Colorectal cancer marker and use thereof

Abstract

The present invention belongs to the field of diagnostic technology, and relates to a colorectal cancer marker and the use thereof. One or more of 90 markers are provided as markers for early screening, diagnosis, staging, monitoring, curative effect evaluation or prognosis evaluation of colorectal cancer. The early screening, diagnosis, severity evaluation, monitoring, curative effect evaluation or prognosis evaluation of colorectal cancer can be realized by means of detecting the content, the expression level and / or the activity of the above-mentioned markers.

Description

Colorectal cancer markers and their applications Technical Field

[0001] The present invention belongs to the field of diagnostic technology, and in particular relates to colorectal cancer markers and applications thereof. Background Art

[0002] Colorectal cancer (CRC) is currently the third most common cancer in the world, with approximately 1.9 million people 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 colorectal cancer usually has no obvious symptoms, but when obvious symptoms appear, it often means that the cancer has developed to a later stage and may have spread to nearby lymph nodes or organs, causing certain effects on the patient's body. Therefore, early screening and diagnosis of colorectal cancer are particularly important for timely treatment interventions to improve treatment outcomes, reduce mortality, and improve national health.

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

[0004] The rapid development of liquid biopsy technology has provided a new way 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 into the blood by tumor cells, and assists in determining the nature, size and progression of the tumor. ctDNA technology performs diagnosis in a non-invasive manner, avoiding the pain and discomfort of traditional tissue biopsy. However, this technology still has considerable limitations: 1) DNA fragments produced by cell apoptosis or tissue damage will interfere with ctDNA detection and have a certain impact on ctDNA specificity; 2) The half-life of ctDNA is only 2 hours 1-2 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 the metastasis will affect the concentration and detection rate of ctDNA. In patients with only peritoneal metastasis or only lung metastasis, RAS mutant fragments are more difficult to detect in the plasma of such patients. 3 4) The costs associated with ctDNA testing 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] The purpose of the first aspect of the present invention is to provide the use of a substance for detecting markers in the preparation of products for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer.

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

[0010] The purpose 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] The fourth aspect of the present invention aims to provide a method for constructing a model for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer.

[0012] The purpose 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] The sixth aspect of the present invention aims to provide a computer device.

[0014] The seventh aspect of the present invention aims to provide a computer storable medium.

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

[0016] The purpose 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 solution adopted by the present invention is:

[0018] The first aspect of the present invention provides the use of a substance for detecting a marker in preparing a product:

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

[0020] The marker 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;

[0021] The B group includes 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, I GSF3, 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] In some embodiments of the present invention, the A comprises any 1, 2, 3, 4, 5, 6, 7, or 8 of the Bs.

[0023] In some embodiments of the present invention, the A comprises a single marker, and the single marker is any one of the B, 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 content, expression and / or activity 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, and NOS2 were increased compared with the reference level, while that of TMPRSS15, RET, PLXDC2, ENPP6, FASLG, ITGA11, PLXDC1, ITGAM, PTPRS, COMP, CNTN5, NTRK2, ADGRG2, and FC The content, expression, and / or activity of RL1, 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, and FCER2 are decreased relative to a reference level, where the reference level represents the content, expression, and / or activity in subjects of the same age group who do not have colorectal cancer.

[0024] In some embodiments of the present invention, the reference level represents the content, expression level and / or activity of healthy subjects of the same age group.

[0025] In some embodiments of the present invention, 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, NTRK 2. PCDH7, PGA4, PKD1, PLXDC1, PROK1, PTPRS, RBFOX3, SELL, SERPINA1, SPON2, TCL1A, TNC, TNFRSF10B, TNFRSF11A, or VSIG4.

[0026] In some embodiments of the present invention, 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] In some embodiments of the present invention, the single marker is: AREG, FCRL1, NTRK2, CNTN5, ITGB1, GCG, IL4R, MMP12, or TNFRSF10B.

[0028] In some embodiments of the present invention, the single marker is: FCRL1 or AREG.

[0029] In some embodiments of the present invention, the A comprises a combination of 2 markers, and the combination of 2 markers is any two of the Bs.

[0030] In some embodiments of the present invention, the 2 markers combination is any 2 of C, and the 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] In some embodiments of the present invention, 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, GDF 15 with ADGRG2, THBS4 with LMNB2, SPP1 with SOD3, PTX3 with KRT19, GDF15 with PLXDC2, PTX3 with POF1B, TMPRSS15 with SOD3, TMPRSS15 with PTX3, COMP with EDA2R, PLXDC2 with POF1B, GDF15 with ITGA2, GDF15 with HMCN2, TMPRSS15 with CEACAM5, TMPRSS15 with AREG, PTX3 with ADGRG2, GDF15 with THBS4, SPP1 with CLEC3B, TMPRSS15 with FCRL1, RET with SOD3, TMPRSS15 with I TGA11, 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 ITG AM, 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 PL XDC2, 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, K RT19 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, FCRL1, ENPP6 and LMNB2, ADGRG2 and KRT19, CEACAM5 and ITGAM, PTX3 and EDA2R, GDF15 and ENP P6, 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 EDA2R, ITGA11 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, P OF1B 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, ITGA 11 with EDA2R, CEACAM5 with FASLG, RET with ITGA2, ENPP6 with FASLG, ITGA11 with FASLG, COMP with SELL, ENPP6 with RET, THBS4 with FASLG, ITGA11 with COMP, ITGA2 with SOD3, ITGA11 with SELL, TMPRSS15 with ADGRE5, THBS4 with CLEC3B, PLXDC2 with ITGB7, ITGA11 with RET, HMCN2 with KRT19, PLXDC1 with EDA2R, CEACAM5 with EXTL1, FCRL1 with THBS4, RET with AREG, FCRL1 with EXTL 1, 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 EDA 2R, 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, LMN B2 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, HM CN2 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, THB S4 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 SELL, ITGA2 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] In some embodiments of the present invention, the two markers are combined into any one of a1)-a2):

[0033] a1) Any two of D;

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

[0035] The 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, IGS F3, 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).

[0036] In some embodiments of the present invention, 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, CD 48 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 TN FRSF10B, 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 PK D1, 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, TN FRSF10B 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, TNFRS F11A 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 CNTN1,TMPRSS15 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, GD F15 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 with PKD1, NTRK2 with EDA2R, ITGB1 with PGA4, KRT19 with DLK1, IL4R with PTPRS, KRT19 with CFP, ENPP6 with IGFBP1, SOD3 with ESM1, HMCN2 with C9, MMP12 with PLXDC1, HMCN2 with ITIH3, COMP with IL6, SPP1 with IGSF3, PTX3 with IL6, NOTCH1 with PTX3, SPON2 with DLK1, TNFRSF10B with NPY, ENPP6 with TNFRSF10B, KRT19 with PCDH7, ITGB1 with MMP12, LMNB2 with PTPRS, CD48 with 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 AD GRE5, 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] In some embodiments of the present invention, the two markers are combined into any two of E, wherein E is: AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1.

[0038] In some embodiments of the present invention, the 2 marker combinations are: 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 GDF15. with AREG, GDF15 with EDA2R, CEACAM5 with AREG, NOTCH1 with GDF15, TMPRSS15 with TNC, TMPRSS15 with SERPINA1, NOTCH1 with PTX3, NOTCH1 with TMPRSS15, PTX3 with TNC, COMP with SERPINA1, NOTCH1 with CEACAM5, COMP with TNC, FCRL1 with SERPINA1, NOTCH1 with SERPINA1, CEACAM5 with SERPINA1, PTX3 with SERPINA1, NOTCH1 with AREG, NOTCH1 with FCRL1, FCRL1 with TNC, CEACAM5 with TNC, NOTCH1 with TNC, NOTCH1 with COMP, AREG with TNC, SERPINA1 with TNC, or SERPINA1 with AREG.

[0039] In some embodiments of the present invention, the A comprises a combination of 3 markers, and the combination of 3 markers is any 3 of the B.

