100 random models is also very close, that is, the stability is also very close; indicating the replaceability of the model algorithms in the implementation column scheme.

[0274] Table 7 Some 3 - markers combinations in the test set with the prediction efficacy AUC greater than or equal to 0.92 (the above 117,480 markers combinations)

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309] Table 8 Combinations of 3 markers with a predicted efficacy AUC greater than or equal to 0.77 in the test set (partial 3 - marker combinations among combinations of any three of the 11 protein markers: AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1)

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318] 4-marker combinations: Based on the combinations in the 3-marker combinations with an AUC greater than or equal to 0.92 (622 combinations, Table 7, i.e., the 622 3-marker combinations in the invention content), combined with the remaining 87 proteins (i.e., 90 proteins minus 3 proteins in the 3-marker combinations), there are a total of 622*(90 - 3) = 54114 combinations. For example: ADGRE1, GDF15, PTX3, and THBS4; PTX3, HMCN2, POF1B, and FASLG; SPP1, COMP, FCRL1, and LMNB2; etc.; The range of the predicted efficacy AUC values of these 54114 4-marker combinations is 0.856 - 0.9687. Among them, the range of the predicted efficacy AUC values of the 4-marker combinations in Table 9 is 0.950 - 0.9687, the range of sensitivity is 0.7643 - 0.9477, and the range of specificity is 0.7685 - 0.9817 (due to the large number of combinations, the AUC values of the 4-marker combinations are not listed one by one, only the range of the AUC values of the 54114 4-marker combinations is given to show the diagnostic effect of the above 54114 4-marker combinations); Among them, some 4-marker combinations with an AUC greater than or equal to 0.95 are shown in Table 9, and the ROC curves of some 4-marker combinations (SPP1, COMP, FCRL1, and LMNB2; ADGRE1, GDF15, PTX3, and THBS4;) are as Figure 6 shown. It can be seen that the above 54114 4-marker combinations can be used for the diagnosis of colorectal cancer.

[0319] At the same time, some of the 4-marker combinations (combinations of any four of the 11 protein markers AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1) shown in Table 10 were verified separately, and the results are shown in Table 10. The range of the predicted efficacy AUC values is 0.8121 - 0.9494. The 4-marker combinations shown in Table 10 can be used for the diagnosis of colorectal cancer.

[0320] The comparison results of the AUC of the RandomForest model and the XGBboost model are as Figure 7 shown: The AUC consistency of the RandomForest model and the XGBboost model is very good: The average AUC of 100 random models is basically the same, and the standard deviation SD (black line) of the AUC of 100 random models is also very close, that is, the stability is also very close; indicating the replaceability of the model algorithms in the implementation column scheme.

[0321] Table 9 Combinations of 4 markers with predicted efficacy AUC greater than or equal to 0.95 in the test set (among the above 54,114 combinations of 4 markers)

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341] Table 10 Combinations of 4 markers with predicted efficacy AUC greater than or equal to 0.81 in the test set (partial 4-marker combinations among combinations of any four of the 11 protein markers AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1)

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359] 5 - marker combinations: To further verify the effectiveness of each protein, based on the combinations with an AUC of greater than or equal to 0.95 in the 4 - marker combinations (332 combinations, Table 9, i.e., the 332 4 - marker combinations in the invention content), and the remaining 86 proteins (i.e., 90 proteins minus the 4 proteins in the 4 - marker combinations), 332×(90 - 4)=28552 combinations were formed. For example: AREG, CEACAM5, PTX3, SPP1, and PLXDC2; TMPRSS15, COMP, PTX3, PGA4, and POF1B; SPP1, PLXDC2, SOD3, IL4R, and BAG3; NOTCH1, COMP, GDF15, PTX3, and PGA4, etc.; The range of the AUC values of the predictive power of these 28552 5 - marker combinations is 0.93 - 0.9886, the range of sensitivity is 0.7465 - 0.9483, and the range of specificity is 0.7683 - 0.9900 (due to the large number of combinations, the AUC values, sensitivity, and specificity of the 5 - marker combinations are not listed one by one, only the range values of the AUC values, sensitivity, and specificity of the 28552 5 - marker combinations are given to show the diagnostic effects of the above 28552 5 - marker combinations); Among them, some 5 - marker combinations with an AUC greater than or equal to 0.965 are shown in Table 11, and the ROC curves of some 5 - marker combinations (AREG, CEACAM5, PTX3, SPP1, and PLXDC2; TMPRSS15, COMP, PTX3, PGA4, and POF1B; SPP1, PLXDC2, SOD3, IL4R, and BAG3; NOTCH1, COMP, GDF15, PTX3, and PGA4;) are as Figure 8 shown. It can be seen that the above 28552 5 - marker combinations can be used for the diagnosis of colorectal cancer.