[0040] In some embodiments of the present invention, the three 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. 5 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 THBS 4, 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 HMCN2,PTX3, 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 P LXDC2, 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 PO F1B, 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 with SPP1, TMPRSS15 and PTX3 with SPP1, TMPRSS15 and KRT19 with TNFRSF10B, NOTCH3 and POF1B with PTX3, SPP1 and COMP with POF1B, TMPRSS15 and GDF15 with POF1B, TMPRSS15 and GDF15 with MMP12, NOTCH3 and LMNB2 with SPP1, GDF15 and ADGRG2 with DLK1, TMPRSS15 and GDF15 with DLK1, TMPRSS15 and FCRL1 with TNFRSF10B, PTX3 and THBS4 with FASLG, PTX3 and POF1B with 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 MMP12,GDF15, 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 I L4R, 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, C OMP, 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 PLXDC2,TMPRSS15, 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, GN AS, 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, PLX DC2 and THBS4, ADGRE2 and ENPP6 and SPP1, NT5C1A and THBS4 and PTX3, TMPRSS15 and SPP1 and ITGA2, TMPRSS15 and ITGB1 and TNFRSF10B, CRTAC1 and GDF15 and PTX3, CEACAM5 and RET and SOD3, NOTCH1 and LPL and SPP1, TMPRSS15 and POF1B and FASLG, TMPRSS15 and GDF15 and ADGRG2, NOTCH3 and TMPRSS15 and TNFRSF10B, TMPRSS15 and FASLG and IL4R, TMPRSS15 and COMP with 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 TNFRSF10B,TNFRSF11A, 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, IT GA11 and LMNB2, GNAS and TMPRSS15 and LMNB2, GNAS and TMPRSS15 and SPP1, GNAS and TMPRSS15 and AREG, PTX3 and KRT19 and FASLG, PTX3 and SPP1 and HMCN2, ADGRE1 and GDF15 and ITGA2, PTX3 and COMP and IL4R, PTX3 and SPP1 and CNTN4, PTX3 and POF1B and EXTL1, TMPRSS15 and PTX3 and TNFRSF10B, TMPRSS15 and GDF15 and ITGA11, PTX3 and TNFRSF10B and CNTN4, TMPRSS15 and SPP1 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, TNFRSF1 1A, 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, AR EG, 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, PTX 3. 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, TMPRS S15, 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, GDF15 and THBS4. with 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, TM PRSS15, 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 A DGRE5, 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 with 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 TNF RSF10B, 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 IL4R,NOTCH3, 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 with 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, GDF1 5. 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, AD GRE2, 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, CLE C3B 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, TMPRS S15, 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; that is, any one of the above 622 3-marker combinations.

[0041] In some embodiments of the present invention, the three markers are combined into any three of the E.

[0042] In some embodiments of the present invention, the three 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. DF15 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 PTX3,AREG, 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 TMPRSS1 5, 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 TMPRSS 15, 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 NOTC H1, 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, CEACAM M5, 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 SERPINA1,AREG, 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] In some embodiments of the present invention, the A comprises a combination of 4 markers, and the combination of 4 markers is any 4 of the B.

[0044] In some embodiments of the present invention, the four markers are combined into b1) and b2):

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

[0046] b2) Any one of F, the union of F and the combination of the 3 markers is B.

[0047] In some embodiments of the present invention, the four markers are combined as follows: 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, LMN B2, 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. PP1, 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, N OTCH1 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 GSN,PTX3, 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, LM NB2, 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, SP P1, 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 IL4 R, 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, SOD 3. 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 C LEC3B, 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, NT 5C1A, 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, TMPRSS1 5. 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 CNT N4, 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 SO D3, 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, C OMP 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, PTX 3, 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 SO D3, 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 TMPRSS 15, 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 FA SLG, 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; i.e. any one of the above 332 4 markers combinations.

[0048] In some embodiments of the present invention, the four markers are combined into any four of the E.

[0049] In some embodiments of the present invention, the four 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 DF15 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 AM5, 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, CEACAM 5. 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 NOT CH1, 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, NOTCH 1 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. F15 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 T NC, 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 A1 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, CEACAM 5. 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 TM PRSS15, 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, CEACAM 5, 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, ACAM5, 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, CEAC AM5, 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 TN C, 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. NA1 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 PT X3, 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, F CRL1, 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, N OTCH1, 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, EDA 2R, 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, EDA 2R, 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, P TX3 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, TM PRSS15 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.

[0050] In some embodiments of the present invention, the A comprises a combination of 5 markers, and the combination of 5 markers is any five of the B.

[0051] In some embodiments of the present invention, the 5 markers are combined into c1) and c2):

[0052] c1) the 4 markers combination (preferably any one of the 332 4 markers combinations mentioned above);

[0053] c2) Any one of G, the union of G and the combination of the 4 markers is B.

[0054] In some embodiments of the present invention, the five 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, TMPR SS15, 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, SO D3 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 ENP P6, 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 CF P, 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, PT X3, 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, POF 1B, 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, P TX3, 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, PO F1B, 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, FCR L1 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, PLXD C2, 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, S PP1, 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, PROK 1 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, ADGR E5 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 PLXDC2, PTX3, GDF15, COMP, ADGRE5 2 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, GD F15, 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 ADG RE2, 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, ADGRE 5 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, NOT CH1 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, ADGRE 2, 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, L MNB2, 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 A DGRE1, 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, T HBS4 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, LMN B2, 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. RE5 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, E XTL1 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, G DF15, 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, PLXDC 2. 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 NOTCH1,NOTCH1, 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, TH BS4 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 CAM5, 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 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, 5. 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.

[0055] In some embodiments of the present invention, the 5 marker combination is: 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, IL4 R 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, FCR L1, 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, T MPRSS15 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, PTX 3, 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; that is, any one of the above 63 5-marker combinations.

[0056] In some embodiments of the present invention, the 5 markers are combined into any five of the E.

[0057] In some embodiments of the present invention, the 5 marker combination is: 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, T MPRSS15 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, CEACAM 5. 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 SERPINA1, COMP, 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, SERPINA 1 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 T NC, 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 TMPR SS15, 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 PT X3, 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, A REG, 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 M5, 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, 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, ED A2R, 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 SERPINA1,CEACAM5, 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, CE ACAM5, 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, CEACAM 5. 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, T MPRSS15 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 SERPINA 1, 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, S ERPINA1 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, E DA2R, 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, FCR L1, 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, CEAC AM5, 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, and TNC S15 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 TNC,AREG, 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, CE ACAM5, 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, CO MP, 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, NOT CH1 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, NOT CH1, 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 TNC,EDA2R, FCRL1, NOTCH1, PTX3 and SERPINA1, AREG, CEACAM5, NOTCH1, PTX3 and SERPINA1, AREG, CEACAM5, FCRL1, NOTCH1 and TMPRSS15, FCRL1, NOTCH1, PTX3, SERP INA1 and TMPRSS15, AREG, CEACAM5, NOTCH1, SERPINA1 and TMPRSS15, FCRL1, PTX3, SERPINA1, TMPRSS15 and TNC, AREG, COMP, EDA2R, SERPINA1 and TNC, AREG, CEACA M5, 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, SE RPINA1 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, N OTCH1, 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, F CRL1, 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, F CRL1, 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, SERPI NA1 and TNC, AREG, CEACAM5, EDA2R, FCRL1 and PTX3, AREG, COMP, FCRL1, NOTCH1 and SERPINA1, CEACAM5, FCRL1, GDF15, PTX3 and SERPINA1, AREG, EDA2R, FCRL1, NOTC H1 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 with 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, CE ACAM5, 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 with 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, 5. 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. ,

[0058] In some embodiments of the present invention, the A comprises a combination of 6 markers, and the combination of 6 markers is any six of the combinations in B.

[0059] In some embodiments of the present invention, the 6 markers are combined into d1) and d2):

[0060] d1) the 5-marker combination (preferably any one of the 63 5-marker combinations mentioned above);

[0061] d2) Any one of H, the union of H and the combination of the 5 markers is B.

[0062] In some embodiments of the present invention, the 6 marker combination is: 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, CO MP, 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, P TX3, 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 LMNB2, ADGRE1, 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, P OF1B, 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, FCRL 1. 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, PROK 1 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, TMPRSS1 5, 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,SPP 1, 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 CDH23, SPP1, 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, LMNB 2 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 PLX DC1, 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 ASAH2, AREG, 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, PT X3, 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 NP Y, 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 THB S4, 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 with 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 with IL4R, AREG, CEACAM5, SOD3, RET, CCL7 with IL4R, SPP1, LMNB2, FCRL1, SOD3, PLXDC1 with GCG, SPP1, COMP, FCRL1, SOD3, LMNB2 with PLXDC1, SPP1, COMP, LMNB2, FCRL1, PLXDC2 with TNC, PTX3, POF1B, THBS4, EXTL1, PGA4 with CLEC3B, SPP1, COMP, LMNB2, SOD3, ADGRE1 with TCL1A, TMPRSS15, PTX3, COMP, POF1B, PGA4 with 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, SPP 1, 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, CO MP, 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, PT X3, 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, CRT AC1, 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, TMP RSS15, 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 EDA2R, SPP1, 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, POF1 B, 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, L MNB2, 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, PGA 4 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 CEACAM 16, 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, AD GRE1 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 ME GF9, 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, PT X3, 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, ARE G, 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, SP P1, 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, P LXDC2, 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, CC L7 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 DLK1, SPP1, 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, E NPP6, 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 E5, 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, CCL 7 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 CNTN1, CRTAC1, 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 NT5C1 A,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, PRO K1 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, LM NB2 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 FASL G, 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, AR EG, 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 IL6, SPP1, 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, FCR L1, 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, L MNB2 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 IFNL 1, 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 POF1 B, 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, GD F15, 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, GDF1 5. 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, POF 1B, 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, TH BS4, 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, C CL7 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 CLEC3B, SPP1, 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 CNT N5,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, SO D3, 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, SO D3, 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 with 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.

[0063] In some embodiments of the present invention, the 6 markers combination is: 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, P LXDC2, 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, TMPRSS 15, 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 LMNB2, ADGRE1, 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, P OF1B, 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, FCRL 1. 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, PROK 1 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, TMPRSS1 5, 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 marker combinations.

[0064] In some embodiments of the present invention, the 6 markers are combined into any six of the E.

[0065] In some embodiments of the present invention, the six 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, F CRL1, 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, TMPRSS 15, 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 GDF15,COMP, 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, FCR L1, 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, TMPRSS 15, 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 GDF 15, 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, P TX3, 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, GD F15 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 GDF15,TMPRSS15, 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, FCRL 1. 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, FC RL1, 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, NO TCH1, 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, SERPINA 1 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 A2R, 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, NO TCH1, 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, SER PINA1 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 EG, 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, S ERPINA1 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, N OTCH1 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, F CRL1, 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, P TX3, 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, C OMP, 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, SE RPINA1 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, TNC, and EDA2R, TMPRSS15, CEACAM5, C EACAM5, 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, CEAC AM5, 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, T NC and GDF15, TMPRSS15, CEACAM5, FCRL1, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, FCRL1, PTX3, TNC, SERPINA1 and EDA2R, TMPRSS15, FCRL1, PTX3, AREG, SERPIN A1 and EDA2R, CEACAM5, FCRL1, PTX3, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, FCRL1, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, FCRL1, PTX3, AR EG 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, CEACAM 5, 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, NOTCH H1 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, FC RL1, 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 SERPI NA1, 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, CO MP, 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 EDA2R,TMPRSS15, 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 1, 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, SER PINA1 and GDF15, TMPRSS15, FCRL1, PTX3, AREG, NOTCH1 and SERPINA1, CEACAM5, FCRL1, PTX3, SERPINA1, GDF15 and EDA2R, TMPRSS15, FCRL1, PTX3, TNC, NOT CH1 and SERPINA1, TMPRSS15, CEACAM5, FCRL1, AREG, TNC and SERPINA1, CEACAM5, FCRL1, PTX3, AREG, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, AREG, NOT CH1 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, NOTCH 1 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, EDA2R, CEACAM5, PTX3, AREG, TNC, GDF15 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、EDA2R、CEACAM5、FCRL1、AREG、TNC、GDF15、EDA2R、CEACAM5、PTX3、AREG、TNC、SERPINA1、EDA2R、FCRL1、AREG、TNC、SERPINA1、GD F15 and EDA2R, PTX3, AREG, TNC, SERPINA1, GDF15 and EDA2R, CEACAM5, FCRL1, AREG, SERPINA1, GDF15 and EDA2R, or CEACAM5, AREG, TNC, SERPINA1, GDF15 and EDA2R.

[0066] In some embodiments of the present invention, the A comprises a combination of 7 markers, and the combination of 7 markers is any seven of the B.

[0067] In some embodiments of the present invention, the 7 markers are combined into e1) and e2):

[0068] e1) the 6 markers combination (preferably any one of the 84 6 markers combinations mentioned above);

[0069] e2) Any one of I, the union of I and the combination of the 6 markers is B.

[0070] In some embodiments of the present invention, the 7 marker combination is: 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 ADGRG2. CL1A 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 IT M2A, 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 SOD3,SPP1, 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, LMNB 2. 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; i.e., the above 40 7 Any one of the markers combination.

[0071] In some embodiments of the present invention, the 7 markers are combined into any seven of the E markers.

[0072] In some embodiments of the present invention, the 7 marker 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, CEA CAM5, 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, PT X3, 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 SS15, 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, FCR L1, 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, P TX3, 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, TMPRSS 15, 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, TN C 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, TNC, NOTCH1, and EDA2R, COMP, FCRL1, PTX3, TNC, NOTCH H1, 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, P TX3, 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, T NC, 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, TMPR SS15, 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, FC RL1, 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, NOT CH1, 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, NOTCH 1, 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, FC RL1, 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, T NC, 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 TNC,TMPRSS15, 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. G, 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, TMPRSS 15. FCRL1, PTX3, AREG, NOTCH1, SERPINA1 and GDF15, FCRL1, PTX3, AREG, TNC, NOTCH1, SERPINA1 and GDF15, TMPRSS15, CEACAM5, COMP, PTX3, NOTCH1, SERPI NA1 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, NO TCH1, 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, TMPRSS1 5. 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. ERPINA1 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, SERP INA1, 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, TMPRS S15, FCRL1, PTX3, AREG, TNC, SERPINA1 and GDF15, TMPRSS15, FCRL1, PTX3, AREG, TNC, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, FCRL1, AREG, TNC, GDF15 and EDA 2R, TMPRSS15, FCRL1, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, AREG, TNC, SERPINA1, GDF15 and EDA2R, TMPRSS15, CEACAM5, FCRL1, PTX3, S ERPINA1, 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, CEA CAM5、COMP、FCRL1、AREG、TNC、NOTCH1、TMPRSS15、CEACAM5、FCRL1、AREG、NOTCH1、SERPINA1、GDF15、TMPRSS15、CEACAM5、FCRL1、TNC、NOTCH1、SERPIN A1 and EDA2R, TMPRSS15, CEACAM5, AREG, TNC, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, PTX3, AREG, NOTCH1, SERPINA1 and EDA2R, TMPRSS15, CEACAM5, COMP、FCRL1、PTX3、NOTCH1、SERPINA1、TMPRSS15、CEACAM5、PTX3、TNC、NOTCH1、SERPINA1、EDA2R、CEACAM5、COMP、FCRL1、PTX3、AREG、TNC、NOTCH1、TM PRSS15、CEACAM5、FCRL1、AREG、TNC、SERPINA1、EDA2R、TMPRSS15、CEACAM5、FCRL1、TNC、SERPINA1、GDF15、EDA2R、TMPRSS15、CEACAM5、FCRL1、AREG、TN C, 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 SERPINA1,TMPRSS15, 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, TMP RSS15, 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, TN C, 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、SERPINA1、TMPRSS15、CEACAM5、FCRL1、AREG、SERPINA1、GDF15、EDA2R、CEACAM5、FCRL1、AREG、NOTCH1、 SERPINA1, GDF15, EDA2R, TMPRSS15, COMP, FCRL1, PTX3, TNC, NOTCH1, SERPINA1, TMPRSS15, CEACAM5, COMP, PTX3, TNC, NOTCH1, SERPINA1, COMP, FCRL1 、PTX3、AREG、TNC、NOTCH1、SERPINA1、TMPRSS15、COMP、FCRL1、PTX3、AREG、NOTCH1、SERPINA1、TMPRSS15、CEACAM5、FCRL1、AREG、TNC、NOTCH1、SERPINA 1、CEACAM5、COMP、FCRL1、AREG、TNC、NOTCH1、SERPINA1、TMPRSS15、CEACAM5、FCRL1、PTX3、AREG、TNC、SERPINA1、TMPRSS15、COMP、PTX3、AREG、TNC、NOTC H1 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, 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.

[0073] In some embodiments of the present invention, the A comprises a combination of 8 markers, and the combination of 8 markers is any eight of the combinations in B.

[0074] In some embodiments of the present invention, the 8 markers are combined into f1) and f2):

[0075] f1) the 7 markers combination (preferably any one of the 40 7 markers combinations mentioned above);

[0076] f2) Any one of J, the union of J and the 7 markers is B.

[0077] In some embodiments of the present invention, 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. , 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, IT M2A, 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 ADGRE1,PTX3, 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, POF1 B. 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 CCL7,PTX3, POF1B, THBS4, ADGRE5, PGA4, ITM2A, FCER2 and BAG3, PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PROK1 and TNC, PTX3, POF1B, THBS4, ADGRE5, PGA4, I TM2A, 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, ITM2A, PCDH7 and CEACAM16, PTX3, POF1B, THBS4, ADGRE5, PGA4, ITM2A, NPY and TNC, PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, 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, ITM2A, PCDH7 and NT5C1A, PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PCDH7 and IGFBP1, PTX3, POF1B, THBS4, FASLG, ITM2A, EXTL1, TNC and PROK1, PTX3, POF1B, THBS4, EXTL1, PGA4, ADGRE1, ITM2A M2A 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, IT M2A 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, I TM2A, 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.

[0078] In some embodiments of the present invention, the 8 markers are combined into any eight of the E.