[0360] At the same time, some of the 5 - marker combinations shown in Table 12 (i.e., some of the combinations of any five of the 11 protein markers AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1) were verified separately, and the results are shown in Table 12. The range of the AUC values of the predictive power is 0.8466 - 0.9648. The 5 - marker combinations shown in Table 12 can be used for the diagnosis of colorectal cancer.

[0361] The comparison results of the AUC of the RandomForest model and the XGBboost model are as Figure 9As shown: The AUC consistency of the RandomForest model and the XGBboost model is very good. The average AUC of 100 random models is basically equivalent, and the standard deviation SD (black line) of the AUC of 100 random models is also very close, that is, the stability is also very close, indicating the replaceability of the model algorithms in the implementation column scheme.

[0362] Table 11 Combinations of 5 markers with predicted efficacy AUC greater than or equal to 0.965 in the test set (the above 28,552 combinations of 5 markers)

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390] Table 12: Some combinations of 5 markers with predicted efficacy AUC ≥ 0.84 in the test set (partial 5 - marker combinations among the combinations of any five of the 11 protein markers AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1)

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416] 6 - marker combinations: Based on the combinations (486 combinations) with an AUC greater than or equal to 0.965 among the 5 - marker combinations, among the combinations with 4 protein repetitions, select the combination with the highest AUC, eliminate other combinations, and the remaining 63 combinations (the italicized 5 - marker combinations in Table 11, which are the 63 5 - marker combinations in the invention content), and combine them with the remaining 85 proteins (i.e., 90 proteins minus the 5 proteins in the 5 - marker combinations) to form 63×(90 - 5)=5355 combinations. For example, SPP1, PLXDC2, SOD3, IL4R, BAG3, and PROK1; AREG, CEACAM5, PTX3, CD48, CCL7, and IGFBP1; NOTCH1, COMP, GDF15, PTX3, PGA4, and CEACAM5, etc.; The range of the AUC values of the predictive power of these 5355 6 - marker combinations is 0.954 - 0.9836, the range of sensitivity is 0.801 - 0.964, and the range of specificity is 0.809 - 0.989 (due to the large number of combinations, the AUC values, sensitivity, and specificity of the 6 - marker combinations are not listed one by one, only the range values of the AUC values, sensitivity, and specificity of the 5355 6 - marker combinations are given to show the diagnostic effect of the above 5355 6 - marker combinations); Among them, some 6 - marker combinations with an AUC greater than or equal to 0.975 are shown in Table 13, and the ROC curves of some 6 - marker combinations (SPP1, PLXDC2, SOD3, IL4R, BAG3, and PROK1; AREG, CEACAM5, PTX3, CD48, CCL7, and IGFBP1; NOTCH1, COMP, GDF15, PTX3, PGA4, and CEACAM5) are as Figure 10 shown. It can be seen that the above 5355 6 - marker combinations can be used for the diagnosis of colorectal cancer.

[0417] At the same time, some of the 6 - marker combinations shown in Table 14 (some 6 - marker combinations among the combinations of any six of the 11 protein markers AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1) were verified separately, and the results are shown in Table 14. The range of the AUC values of the predictive power is 0.8832 - 0.9714. The 6 - marker combinations shown in Table 14 can be used for the diagnosis of colorectal cancer.

[0418] The comparison results of the AUC of the RandomRorest model and the XGBboost model are as Figure 11As shown: The AUC consistency of the RandomRorest model and the XGBboost model is very good. The average AUC of 100 random models is basically equivalent, and the standard deviation SD (black line) of the AUC of 100 random models is also very close, that is, the stability is also very close, indicating the replaceability of the model algorithms in the implementation column scheme.

[0419] Table 13 6 - markers combinations with predicted efficacy AUC greater than or equal to 0.975 in the test set (among the above 5355 6 - markers combinations)

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

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[0447]

[0448]

[0449]

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[0452]

[0453]

[0454]

[0455] Table 14 Partial 6 - marker combinations with predicted efficacy AUC ≥ 0.88 in the test set (partial 6 - marker combinations from combinations of any six of the 11 protein markers: AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1)

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

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[0477]

[0478]

[0479]

[0480]

[0481] 7 - marker combinations: Based on the combinations (650 combinations) with an AUC greater than or equal to 0.975 among the 6 - marker combinations, among the combinations with 5 protein repetitions, the combination with the highest AUC was selected, and other combinations were excluded, resulting in 84 combinations (the italic 6 - marker combinations in Table 13, which are the 84 6 - marker combinations in the invention content), and these 84 proteins were combined with the remaining proteins to form 84*(90 - 6)=7056 combinations. For example, SPP1, COMP, LMNB2, PLXDC2, TCL1A, PROK1, and ADGRG2; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, and SOD3, etc.; the range of the AUC values of the predictive power of these 7056 7 - marker combinations is 0.961 - 0.989, the range of sensitivity is 0.7113 - 0.96, and the range of specificity is 0.7916 - 0.9868 (due to the large number of combinations, the AUC values, sensitivity, and specificity of the 7 - marker combinations are not listed one by one, and only the range values of the AUC values, sensitivity, and specificity of the 7056 7 - marker combinations are given to show the diagnostic effect of the above 7056 7 - marker combinations); among them, some 7 - marker combinations with an AUC greater than or equal to 0.987 are shown in Table 15, and the ROC curves of some 7 - marker combinations (SPP1, COMP, LMNB2, PLXDC2, TCL1A, PROK1, and ADGRG2;

[0482] PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, and SOD3) are as Figure 12 shown. It can be seen that the above 7056 7 - marker combinations can be used for the diagnosis of colorectal cancer.

[0483] At the same time, the 7 - marker combinations shown in Table 16 (some 7 - marker combinations in any combination of seven of the 11 protein markers AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1) were separately verified, and the results are shown in Table 16. The range of the AUC values of the predictive power is 0.8884 - 0.9751. The 7 - marker combinations shown in Table 16 can be used for the diagnosis of colorectal cancer.

[0484] The comparison results of the AUC of the RandomForest model and the XGBboost model are as Figure 13Shown as follows: The AUC consistency between the RandomForest model and the XGBboost model is very good. The average AUC of 100 random models is basically the same, and the standard deviation SD (black line) of the AUC of 100 random models is also very close, that is, the stability is also very close, indicating the replaceability of the model algorithms in the implementation column scheme.

[0485] Table 15 Combinations of 7 markers with a predicted efficacy AUC greater than or equal to 0.985 in the test set (the above 7056 combinations of 7 markers)

[0486]

[0487]

[0488]

[0489] Table 16 Combinations of 7 markers with a predicted efficacy AUC greater than or equal to 0.88 in the test set (partial 7-marker combinations among the combinations of any seven of the 11 protein markers AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1)

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508] 8 - marker combinations: Based on the combinations (40 combinations, the 7 - marker combinations in Table 15, which are the 40 7 - marker combinations in the invention content) where the AUC is greater than or equal to 0.985 among the 7 - markers, and combined with the remaining 83 proteins (i.e., 90 proteins minus the 7 proteins in the 7 - marker combinations), 40×(90 - 7)=3320 combinations are formed. For example, PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PROK1, and PCDH7; SPP1, LMNB2, SOD3, ADGRE5, PLXDC1, PROK1, LBP, and FASLG, etc.; the range of the AUC values of the predictive efficacy of these 3320 8 - marker combinations is 0.953 - 0.992, the range of the sensitivity is 0.798 - 0.9685, and the range of the specificity is 0.8264 - 0.9855. Due to the large number of combinations, the AUC values, sensitivity, and specificity of the 8 - marker combinations are not listed one by one. Only the range values of the AUC values, sensitivity, and specificity of the 3320 8 - marker combinations are given to show the diagnostic effect of the above 3403 8 - marker combinations); among them, some 8 - marker combinations with AUC greater than or equal to 0.987 are shown in Table 17, and the ROC curves of some 8 - marker combinations (PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PROK1, and PCDH7; SPP1, LMNB2, SOD3, ADGRE5, PLXDC1, PROK1, LBP, and FASLG) are as Figure 14 shown. It can be seen that the above 3320 8 - marker combinations can be used for the diagnosis of colorectal cancer.

[0509] Meanwhile, the 8 - markers combinations shown in Table 18 (partial 8 - markers combinations among the combinations of any eight of the 11 protein markers AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1) were verified separately. The results are shown in Table 18, and the range of the predicted efficacy AUC value is 0.9121 - 0.9740. The 8 - markers combinations shown in Table 18 can be used for the diagnosis of colorectal cancer.

[0510] The comparison results of the AUC of the RandomForest model and the XGBboost model are as Figure 15 shown: The AUC consistency of the RandomForest model and the XGBboost model is very good: The average AUC of 100 random models is basically equivalent, and the standard deviation SD (black line) of the AUC of 100 random models is also very close, that is, the stability is also very close; indicating the replaceability of the model algorithms in the implementation column plan.