[0079] In some embodiments of the present invention, the 8 marker combination is: 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, NOTCH1, GDF15 and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, PTX3, AREG, TNC and EDA2R, 15 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, PTX3, AREG, TNC, NOTCH1, SERPINA1, and GDF15. NA1 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 EDA2R,CEACAM5, COMP, FCRL1, PTX3, AREG, NOTCH1, SERPINA1 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 EDA 2R, 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 EDA2 R, 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, SERPINA 1, 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, P TX3, 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, TMPRSS1 5. 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, SERP INA1, 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, CEACAM5, COMP, FCRL1, PTX3, AREG, TNC, NOTCH1, SERPINA1 and GDF15. RL1, 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, CEAC AM5, 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. A2R, 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, FCRL1, AREG, SERPINA1, GDF15, and EDA2R, TMPRSS15, CEACAM5, COMP, FCRL1, AREG G, 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, GDF15, 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, FC RL1, 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, ARE G, 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, NOTCH 1, 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, FCR L1, 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, GDF15, and EDA2R, TMPRSS15, FCRL1, PTX3, TNC, NOTCH1, SERPINA1, GDF15, and EDA2R,TMPRSS15、CEACAM5、COMP、FCRL1、PTX3、AREG、TNC、NOTCH1、TMPRSS15、CEACAM5、FCRL1、PTX3、AREG、NOTCH1、SERPINA1、GDF15、TMPRSS15、CEACAM5、FCR L1、TNC、NOTCH1、SERPINA1、GDF15、EDA2R、CEACAM5、FCRL1、PTX3、AREG、NOTCH1、SERPINA1、GDF15、EDA2R、TMPRSS15、CEACAM5、FCRL1、AREG、NOTCH1、SE RPINA1, 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, AR EG, 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 CAM5、COMP、PTX3、AREG、TNC、NOTCH1、SERPINA1、TMPRSS15、CEACAM5、COMP、FCRL1、PTX3、AREG、TNC、SERPINA1、TMPRSS15、CEACAM5、FCRL1、PTX3、AREG、 TNC、NOTCH1、EDA2R、TMPRSS15、CEACAM5、FCRL1、PTX3、AREG、SERPINA1、GDF15、EDA2R、TMPRSS15、CEACAM5、COMP、FCRL1、AREG、TNC、NOTCH1、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 GD F15, 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 SERP INA1, 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. ,

[0080] In some embodiments of the present invention, the A further includes at least one of K, and the union of K and A is B (for example, if the A includes FCRL1, then K is B that does not include FCRL1).

[0081] In some embodiments of the present invention, the test sample of the product is selected from at least one of body fluids, tissues, cells, and excretions of the subject to be tested; further, it is body fluid.

[0082] In some embodiments of the present invention, the body fluid comprises at least one of blood, lymph, pleural effusion, cerebrospinal fluid, joint fluid, ascites, saliva, lymph, and body fluid; further comprising blood.

[0083] In some embodiments of the invention, the tissue comprises intestinal mucosal tissue.

[0084] In some embodiments of the present invention, the blood comprises at least one of serum, plasma, dried blood spots, and whole blood; further comprises serum.

[0085] In some embodiments of the present invention, the excreta comprises at least one of urine, feces, tears, and sweat.

[0086] In some embodiments of the present invention, the test sample is selected from the serum of the subject to be tested.

[0087] In some embodiments of the present invention, the subject to be tested includes mammals, such as humans, non-human primates (such as gorillas, apes), rodents (such as rats, mice, guinea pigs), pets (such as cats, dogs), and livestock (such as horses, cows, sheep, pigs, rabbits).

[0088] In some embodiments of the present invention, the subject to be tested includes humans.

[0089] In some embodiments of the present invention, the substance for detecting a marker comprises a substance for quantitatively detecting a marker.

[0090] In some embodiments of the present invention, the substance for detecting a marker comprises a substance for detecting a marker at the gene level and / or protein level.

[0091] In some embodiments of the present invention, the substance comprises a substance 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.

[0092] In some embodiments of the present invention, the immunohistochemistry method comprises at least one of enzyme-linked immunosorbent assay, immunofluorescence assay, radioimmunoassay, immunocoprecipitation, immunochemiluminescence, colloidal gold immunoassay, fluorescence immunochromatography, complement fixation analysis, flow cytometry fluorescence resolution, and single molecule detection technology; further enzyme-linked immunosorbent assay; and further double antibody sandwich method.

[0093] In some embodiments of the present invention, the substance for detecting the marker is selected from: one or more of a substance specific to the marker, a marker-specific probe, a gene chip, a protein chip, and a PCR primer.

[0094] In some embodiments of the present invention, the substance specific for the marker comprises any one of h1) to h4):

[0095] h1) an antibody that specifically binds to the marker;

[0096] h2) a ligand protein or polypeptide that specifically binds to the marker;

[0097] h3) non-protein compounds that specifically recognize markers;

[0098] h4) Nucleic acid aptamers that specifically recognize markers.

[0099] In some embodiments of the present invention, 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.

[0100] In some embodiments of the present invention, the product comprises at least one of a reagent, a kit, a test paper, a chip, a device, and a system.

[0101] In some embodiments of the present invention, the product also contains substances for detecting other markers used 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.

[0102] In some embodiments of the present invention, the product further comprises an auxiliary detection reagent for gene expression, and the auxiliary detection reagent for gene expression comprises: 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 for preparing a standard curve, and at least one of a positive control substance.

[0103] In some embodiments of the present invention, the product further comprises an auxiliary detection reagent for protein expression, and the auxiliary detection reagent for protein expression comprises at least one of a color developer, a blocking solution, an antibody diluent, a washing buffer, a color stop solution, a standard substance for preparing a standard curve, and a positive control substance.

[0104] In some embodiments of the present invention, the colorectal cancer includes early colorectal cancer (stage I and stage II) and / or late colorectal cancer (stage III and stage IV).

[0105] In some embodiments of the present invention, the staging is to distinguish between early colorectal cancer (stage I and stage II) and late colorectal cancer (stage III and stage IV).

[0106] In a second aspect of the present invention, a marker combination is provided, wherein the marker combination comprises at least two of B described 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, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101 , 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.

[0107] In some embodiments of the invention, the marker combination comprises: FCRL1; and

[0108] At least one of L, wherein L is B excluding FCRL1 (ie, the union of L and FCRL1 is B).

[0109] In some embodiments of the present invention, the marker combination comprises: AREG; and

[0110] At least one of M, where M is B that does not include AREG (that is, the union of M and AREG is B).

[0111] In some embodiments of the present invention, the marker combination comprises any 2, 3, 4, 5, 6, 7, or 8 of the B.

[0112] In some embodiments of the present invention, the marker combination comprises the 2 marker combination, 3 marker combination, 4 marker combination, 5 marker combination, 6 marker combination, 7 marker combination or 8 marker combination in the first aspect of the present invention.

[0113] In some embodiments of the present invention, the marker combination also includes 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.

[0114] In some embodiments of the present invention, the marker combination is used for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer.

[0115] In some embodiments of the present invention, the marker combination is derived from at least one of the body fluids, tissues, cells, and excretions of the subject to be tested; further, the marker combination is derived from body fluids.

[0116] In some embodiments of the present invention, the subject to be detected, body fluid, tissue, cell, or excretion is the subject to be detected, body fluid, tissue, cell, or excretion in the first aspect of the present invention.

[0117] In some embodiments of the present invention, the colorectal cancer includes early colorectal cancer (stage I and stage II) and / or late colorectal cancer (stage III and stage IV).

[0118] In some embodiments of the present invention, the staging is to distinguish between early colorectal cancer (stage I and stage II) and late colorectal cancer (stage III and stage IV).

[0119] The third aspect of the present invention is to provide a product comprising substances for detecting the marker combination of the second aspect of the present invention.

[0120] In some embodiments of the present invention, the product is used for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer.

[0121] In some embodiments of the present invention, the substance for detecting the marker combination comprises a substance for quantitatively detecting the marker combination.

[0122] In some embodiments of the present invention, the substance for detecting a marker combination comprises a substance for detecting a marker combination at the gene level and / or protein level.

[0123] In some embodiments of the present invention, the substance comprises a substance 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.

[0124] In some embodiments of the present invention, the immunohistochemistry method comprises at least one of enzyme-linked immunosorbent assay, immunofluorescence assay, radioimmunoassay, immunocoprecipitation, immunochemiluminescence, colloidal gold immunoassay, fluorescence immunochromatography, complement fixation analysis, flow cytometry fluorescence resolution, and single molecule detection technology; further enzyme-linked immunosorbent assay; and further double antibody sandwich method.

[0125] In some embodiments of the present invention, the substance for detecting the marker combination is selected from one or more of: a substance specific to the marker, a marker-specific probe, a gene chip, a protein chip, and a PCR primer.

[0126] In some embodiments of the present invention, the substance specific for the marker comprises any one of h1) to h4):

[0127] h1) an antibody that specifically binds to the marker;

[0128] h2) a ligand protein or polypeptide that specifically binds to the marker;

[0129] h3) non-protein compounds that specifically recognize markers;

[0130] h4) Nucleic acid aptamers that specifically recognize markers.

[0131] In some embodiments of the present invention, 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.

[0132] In some embodiments of the present invention, the product comprises at least one of a reagent, a kit, a test paper, a chip, a device, and a system.

[0133] In some embodiments of the present invention, the product also contains substances for detecting other markers used 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.

[0134] In some embodiments of the present invention, the product further comprises an auxiliary detection reagent for gene expression, and the auxiliary detection reagent for gene expression comprises: 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 for preparing a standard curve, and at least one of a positive control substance.

[0135] In some embodiments of the present invention, the product further comprises an auxiliary detection reagent for protein expression, and the auxiliary detection reagent for protein expression comprises at least one of a color developer, a blocking solution, an antibody diluent, a washing buffer, a color stop solution, a standard substance for preparing a standard curve, and a positive control substance.

[0136] In some embodiments of the present invention, the colorectal cancer includes early colorectal cancer (stage I and stage II) and / or late colorectal cancer (stage III and stage IV).

[0137] In some embodiments of the present invention, the staging is to distinguish between early colorectal cancer (stage I and stage II) and late colorectal cancer (stage III and stage IV).

[0138] The fourth aspect of the present invention is to provide a method for constructing a model, which comprises the step of constructing a model using the markers in the first aspect of the present invention.