[0511] Table 17 Partial 8 - markers combinations in the test set with predicted efficacy AUC greater than or equal to 0.985 (the above 3320 8 - markers combinations)

[0512]

[0513]

[0514]

[0515]

[0516]

[0517] Table 18 Partial 8 - markers combinations in the test set with predicted efficacy AUC greater than or equal to 0.91 (partial 8 - markers combinations among the combinations of any eight of the 11 protein markers AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1)

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528] The present invention can also adopt the flow cytometry fluorescence method for multiplex detection of tumor markers. By using the immunocapture multiplex detection method, one antibody in the paired antibodies is conjugated to microspheres, and the other antibody is conjugated to a luminescent substance to detect a corresponding tumor marker. Then, in the same reaction vessel, multiple-index paired antibodies are respectively conjugated to microspheres and luminescent substances, and these conjugated antibodies and samples are mixed and allowed to bind to the target antigen. Through flow cytometry analysis, multiple tumor markers can be simultaneously detected according to the fluorescence of the microspheres and the signal intensity of the luminescent bodies. Then, according to a series of sample data with normal distribution, statistical methods are used to determine the reference intervals at different confidence levels. Through such a flow cytometry immunofluorescence multiplex detection technology, rapid and accurate multi-parameter analysis can be provided in clinical diagnosis, so as to more effectively monitor and evaluate diseases.

[0529] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. Application of reagents for detecting markers in product preparation: The product is used for: early screening and diagnosis of colorectal cancer; The marker is A, and the A comprises a combination of 4 markers, and the 4 markers are CEACAM5, GDF15, PTX3 and TNC.

2. The use according to claim 1, characterized in that: The A comprises a combination of 5 markers, wherein the combination of 5 markers is c1) and c2): c1) The above 4 markers combination: CEACAM5, GDF15, PTX3 and TNC; c2) any one of G, the union of G and the combination of the 4 markers is B; The B is: ADAMTS8, ADGRE1, ADGRE2, ADGRE5, ADGRG2, AGR3, ANGPTL4, AREG, ASAH2, BAG3, BMP4, CCL7, CD48, CDH23, CEACAM16, CEACAM5, CFP, CKAP4, CLEC3B, CNTN1, CNTN4, CNTN5, COMP, CRTAC1, DCC, DLK1, EDA2R, ENPP6, ESM1, EXTL1, FAP, FASLG, FCER2, FCRL1, FGF21, GCG, GDF15, GNAS, GRK5, GSN, HMCN2, IFNL1, IGDCC4, IG FBP1, IGSF3, IL4R, IL6, ITGA11, ITGA2, ITGAM, ITGB1, ITGB7, ITM2A, KRT19, LBP, LMNB2, LPL, MEGF9, MMP12, NOTCH1, NOTCH3, NOS2, NPY, NT5C1A, NTRK2, PCDH7 , PGA4, PKD1, PLXDC1, PLXDC2, POF1B, PROK1, PTPRS, PTX3, RBFOX3, RET, SELL, SOD3, SPON2, SPP1, TCL1A, THBS4, TMPRSS15, TNC, TNFRSF10B, TNFRSF11A, VSIG4.

3. The use according to claim 2, characterized in that: The 5 markers combination is CEACAM5, COMP, GDF15, PTX3 and TNC, CEACAM5, GDF15, NOTCH1, PTX3 and TNC, CEACAM5, GDF15, PTX3, TMPRSS15 and TNC, CEACAM5, FCRL1, GDF15, PTX3 and TNC, CEACAM5, EDA2R, GDF15, PTX3 and TNC, CEACAM5, GDF15, PTX3, SERPINA1 and TNC, or AREG, CEACAM5, GDF15, PTX3 and TNC.

4. The use according to claim 3, characterized in that: The A comprises a combination of 6 markers, and the combination of 6 markers is d1) and d2): d1) the 5 markers combination; d2) Any one of H, the union of H and the combination of the 5 markers is B.

5. The use according to claim 2, characterized in that: The A comprises a combination of 6 markers, and the combination of 6 markers is d1) and d2): d1) the 5 markers combination; d2) Any one of H, the union of H and the combination of the 5 markers is B.

6. The use according to claim 5, characterized in that: The 6 markers combination is: CEACAM5, COMP, PTX3, TNC, NOTCH1 and GDF15, TMPRSS15, CEACAM5, COMP, PTX3, TNC and GDF15, TMPRSS15, CEACAM5, PTX3, TNC, NOTCH1 and GDF15, CEACAM5, COMP, PTX3, TNC, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, TNC and GDF15, CEACAM5 ACAM5, COMP, PTX3, AREG, TNC, and GDF15, CEACAM5, PTX3, TNC, NOTCH1, SERPINA1, and GDF15, CEACAM5, PTX3, AREG, TNC, NOTCH1, and GDF15, CEACAM5, COMP, PTX3, TNC, SERPINA1, and GDF15, CEACAM5, PTX3, TNC, NOTCH1, GDF15, and EDA2R, CEACAM5, FCRL1, PTX 3, TNC, NOTCH1 and GDF15, TMPRSS15, CEACAM5, PTX3, TNC, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, TNC and GDF15, TMPRSS15, CEACAM5, PTX3, TNC, SERPINA1 and GDF15, TMPRSS15, CEACAM5, PTX3, AREG, TNC and GDF15, CEACAM5, FCRL1, PTX3, TNC , GDF15 and EDA2R, CEACAM5, FCRL1, PTX3, TNC, SERPINA1 and GDF15, CEACAM5, FCRL1, PTX3, AREG, TNC and GDF15, CEACAM5, PTX3, AREG, TNC, GDF15 and EDA2R, CEACAM5, PTX3, TNC, SERPINA1, GDF15 and EDA2R, or CEACAM5, PTX3, AREG, TNC, SERPINA1 and GDF15.

7. The use according to claim 6, characterized in that: The A comprises a combination of 7 markers, wherein the combination of 7 markers is e1) and e2): e1) the combination of the 6 markers; e2) Any one of I, the union of the I and the 6 markers is B.

8. The use according to claim 5, characterized in that: The A comprises a combination of 7 markers, wherein the combination of 7 markers is e1) and e2): e1) the combination of the 6 markers; e2) Any one of I, the union of the I and the 6 markers is B.

9. The use according to claim 4, characterized in that: The A comprises a combination of 7 markers, wherein the combination of 7 markers is e1) and e2): e1) the combination of the 6 markers; e2) Any one of I, the union of the I and the 6 markers is B.

10. The use according to claim 9, characterized in that: The 7 markers combination is CEACAM5, COMP, PTX3, TNC, NOTCH1, GDF15 and EDA2R, CEACAM5, COMP, PTX3, AREG, TNC, NOTCH1 and GDF15, CEACAM5, COMP, PTX3, TNC, NOTCH1, SERPINA1 and GDF15, CEACAM5, COMP, FCRL1, PTX3, TNC, NOTCH1 and GDF15, TMPRSS15, CEACAM5, COMP, PTX3, AREG, TNC, NOTCH1 and GDF15. NC, NOTCH1 and GDF15, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, TNC and GDF15, TMPRSS15, CEACAM5, COMP, PTX3, TNC, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, TNC, GDF15 and EDA2R, TMPRSS15, CEACAM5, PTX3, TNC, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, TNC, SERPINA1 and GDF15, TMPRSS15, CEACAM5 , FCRL1, PTX3, TNC, NOTCH1, AND GDF15, CEACAM5, COMP, FCRL1, PTX3, AREG, TNC, AND GDF15, CEACAM5, COMP, FCRL1, PTX3, TNC, SERPINA1, AND GDF15, TMPRSS15, CEACAM5, PTX3, AREG, TNC, NOTCH1, AND GDF15, CEACAM5, COMP, PTX3, TNC, SERPINA1, GDF15, EDA2R, TMPRSS15, CEACAM5, PTX3, TNC, NOTCH1, SERPINA1, AND GDF15, CEA CAM5, PTX3, TNC, NOTCH1, SERPINA1, GDF15, and EDA2R, CEACAM5, COMP, PTX3, AREG, TNC, GDF15, and EDA2R, CEACAM5, FCRL1, PTX3, TNC, NOTCH1, SERPINA1, and GDF15, CEACAM5, COMP, PTX3, AREG, TNC, SERPINA1, and GDF15, CEACAM5, FCRL1, PTX3, AREG, TNC, NOTCH1, GDF15, CEACAM5, PTX3, AREG, TNC, NOTCH1, GDF15, and EDA2R,TMPRSS15, CEACAM5, PTX3, AREG, TNC, GDF15, and EDA2R, CEACAM5, FCRL1, PTX3, TNC, NOTCH1, GDF15, and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, TNC, GDF15, and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, TNC, and GDF15, TMPRSS15, CEACAM5, FCRL1, PTX3, TNC, SERPINA1, and GDF15, CEACAM5, PTX3, AREG, TNC, NOTCH1, SERPINA1, and GDF15, TMPRSS15, CEACAM5, PTX3, TNC, SERPINA1, GDF15, and EDA2R, TMPRSS15, CEACAM5, PTX3, AREG, TNC, SERPINA1, and GDF15, CEACAM5, FCRL1, PTX3, AREG, TNC, SERPINA1, and GDF15, CEACAM5, FCRL1, PTX3, TNC, SERPINA1, GDF15, and EDA2R, CEACAM5, FCRL1, PTX3, AREG, TNC, GDF15, and EDA2R, or CEACAM5, PTX3, AREG, TNC, SERPINA1, GDF15, and EDA2R. , 11. The use according to claim 10, characterized in that: The A comprises 8 markers combination, and the 8 markers combination is f1) and f2): f1) the 7 markers combination; f2) Any one of J, the union of J and the 7 markers is B.