[0139] In some embodiments of the invention, the method comprises the step of constructing a model using the marker combination of the second aspect of the invention.

[0140] In some embodiments of the present invention, the model is used for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer.

[0141] In some embodiments of the present invention, the algorithm for constructing the model includes at least one of logarithmic regression, linear discriminant analysis, eigengene linear discriminant analysis, support vector machine, random forest (RandomRorest), recursive partitioning tree, XGBoost, ShrunkenCentroids, StepAIC, Kth-Nearest Neighbor, Boosting, neural network, Bayesian network, and hidden Markov model; further includes at least one of random forest (RandomRorest) and XGBoost.

[0142] In some embodiments of the present invention, the colorectal cancer includes early colorectal cancer (stage I and stage II) and / or late colorectal cancer (stage III and stage IV).

[0143] In some embodiments of the present invention, the staging is to distinguish between early colorectal cancer (stage I and stage II) and late colorectal cancer (stage III and stage IV).

[0144] A fifth aspect of the present invention is to provide a device or system comprising:

[0145] Detection module: used to detect the content, activity and / or expression of the marker in the first aspect of the present invention in the test sample; and

[0146] Analysis module: used to input the data acquired by the detection module into the model constructed according to the construction method of the fourth aspect of the present invention for analysis.

[0147] In some embodiments of the present invention, the device or system is used for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer.

[0148] In some embodiments of the present invention, the detection module is used to detect the content, activity and / or expression of the marker combination of the second aspect of the present invention in a test sample.

[0149] In some embodiments of the present invention, the test sample is the test sample in the first aspect of the present invention.

[0150] In some embodiments of the present invention, the device or system further includes: an output module, which outputs information according to the analysis results obtained by the analysis module.

[0151] In some embodiments of the present invention, the colorectal cancer includes early colorectal cancer (stage I and stage II) and / or late colorectal cancer (stage III and stage IV).

[0152] In some embodiments of the present invention, the staging is to distinguish between early colorectal cancer (stage I and stage II) and late colorectal cancer (stage III and stage IV).

[0153] A sixth aspect of the present invention provides a computer device, comprising a memory and a processor, wherein the memory stores a program, and when the processor executes the program, it implements any one of the following methods i1)-i2):

[0154] i1) A method for constructing a model according to the fourth aspect of the present invention;

[0155] i2)

[0156] S1: obtaining the content, activity and / or expression of the marker in the first aspect of the present invention in the test sample; and

[0157] S2: Input the data acquired in S1 into the model constructed according to the construction method of the fourth aspect of the present invention for analysis.

[0158] In some embodiments of the present invention, S1 in i2) is to obtain the content, activity and / or expression level of the marker combination in the second aspect of the present invention in the test sample.

[0159] In some embodiments of the present invention, the test sample is the test sample in the first aspect of the present invention.

[0160] In some embodiments of the present invention, i2) further includes the following step: outputting information based on the obtained analysis results.

[0161] The seventh aspect of the present invention provides a computer-storable medium, wherein the computer-readable storage medium includes a stored computer program; wherein, when the computer program is running, the computer-readable storage medium is controlled to implement any one of methods i1)-i2) in the sixth aspect of the present invention.

[0162] The eighth aspect of the present invention provides a method for constructing a colorectal cancer model, comprising adjusting the content, expression and / or activity of the markers of the first aspect of the present invention in the model:

[0163] When the content, expression and / or activity of the marker in the test subject suffering from colorectal cancer is increased relative to that in the test subject not suffering from colorectal cancer (preferably a healthy test subject), increasing the content, expression and / or activity of the marker in the model;

[0164] When the content, expression level and / or activity of the marker in the subject to be tested having colorectal cancer is reduced relative to the subject to be tested not having colorectal cancer (preferably a healthy subject to be tested), the content, expression level and / or activity of the marker in the model is reduced.

[0165] In some embodiments of the invention, the model is an animal model.

[0166] In some embodiments of the invention, the animal is a rat, a mouse, or a guinea pig.

[0167] In some embodiments of the present invention, the colorectal cancer includes early colorectal cancer (stage I and stage II) and / or late colorectal cancer (stage III and stage IV).

[0168] The ninth aspect of the present invention provides a method for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer, comprising the step of detecting the content, expression level and / or activity of the marker in the first aspect of the present invention in a test sample.

[0169] In some embodiments of the present invention, the method comprises the step of detecting the content, expression level and / or activity of the marker combination in the second aspect of the present invention in the test sample.

[0170] In some embodiments of the present invention, the test sample is the test sample in the first aspect of the present invention.

[0171] In some embodiments of the present invention, the product of the first aspect of the present invention is used to detect the content, expression and / or activity of the marker of the first aspect of the present invention in a test sample.

[0172] In some embodiments of the present invention, the product of the third aspect of the present invention is used to detect the content, expression level and / or activity of the marker combination of the second aspect of the present invention in a test sample.

[0173] In some embodiments of the present invention, the method further comprises the step of inputting the data on the content, expression level and / or activity of the marker in the first aspect of the present invention or the combination of markers in the second aspect of the present invention in the obtained test sample into the model constructed according to the construction method of the fourth aspect of the present invention for analysis.

[0174] In some embodiments of the present invention, the method further comprises the step of outputting information based on the obtained analysis results.

[0175] In some embodiments of the present invention, the colorectal cancer includes early colorectal cancer (stage I and stage II) and / or late colorectal cancer (stage III and stage IV).

[0176] In some embodiments of the present invention, the staging is to distinguish between early colorectal cancer (stage I and stage II) and late colorectal cancer (stage III and stage IV).

[0177] The beneficial effects of the present invention are:

[0178] The present invention discloses for the first time 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, and 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, and VSIG4 are used as markers for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer. Early screening, diagnosis, severity assessment, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer can be achieved by detecting the content, expression level and / or activity of the above markers. BRIEF DESCRIPTION OF THE DRAWINGS

[0179] Figure 1 shows the AUC comparison results of some single-marker RandomForest models and XGBboost models.

[0180] FIG2 is a ROC curve diagram of some 2 markers combinations (TMPRSS15 and GDF15; SPP1 and ADGRE5).

[0181] Figure 3 is a graph showing the AUC comparison between the RandomForest model and the XGBboost model for some 2-markers combinations.

[0182] 4A-B are ROC curves of some three marker combinations (SPP1, COMP and FCRL1; TMPRSS15, SPP1 and SOD3; AREG, CEACAM5 and PLXDC2).

[0183] Figure 5 is a graph showing the AUC comparison between the RandomForest model and the XGBboost model for some 3-markers combinations.

[0184] 6A-B are ROC curves of some four marker combinations (SPP1, COMP, FCRL1 and LMNB2; ADGRE1, GDF15, PTX3 and THBS4).

[0185] Figure 7 is a graph showing the AUC comparison between the RandomForest model and the XGBboost model for some 4-markers combinations.

[0186] 8A-B are 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).

[0187] Figure 9 is a graph showing the AUC comparison between the RandomForest model and the XGBboost model for some 5-marker combinations.

[0188] 10A-B are 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).

[0189] Figure 11 is a graph showing the AUC comparison between the RandomForest model and the XGBboost model for some 6-marker combinations.

[0190] 12A-B are ROC curves of a partial 7-marker combination (SPP1, COMP, LMNB2, PLXDC2, TCL1A, PROK1 and ADGRG2; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A and SOD3).

[0191] FIG13 is a graph showing the AUC comparison between the RandomForest model and the XGBboost model for some 7 marker combinations.

[0192] FIG14 is a ROC curve diagram of a partial 8-marker combination (PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PROK1 and PCDH7; SPP1, LMNB2, SOD3, ADGRE5, PLXDC1, PROK1, LBP and FASLG).

[0193] FIG15 is a graph showing the AUC comparison between the RandomForest model and the XGBboost model for some 8-marker combinations. DETAILED DESCRIPTION

[0194] The present invention is further described in detail below through specific examples.

[0195] It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0196] The experimental methods in the following examples, where specific conditions are not specified, were generally performed under conventional conditions or the conditions recommended by the manufacturers. The materials and reagents used in these examples were commercially available unless otherwise specified.

[0197] The information of the proteins involved in the following examples is shown in Table 1.

[0198] Table 1 Protein information

[0199] 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.

[0200] Example 1 Diagnostic markers for colorectal cancer

[0201] 1. Clinical Sample Collection

[0202] In this embodiment, 139 patients diagnosed with colorectal cancer and 40 healthy controls were collected in the hospital. Fresh blood samples were collected before surgery in the hospital, and the protein expression levels in the blood were detected by the protein detection proximity extension technology PEA (Proximity Extension Assay) platform as a marker for detection 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 patients with colorectal cancer were newly diagnosed diseases, and had no other serious diseases or 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 28-83 years old, with an average age of 57.6 years old and a male-to-female ratio of 85:54; the age range in the control group (healthy people) was 22-77 years old, with an average age of 51.5 and a male-to-female ratio of 9:31.

[0203] Sample inclusion criteria:

[0204] Inclusion criteria for the experimental group: (1) patients diagnosed with preoperative colon or rectal cancer; (2) aged 18-80 years, regardless of gender; (3) no history of malignant tumors in other parts of the body; (4) no previous treatment with any other form of anti-tumor therapy before resection; (5) no history of blood transfusion in the past three years.