12. The use according to claim 9, characterized in that: The A comprises 8 markers combination, and the 8 markers combination is f1) and f2): f1) the 7 markers combination; f2) Any one of J, the union of J and the 7 markers is B.

13. The use according to claim 8, characterized in that: The A comprises 8 markers combination, and the 8 markers combination is f1) and f2): f1) the 7 markers combination; f2) Any one of J, the union of J and the 7 markers is B.

14. The use according to claim 7, characterized in that: The A comprises 8 markers combination, and the 8 markers combination is f1) and f2): f1) the 7 markers combination; f2) Any one of J, the union of J and the 7 markers is B.

15. The use according to claim 14, characterized in that: The 8 - marker combinations are CEACAM5, COMP, FCRL1, PTX3, TNC, NOTCH1, GDF15, and EDA2R; TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, NOTCH1, GDF15, and EDA2R; TMPRSS15, CEACAM5, COMP, PTX3, AREG, TNC, GDF15, and EDA2R; TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, TNC, GDF15, and EDA2R; TMPRSS15, CEACAM5, COMP, PTX3, TNC, NOTCH1, GDF15, and EDA2R; TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, TNC, NOTCH1, and GDF15; CEACAM5, COMP, FCRL1, PTX3, AREG, TNC, NOTCH1, and GDF15; TMPRSS15, CEACAM5, COMP, PTX3, AREG, TNC, NOTCH1, and GDF15; CEACAM5, COMP, PTX3, AREG, TNC, NOTCH1, GDF15, and EDA2R; CEACAM5, COMP, PTX3, AREG, TNC, NOTCH1, GDF15, and EDA2R; CEACAM5, COMP, FCRL1, PTX3, TNC, NOTCH1, SERPINA1, and GDF15; CEACAM5, COMP, PTX3, TNC, NOTCH1, SERPINA1, GDF15, and EDA2R; TMPRSS15, CEACAM5, COMP, PTX3, TNC, NOTCH1, SERPINA1, and GDF15; TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, AREG, TNC, and GDF15; TMPRSS15, CEACAM5, COMP, PTX3, TNC, SERPINA1, GDF15, and EDA2R; CEACAM5, COMP, PTX3, AREG, TNC, NOTCH1, SERPINA1, and GDF15; TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, TNC, SERPINA1, and GDF15; TMPRSS15, CEACAM5, PTX3, AREG, TNC, NOTCH1, GDF15, and EDA2R; TMPRSS15, CEACAM5, FCRL1, PTX3, TNC, NOTCH1, SERPINA1, and GDF15TMPRSS15, CEACAM5, PTX3, TNC, NOTCH1, SERPINA1, GDF15, and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, TNC, NOTCH1, GDF15, and EDA2R, TMPRSS15, CEACAM5, COMP, PTX3, AREG, TNC, SERPINA1, and GDF15, CEACAM5, COMP, FCRL1, PTX3, TNC, SERPINA1, GDF15, and EDA2R, TMPRSS15, CEACAM5, PTX 3, AREG, TNC, NOTCH1, SERPINA1 and GDF15, CEACAM5, COMP, FCRL1, PTX3, AREG, TNC, SERPINA1 and GDF15, CEACAM5, FCRL1, PTX3, TNC, NOTCH1, SERPINA1, GDF15 and EDA2R, CEACAM5, COMP, FCRL1, PTX3, AREG, TNC, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, TNC, NOTCH1 and GDF15 , TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, TNC, GDF15, and EDA2R, CEACAM5, COMP, PTX3, AREG, TNC, SERPINA1, GDF15, and EDA2R, CEACAM5, FCRL1, PTX3, AREG, TNC, NOTCH1, GDF15, and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, TNC, SERPINA1, GDF15, and EDA2R, CEACAM5, PTX3, AREG, TNC, NOTCH1 , SERPINA1, GDF15 and EDA2R, CEACAM5, FCRL1, PTX3, AREG, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, FCRL1, PTX3, AREG, TNC, SERP INA1 and GDF15, TMPRSS15, CEACAM5, PTX3, AREG, TNC, SERPINA1, GDF15 and EDA2R, or CEACAM5, FCRL1, PTX3, AREG, TNC, SERPINA1, GDF15 and EDA2R. , 16. The use according to any one of claims 1 to 15, characterized in that: The A further includes at least one of K, the union of K and A is B, and K and A have no intersection.

17. The use according to any one of claims 1 to 15, characterized in that: The test sample of the product is selected from at least one of the body fluids, tissues, cells and excrement of the subject to be tested.

18. The use according to claim 17, characterized in that: The body fluid comprises at least one of blood, lymph, pleural effusion, cerebrospinal fluid, joint fluid, ascites, saliva, and body fluid.

19. The use according to claim 17, characterized in that: The tissue comprises intestinal mucosal tissue.

20. The use according to claim 18, characterized in that: The blood includes at least one of serum, plasma, dried blood spots and whole blood.

21. The use according to claim 17, characterized in that: The excreta includes at least one of urine, feces, tears and sweat.

22. The use according to claim 17, characterized in that: The subject to be tested includes mammals.

23. The use according to claim 1, characterized in that: The reagent for detecting a marker includes a reagent for detecting a marker at a gene level and / or a protein level.

24. The use according to claim 23, characterized in that: The reagents include reagents for one or more detection techniques or methods selected from the following groups: immunohistochemistry, Western blotting, Northern blotting, PCR, biochip method, nucleic acid sequencing, amino acid sequencing, high performance liquid chromatography, capillary gel electrophoresis, near infrared spectroscopy, mass spectrometry, surface plasmon resonance technology, immuno-PCR technology, biotin-avidin technology.

25. The use according to claim 24, characterized in that: The immunohistochemistry method includes at least one of enzyme-linked immunosorbent assay, immunofluorescence assay, radioimmunoassay, immunocoprecipitation, immunochemiluminescence, colloidal gold immunoassay, fluorescent immunochromatography, complement fixation analysis, flow cytometry fluorescence resolution, and single molecule detection technology.

26. The use according to claim 1, characterized in that: The reagent for detecting the marker is selected from: one or more of a marker-specific probe, a gene chip, a protein chip, and a PCR primer.

27. The use according to claim 1, characterized in that: The reagent for detecting the marker is selected from a substance that is specific to the marker, and the substance that is specific to the marker includes any one of h1) to h4): h1) Antibodies that specifically bind to the marker; h2) ligand protein or peptide that specifically binds to the marker; h3) Non-protein compounds that specifically recognize markers; h4) Nucleic acid aptamers that specifically recognize markers.

28. The use according to claim 27, characterized in that: The antibody comprises at least one of a polyclonal antibody, a monoclonal antibody, a single-chain antibody, a functional antibody fragment, an antibody Fab region, a nanobody, a chimeric antibody, and a multispecific antibody.

29. The use according to claim 1, characterized in that: The product comprises at least one of a test kit, a test paper, a chip, a device, and a system.

30. The use according to claim 1, characterized in that: The product also includes reagents for detecting other markers for early screening and diagnosis of colorectal cancer.

31. The use according to claim 1, characterized in that: The product also contains auxiliary detection reagents for gene expression, which include: a reaction reagent for visualizing the amplicon corresponding to the primer, an RNA extraction reagent, a reverse transcription reagent, a cDNA amplification reagent, a standard substance used to prepare a standard curve, and at least one of a positive control substance.

32. The use according to claim 1, characterized in that: The product also contains auxiliary detection reagents for protein expression, and the auxiliary detection reagents for protein expression include at least one of a color developer, a blocking solution, an antibody diluent, a washing buffer, a color stop solution, a standard substance used to prepare a standard curve, and a positive control substance.

33. A marker combination, comprising the 4-markers combination, the 5-markers combination, the 6-markers combination, the 7-markers combination or the 8-markers combination in any one of claims 1 to 32.

34. A product comprising reagents for detecting the marker combination of claim 33.

35. The product according to claim 34, characterized in that: The reagents for detecting the marker combination include reagents for detecting the marker combination at the gene level and / or protein level.