[0205] 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 patients with colorectal metastasis from other tumors.

[0206] 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.

[0207] In this example, the experimental and control groups were patients who visited the Sixth Affiliated Hospital of Sun Yat-sen University between January 2021 and January 2023. They were recruited in strict accordance with the aforementioned inclusion criteria. A total of 139 patients diagnosed with colorectal cancer and 40 healthy individuals were recruited. All specimen collection was conducted with the informed consent signed by the subjects' families and approved by the Institutional Review Board of the Sixth Affiliated Hospital of Sun Yat-sen University.

[0208] 2. Blood Sample Processing

[0209] 5 mL of peripheral venous blood was collected from the patients and healthy controls using EDTA anticoagulant purple-top tubes, centrifuged for 10 minutes, and the upper plasma was collected and stored vertically in a -80°C refrigerator.

[0210] 3. Protein Detection

[0211] In this example, the inventors performed plasma proteomic testing on 179 plasma samples using the proximity extension assay (PEA) platform. Specifically, in the test, 3072 protein-specific antibodies were individually labeled with unique PEA oligonucleotide probes. Each antibody was labeled with two independent and complementary sequences. These bound antibodies were mixed into eight independent 384-well plates, each of which included three protein replicates for inter-plate quality control. During the test, 179 samples were randomly distributed on three different 96-well plates and incubated with antibodies labeled with PEA probes at +4°C overnight. After the immune reaction, the extension and pre-amplification mixture was added to the incubated samples for PCR amplification at room temperature. The PCR amplification products were then mixed before adding the individual sample index sequence, followed by a second PCR amplification. After sample mixing, the generated library was magnetic bead purified and quality controlled on a Bioanalyzer. Finally, sequencing was performed using an Illumina NovaSeq 6000 instrument, using two S1 flow cells with a read length of 2 × 50 bases. Counts of known barcode sequences were then converted to normalized protein expression units (NPX) through a quality control and normalization process, resulting in a total of 2,884 proteins being quantified.

[0212] 4. Construction of a colorectal cancer protein marker screening model

[0213] The inventors used the XGBoost machine learning method to evaluate potential proteins that can distinguish colorectal cancer from healthy individuals. To avoid bias in sample selection during machine learning modeling, 100 random modeling runs were performed using the bootstrap method. In each run, 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.

[0214] (1) The independent predictive ability of each protein for colorectal cancer was evaluated by AUC (area under the curve), sensitivity, and specificity. The mean and confidence interval were calculated 100 times. The predictive efficacy of the proteins was ranked, and proteins with an AUC greater than 0.7 were screened out.

[0215] (2) The XGBoost machine learning algorithm with no restriction on the number of proteins was used to build a model, and a model with high classification accuracy was screened out. The weight and frequency of each protein in the model were counted, thereby identifying four key proteins, GDF15, PTX3, SPP1, and TMPRSS15, for use in predictive model construction.

[0216] (3) Among the 2884 proteins, the XGBoost machine learning method was used to evaluate the combination of each protein with one of GDF15, PTX3, SPP1, or TMPRSS15. AUC, sensitivity, and specificity were evaluated, and protein combinations with an AUC greater than 0.87 were selected.

[0217] After the above three steps, the proteins obtained in each step were combined to obtain 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, ED A2R, 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, NO TCH3, 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; 90 proteins showed significant differences, as shown in Table 2 (Table 2). 2: p.adj is the corrected P value for the t-test, Mean_CRC is the normalized mean expression value of the protein in colorectal cancer, Mean_Healthy is the normalized mean expression value of the protein in healthy controls, and logFC is the fold difference between the mean expression values ​​of the two groups (a logFC greater than 0 indicates that the protein is overexpressed in colorectal cancer patients; a logFC less than 0 indicates that the protein is underexpressed in colorectal cancer patients, the same below). The AUCs for the 90 significantly differentially expressed proteins ranged from 0.6107 to 0.8546. Among them, 61 proteins had a predictive efficacy AUC greater than 0.7, as shown in Table 3 (where Mean_AUC represents the mean AUC of the protein combination across 100 training classifications in the XGBoost machine learning model, sd_AUC represents the standard deviation of the AUC across 100 training classifications, and Median_AUC represents the median AUC across 100 training classifications, the same below). Therefore, the above 90 markers can be used for the diagnosis of colorectal cancer.

[0218] Table 2 90 proteins with significant differences in the training set

[0219] Table 3 61 proteins with prediction efficiency AUC greater than 0.7 in the test set

[0220] Furthermore, in order to verify the accuracy and stability of the above-selected markers, the inventors used the RandoForest machine learning method to perform modeling and prediction analysis on the 10 markers with better performance. The modeling method is as follows: 70% (125 cases) of 139 colorectal cancer samples and 40 healthy controls were randomly selected as the training set, and the remaining 30% (54 cases) were used as the test set. The model was trained 100 times, and then the average AUC of the 100 models was statistically compared with that of XGBboost. The results are shown in Figure 1: The AUC of the RandomForest model and the XGBboost model are very consistent: the average AUC of the 100 random models is basically the same, 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 interchangeability of the model algorithm in the implementation scheme.

[0221] Among the 90 protein markers mentioned above, the combination marker examples are as follows. Combinations of, but not limited to, 2, 3, 4, 5, 6, 7, and 8 proteins are used, and the AUC, sensitivity, and specificity of each combination are evaluated using the XGBoost machine learning method. The Random Forest machine learning method is used to further verify the combinations with the best results, as follows:

[0222] 2 markers combination: Among the 90 markers, all proteins are arranged and combined, with a total of 90×89 / 2=4005 combinations, and the range of the predictive efficacy AUC value is 0.653-0.92, that is, the above 4005 2 markers combination can be used to diagnose colorectal cancer; among them, ADGRE5, ADGRG2, AREG, CEACAM5, CLEC3B, CNTN5, COMP, EDA2R, ENPP6, EXTL1, FASLG, FCRL1, GDF15, HMC Combinations of any two of the 30 markers N2, ITGA11, ITGA2, ITGAM, ITGB7, KRT19, LMNB2, PLXDC1, PLXDC2, POF1B, PTX3, RET, SELL, SOD3, SPP1, THBS4, and TMPRSS15 yielded 435 combinations with predictive efficacy AUC values ​​ranging from 0.79 to 0.92, with 427 combinations having AUCs greater than 0.8, as shown in Table 4. This group of proteins exhibits a high and stable predictive AUC. For example, ROC curves for some two-marker combinations (TMPRSS15 and GDF15; SPP1 and ADGRE5) are shown in Figure 2.

[0223] Among the 90 marker-based 2-marker combinations (i.e., excluding the 435 marker combinations mentioned above from the 4005 marker combinations mentioned above), there are also some 2-marker combinations with good protein complementarity, with AUCs greater than 0.85, as shown in Table 5. The predictive efficacy AUC values ​​range from 0.85 to 0.92. The 2-marker combinations shown in Table 5 can be used to diagnose colorectal cancer.

[0224] The two-marker combinations shown in Table 6 (partial two-marker combinations of any two of the 11 protein markers: AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, and SERPINA1) were also validated separately. The results are shown in Table 6, with predictive efficacy AUC values ​​ranging from 0.7458 to 0.8486. The two-marker combinations shown in Table 6 can be used to diagnose colorectal cancer.

[0225] The AUC comparison results of the RandomRorest model and the XGBboost model are shown in Figure 3. The AUC consistency of the RandomRorest model and the XGBboost model is very good: the average AUC of the 100 random models is basically the same, 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, which shows the interchangeability of the model algorithms in the implementation scheme.

[0226] Table 4 Two-marker combinations with predictive efficacy AUC greater than or equal to 0.8 in the test set (combination of any two of the 30 proteins)

[0227] Table 5: Some 2-marker combinations with predictive 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)

[0228] Table 6: Some 2-marker combinations with predictive efficacy AUC greater than or equal to 0.74 in the test set (some 2-marker combinations in the combination of any two of the 11 protein markers AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1)

[0229] 3-marker combinations: 90 markers were permuted into 90 × 89 × 88 / 6 = 117,480 combinations. Examples include SPP1, COMP, and FCRL1; TMPRSS15, SPP1, and SOD3; and PTX3, GDF15, and THBS4. The predictive efficacy AUC values ​​for these 117,480 3-marker combinations ranged from 0.66 to 0.9543 (due to the large number of combinations, the AUC values ​​for each 3-marker combination are not listed individually; only the range of AUC values ​​for these 117,480 combinations is provided to demonstrate their diagnostic efficacy), with an average AUC of 0.8388. Among them, the predictive efficacy AUC values ​​of the 3 markers combination in Table 7 ranged from 0.92 to 0.9543, the sensitivity ranged from 0.6856 to 0.9374, and the specificity ranged from 0.716 to 0.9842; among them, some 3 marker combinations with AUC greater than or equal to 0.92 are shown in Table 7 (wherein, Mean_AUC in Table 7 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 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 correct rate of 100 training classifications, PPV is the positive predictive value, and NPV is the negative predictive value, the same below), some 3 The ROC curves of the marker combinations (SPP1, COMP, and FCRL1; TMPRSS15, SPP1, and SOD3; AREG, CEACAM5, and PLXDC2) are shown in Figure 4A-B. It can be seen that the above 117,480 3-marker combinations can be used to diagnose colorectal cancer.