36. The product according to claim 35, characterized in that: The reagents include reagents for one or more detection techniques or methods selected from the following groups: immunohistochemistry, Western blotting, Northern blotting, PCR, biochip method, nucleic acid sequencing, amino acid sequencing, high performance liquid chromatography, capillary gel electrophoresis, near infrared spectroscopy, mass spectrometry, surface plasmon resonance technology, immuno-PCR technology, biotin-avidin technology.

37. The product according to claim 36, characterized in that: The immunohistochemistry method includes at least one of enzyme-linked immunosorbent assay, immunofluorescence assay, radioimmunoassay, immunocoprecipitation, immunochemiluminescence, colloidal gold immunoassay, fluorescent immunochromatography, complement fixation analysis, flow cytometry fluorescence resolution, and single molecule detection technology.

38. The product according to claim 34, characterized in that: The reagents for detecting the marker combination are selected from: one or more of marker-specific probes, gene chips, protein chips, and PCR primers.

39. The product according to claim 34, characterized in that: The reagent for detecting the marker combination is selected from substances that are specific to the marker, and the substance that is specific to the marker includes any one of h1) to h4): h1) Antibodies that specifically bind to the marker; h2) ligand protein or peptide that specifically binds to the marker; h3) Non-protein compounds that specifically recognize markers; h4) Nucleic acid aptamers that specifically recognize markers.

40. The product according to claim 39, characterized in that: The antibody comprises at least one of a polyclonal antibody, a monoclonal antibody, a single-chain antibody, a functional antibody fragment, an antibody Fab region, a nanobody, a chimeric antibody, and a multispecific antibody.

41. The product according to claim 34, characterized in that: The product comprises at least one of a test kit, a test paper, a chip, a device, and a system.

42. The product of claim 34, wherein: The product also includes reagents for detecting other markers for early screening and diagnosis of colorectal cancer.

43. The product according to claim 42, characterized in that: The product also contains auxiliary detection reagents for gene expression, which include: a reaction reagent for visualizing the amplicon corresponding to the primer, an RNA extraction reagent, a reverse transcription reagent, a cDNA amplification reagent, a standard substance used to prepare a standard curve, and at least one of a positive control substance.

44. The product according to claim 42, characterized in that: The product also contains auxiliary detection reagents for protein expression, and the auxiliary detection reagents for protein expression include at least one of a color developer, a blocking solution, an antibody diluent, a washing buffer, a color stop solution, a standard substance used to prepare a standard curve, and a positive control substance.

45. A method for constructing a model, the method comprising the step of constructing a model using the markers described in any one of claims 1 to 32.

46. ​​The construction method according to claim 45, characterized in that: The method comprises the step of constructing a model using the marker combination of claim 33.

47. The construction method according to claim 45, characterized in that: The algorithm for constructing the model includes at least one of logarithmic regression, linear discriminant analysis, characteristic gene linear discriminant analysis, support vector machine, random forest, recursive partition tree, XGBoost, ShrunkenCentroids, StepAIC, Kth-NearestNeighbor, Boosting, neural network, Bayesian network, and hidden Markov model.

48. An apparatus or system comprising: Detection module: used to detect the content, activity and / or expression of the marker described in any one of claims 1 to 32 in the test sample; and Analysis module: used to input the data obtained by the detection module into the model constructed according to any one of the construction methods according to claims 45 to 47 for analysis.

49. The device or system according to claim 48, characterized in that: The detection module is used to detect the content, activity and / or expression level of the marker combination described in claim 33 in the test sample.

50. The device or system according to claim 49, characterized in that: The test sample is the test sample described in any one of claims 17 to 22.

51. The device or system of claim 48, wherein: The device or system further comprises: an output module, which outputs information according to the analysis result obtained by the analysis module.

52. A computer device, comprising a memory and a processor, wherein the memory stores a program, and when the processor executes the program, any one of the following methods i1) to i2) is implemented: i1) A method for constructing a model according to any one of claims 45 to 47; i2) S1: Obtaining the content, activity and / or expression of the marker described in any one of claims 1 to 32 in the test sample; and S2: Input the data obtained in S1 into the model constructed according to any one of the construction methods described in claims 45 to 47 for analysis.

53. The computer device according to claim 52, characterized in that: In i2), S1 is to obtain the content, activity and / or expression level of the marker combination according to claim 33 in the test sample.

54. The computer device according to claim 53, characterized in that: The test sample is the test sample described in any one of claims 17 to 22.

55. The computer device according to claim 54, characterized in that: i2) also includes the following steps: outputting information based on the obtained analysis results.

56. A computer-readable storage medium, the computer-readable storage medium comprising a stored computer program; wherein: When the computer program is running, the computer-readable storage medium is controlled to implement any method i1) to i2) in any one of claims 52 to 55.

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