[0230] The three-marker combinations shown in Table 8 (selected combinations of any three of the 11 protein markers: AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, and SERPINA1) were also validated. The results are shown in Table 8, with predictive efficacy AUC values ​​ranging from 0.7458 to 0.8486. The three-marker combinations shown in Table 8 can be used to diagnose colorectal cancer.

[0231] The AUC comparison results of the RandomForest model and the XGBboost model are shown in Figure 5. The AUC consistency of the RandomForest model and the XGBboost model is very good: the average AUC of the 100 random models is basically the same, 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, which shows the interchangeability of the model algorithms in the implementation scheme.

[0232] Table 7: Some 3-marker combinations with predictive efficacy AUC greater than or equal to 0.92 in the test set (the above 117,480 marker combinations)

[0233] Table 8 Some 3-marker combinations with prediction efficacy AUC greater than or equal to 0.77 in the test set (some 3-marker combinations in the combination of any three of the 11 protein markers AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1)

[0234] 4 markers combination: Based on the combinations with AUC greater than or equal to 0.92 in the 3 markers combination (622 combinations, Table 7, i.e., the 622 3 markers combinations in the content of the invention), and the remaining 87 proteins (i.e., 90 proteins minus the 3 proteins in the 3 markers combination), a total of 622×(90-3)=54114 combinations, such as: ADGRE1, GDF15, PTX3 and THBS4; PTX3, HMCN2, POF1B and FASLG; SPP1, COMP, FCRL1 and LMNB2; etc.; these 54114 4 markers combinations The predictive efficacy AUC values ​​for the marker combinations ranged from 0.856 to 0.9687. The predictive efficacy AUC values ​​for the four-marker combinations in Table 9 ranged from 0.950 to 0.9687, the sensitivity ranged from 0.7643 to 0.9477, and the specificity ranged from 0.7685 to 0.9817. (Due to the large number of combinations, the AUC values ​​for each of the four-marker combinations are not listed one by one; only the AUC ranges for 54,114 four-marker combinations are given to demonstrate the diagnostic efficacy of these 54,114 four-marker combinations.) Table 9 lists some four-marker combinations with AUCs greater than or equal to 0.95. The ROC curves for some of these four-marker combinations (SPP1, COMP, FCRL1, and LMNB2; ADGRE1, GDF15, PTX3, and THBS4) are shown in Figures 6A and 6B. Consequently, these 54,114 four-marker combinations can be used to diagnose colorectal cancer.

[0235] The four-marker combination shown in Table 10 (partial four-marker combination of any four of the 11 protein markers: AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, and SERPINA1) was also independently validated. The results are shown in Table 10, with predictive efficacy AUC values ​​ranging from 0.8121 to 0.9494. The four-marker combination shown in Table 10 can be used to diagnose colorectal cancer.

[0236] The AUC comparison results of the RandomForest model and the XGBboost model are shown in Figure 7. The AUC consistency of the RandomForest model and the XGBboost model is very good: the average AUC of the 100 random models is basically the same, 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, which shows the interchangeability of the model algorithms in the implementation scheme.

[0237] Table 9: Some 4-marker combinations with predictive efficacy AUC greater than or equal to 0.95 in the test set (the above 54,114 4-marker combinations)

[0238] Table 10: Some 4-marker combinations with prediction efficacy AUC greater than or equal to 0.81 in the test set (some 4-marker combinations in the combination of any four of the 11 protein markers AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1)

[0239] 5-marker combinations: To further verify the effectiveness of each protein, the combinations with an AUC greater than or equal to 0.95 among the 4 markers (332 combinations, Table 9, i.e., the 332 4-marker combinations in the Summary of the Invention) were combined with the remaining 86 proteins (i.e., the 90 proteins minus the 4 proteins in the 4-marker combination) to form 332 × (90-4) = 28,552 combinations. 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 predictive efficacy AUC values ​​of these 28552 5-marker combinations range from 0.93 to 0.9886, the sensitivity ranges from 0.7465 to 0.9483, and the specificity ranges from 0.7683 to 0.9900 (due to too many 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 demonstrate the diagnostic effect of the above 28552 5-marker combinations); among them, some 5-marker combinations with AUC greater than or equal to 0.965 are shown in Table 11, and some 5 The ROC curves for the 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 shown in Figures 8A and 8B. As can be seen, the above 28,552 5-marker combinations can be used to diagnose colorectal cancer.

[0240] The five-marker combinations shown in Table 12 (partial combinations of any five of the 11 protein markers: AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, and SERPINA1) were also independently validated. The results are shown in Table 12, with predictive efficacy AUC values ​​ranging from 0.8466 to 0.9648. The five-marker combinations shown in Table 12 can be used to diagnose colorectal cancer.

[0241] The AUC comparison results of the RandomForest model and the XGBboost model are shown in Figure 9. The AUC consistency of the RandomForest model and the XGBboost model is very good: the average AUC of the 100 random models is basically the same, 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, which shows the interchangeability of the model algorithms in the implementation scheme.

[0242] Table 11: Some 5-marker combinations with predictive efficacy AUC greater than or equal to 0.965 in the test set (the above 28,552 5-marker combinations)

[0243] Table 12: Some 5-marker combinations with prediction efficacy AUC greater than or equal to 0.84 in the test set (some 5-marker combinations in any combination of five of the 11 protein markers: AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, and SERPINA1)

[0244] 6-marker combinations: Based on the combinations with an AUC greater than or equal to 0.965 in the 5-marker combination (486 combinations), the combination with the highest AUC among the combinations with 4 protein repeats was selected, and the other combinations were eliminated. The remaining 63 combinations (the 5-marker combinations in italics in Table 11, i.e., the 63 5-marker combinations in the Summary of the Invention) and the remaining 85 proteins (i.e., the 90 proteins minus the 5 proteins in the 5-marker combination) were combined into 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; the predictive efficacy AUC values ​​of these 5355 6-marker combinations ranged from 0.954 to 0.9836, the sensitivity ranged from 0.801 to 0.964, and the specificity ranged from 0.809 to 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 demonstrate the diagnostic effect of the above 5355 6-marker combinations); among them, some 6-marker combinations with AUC greater than or equal to 0.975 are shown in Table 13, and some 6 The ROC curves for the marker combinations (SPP1, PLXDC2, SOD3, IL4R, BAG3, and PROK1; AREG, CEACAM5, PTX3, CD48, CCL7, and IGFBP1; NOTCH1, COMP, GDF15, PTX3, PGA4, and CEACAM5) are shown in Figure 10A-B. As can be seen, the above 5355 6-marker combinations can be used to diagnose colorectal cancer.

[0245] The six-marker combination shown in Table 14 (partial six-marker combination of any six of the 11 protein markers: AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, and SERPINA1) was also independently validated. The results are shown in Table 14, with predictive efficacy AUC values ​​ranging from 0.8832 to 0.9714. The six-marker combination shown in Table 14 can be used to diagnose colorectal cancer.

[0246] The AUC comparison results of the RandomRorest model and the XGBboost model are shown in Figure 11. The AUC consistency of the RandomRorest model and the XGBboost model is very good: the average AUC of the 100 random models is basically the same, 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; this shows the interchangeability of the model algorithms in the implementation scheme.

[0247] Table 13: Some 6-marker combinations with predictive efficacy AUC greater than or equal to 0.975 in the test set (among the 5355 6-marker combinations mentioned above)

[0248] Table 14 Six-marker combinations with partial prediction efficacy AUC greater than or equal to 0.88 in the test set (partial six-marker combinations in the combination of any six of the 11 protein markers AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1)

[0249] 7-marker combinations: Based on the 6-marker combinations with an AUC greater than or equal to 0.975 (650 combinations), the combinations with the highest AUC among the combinations with 5 protein replicates were selected, and the other combinations were eliminated, resulting in 84 combinations (the 6-marker combinations in italics in Table 13, i.e., the 84 6-marker combinations in the Summary of the Invention). These were combined with the remaining 84 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; the predictive efficacy AUC values ​​of these 7056 7-marker combinations ranged from 0.961 to 0.989, the sensitivity ranged from 0.7113 to 0.96, and the specificity ranged from 0.7916 to 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. Only the range values ​​of the AUC values, sensitivity, and specificity of the 7056 7-marker combinations are given to demonstrate the diagnostic effect of the above 7056 7-marker combinations); among them, some 7-marker combinations with AUC greater than or equal to 0.987 are shown in Table 15, and some 7 The ROC curves for the marker combinations (SPP1, COMP, LMNB2, PLXDC2, TCL1A, PROK1, and ADGRG2; PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, and SOD3) are shown in Figure 12A-B. It can be seen that the above 7056 7-marker combinations can be used to diagnose colorectal cancer.

[0250] The seven-marker combination shown in Table 16 (partial seven-marker combination of any seven of the 11 protein markers: AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, and SERPINA1) was also independently validated. The results are shown in Table 16, with predictive efficacy AUC values ​​ranging from 0.8884 to 0.9751. The seven-marker combination shown in Table 16 can be used to diagnose colorectal cancer.

[0251] The AUC comparison results of the RandomForest model and the XGBboost model are shown in Figure 13. The AUC consistency of the RandomForest model and the XGBboost model is very good: the average AUC of the 100 random models is basically the same, 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, which shows the interchangeability of the model algorithms in the implementation scheme.

[0252] Table 15: Some 7-marker combinations with predictive efficacy AUC greater than or equal to 0.985 in the test set (the above 7056 7-marker combinations)

[0253] Table 16: Some 7-marker combinations with prediction efficacy AUC greater than or equal to 0.88 in the test set (some 7-marker combinations in the combination of any seven of the 11 protein markers AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1)

[0254] 8-marker combinations: Based on the 7-marker combinations with an AUC greater than or equal to 0.985 (40 combinations, the 7-marker combinations in Table 15, i.e., the 40 7-marker combinations in the Summary of the Invention), the remaining 83 proteins (i.e., 90 proteins minus the 7 proteins in the 7-marker combination) were combined into 40 × (90 - 7) = 3320 combinations. For example, PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PROK1 and PCDH7; SPP1, LMNB2, SOD3, ADGRE5, PLXDC1, PROK1, LBP and FASLG; the predictive efficacy AUC values ​​of these 3320 8-marker combinations ranged from 0.953 to 0.992, the sensitivity ranged from 0.798 to 0.9685, and the specificity ranged from 0.8264 to 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 demonstrate 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 some 8 The ROC curve of the marker combination (PTX3, POF1B, THBS4, EXTL1, PGA4, ITM2A, PROK1, and PCDH7; SPP1, LMNB2, SOD3, ADGRE5, PLXDC1, PROK1, LBP, and FASLG) is shown in Figure 14. It can be seen that the above 3320 8-marker combinations can be used to diagnose colorectal cancer.

[0255] The eight marker combinations shown in Table 18 (partial eight marker combinations of any eight of the 11 protein markers: AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, and SERPINA1) were also independently validated. The results are shown in Table 18, with predictive efficacy AUC values ​​ranging from 0.9121 to 0.9740. The eight marker combinations shown in Table 18 can be used to diagnose colorectal cancer.

[0256] The AUC comparison results of the RandomForest model and the XGBboost model are shown in Figure 15. The AUC consistency of the RandomForest model and the XGBboost model is very good: the average AUC of the 100 random models is basically the same, 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, which shows the interchangeability of the model algorithms in the implementation scheme.

[0257] Table 17: Some 8-marker combinations with predictive efficacy AUC greater than or equal to 0.985 in the test set (the above 3320 8-marker combinations)

[0258] Table 18 Partial prediction efficacy AUC of 8 marker combinations greater than or equal to 0.91 in the test set (partial 8 marker combinations in any eight combinations of the 11 protein markers AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1)

[0259] The present invention can also employ flow cytometry for multiplexed detection of tumor markers. Using an immunosandwich multiplex assay, one of the paired antibodies is coupled to a microsphere, and the other is coupled to a luminescent substance, to detect a corresponding tumor marker. Then, in the same reaction vessel, the multi-marker paired antibodies are coupled to the microspheres and the luminescent substance, respectively. These coupled antibodies and the sample are mixed and allowed to bind to the target antigen. Flow cytometric analysis allows for simultaneous detection of multiple tumor markers based on the fluorescence of the microspheres and the signal intensity of the luminescent substance. Subsequently, statistical methods are employed to determine reference intervals at different confidence levels based on a series of normally distributed sample data. This flow immunofluorescence multiplex assay technology can provide rapid and accurate multi-parameter analysis in clinical diagnosis, enabling more effective monitoring and assessment of diseases.

[0260] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. Use of a substance as a detection marker in the preparation of a product: The product is used for: early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer; The marker is A, and A contains at least one of B; 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.

2. The application according to claim 1, wherein: A contains any 1, 2, 3, 4, 5, 6, 7, or 8 of B; Preferably, A contains a single marker, and the single marker is any 1 of B; 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; 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.

3. The application according to claim 1, wherein: A contains a combination of 2 markers, and the combination of 2 markers is any 2 of those in B; Preferably, the combination of 2 markers is any 2 of those in C, and 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; Preferably, the combination of 2 markers is any one of a1)-a2): a1) Any two of those in D; a2) Any one of those in C and any one of those in D; 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; Preferably, the 2 - markers combination is any two of E, where E is: AREG, CEACAM5, COMP, EDA2R, FCRL1, GDF15, PTX3, TMPRSS15, TNC, NOTCH1, SERPINA1; 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; Preferably, A contains a 3 - markers combination, and the 3 - markers combination is any three of B; Preferably, the 3 - markers combination is any three of E; Preferably, A contains a 4 - markers combination, and the 4 - markers combination is any four of B; Preferably, the 4 - markers combination is b1) and b2): b1) the 3 - markers combination; b2) any one of F, where the union of F and the 3 - markers combination is B; Preferably, the 4 - markers combination is any four of E; Preferably, A comprises a combination of 5 markers, and the combination of 5 markers is any five of B; Preferably, the combination of 5 markers is c1) and c2): c1) the combination of 4 markers; c2) any one of G, and the union of G and the combination of 4 markers is B; Preferably, the combination of 5 markers is any five of E; Preferably, A comprises a combination of 6 markers, and the combination of 6 markers is any six of B; Preferably, the combination of 6 markers is d1) and d2): d1) the combination of 5 markers; d2) any one of H, and the union of H and the combination of 5 markers is B; Preferably, the combination of 6 markers is any six of E; Preferably, A comprises a combination of 7 markers, and the combination of 7 markers is any seven of B; Preferably, the combination of 7 markers is e1) and e2): e1) the combination of 6 markers; e2) any one of I, and the union of I and the combination of 6 markers is B; Preferably, the combination of 7 markers is any seven of E; Preferably, A comprises a combination of 8 markers, and the combination of 8 markers is any eight of B; Preferably, the combination of 8 markers is f1) and f2): f1) the combination of 7 markers; f2) any one of J, and the union of J and the combination of 7 markers is B; Preferably, the combination of 8 markers is any eight of E.

4. The application according to any one of claims 1-3, wherein: A further comprises at least one of K, and the union of K and A is B; Preferably, the test sample of the product is selected from at least one of body fluids, tissues, cells, and excreta of the object to be tested; Preferably, the body fluid comprises at least one of blood, lymph, pleural effusion, cerebrospinal fluid, synovial fluid, ascites, saliva, lymph, and internal body fluid; Preferably, the tissue comprises intestinal mucosal tissue; Preferably, the blood comprises at least one of serum, plasma, dried blood spot, and whole blood; Preferably, the excreta comprises at least one of urine, feces, tears, and sweat; Preferably, the object to be tested comprises a mammal; Preferably, the substance for detecting the biomarker comprises a substance for detecting the biomarker at the gene level and / or protein level; Preferably, the substance comprises substances for one or more detection techniques or methods selected from the group consisting of: 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, immunological PCR technology, biotin-avidin technology; Preferably, the immunohistochemistry comprises at least one of enzyme-linked immunosorbent assay, immunofluorescence, radioimmunoassay, immunoprecipitation, immunochemiluminescence, colloidal gold immunotechnology, fluorescence immunochromatography technology, complement fixation analysis, flow cytometry fluorescence resolution, single molecule detection technology; Preferably, the substance for the detection marker is selected from one or more of: a substance specific to the marker, a probe specific to the marker, a gene chip, a protein chip, a PCR primer; Preferably, the substance specific to the marker comprises any one of h1)-h4): h1) An antibody that specifically binds to the marker; h2) A ligand protein or polypeptide that specifically binds to the marker; h3) A non-protein compound that specifically recognizes the marker; h4) A nucleic acid aptamer that specifically recognizes the marker; Preferably, the antibody comprises at least one of polyclonal antibody, monoclonal antibody, single-chain antibody, functional antibody fragment, antibody Fab region, nanobody, chimeric antibody, multispecific antibody; Preferably, the product comprises at least one of a reagent, a kit, a test strip, a chip, a device, a system; 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; Preferably, the product further comprises a reagent for assisting in detecting gene expression levels, and the reagent for assisting in detecting gene expression levels includes: 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 for preparing a standard curve, a positive control; Preferably, the product further comprises a reagent for assisting in detecting protein expression levels, and the reagent for assisting in 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, a positive control.

5. A marker combination, the marker combination comprising at least two of the Bs in any one of claims 1-4.

6. The marker combination according to claim 5, characterized in that: The marker combination comprises any 2, 3, 4, 5, 6, 7, or 8 of the Bs in any one of claims 1-4; Preferably, the marker combination comprises: FCRL1; and At least one of L, where L is B that does not include FCRL1; Preferably, the marker combination comprises: AREG; and At least one of M, where M is B that does not include AREG; Preferably, the marker combination is the A in any one of claims 3-4.

7. A product comprising a substance for detecting the biomarker combination according to any one of claims 5 - 6.

8. The product according to claim 7, wherein: The substance for detecting the biomarker combination comprises a substance for detecting the biomarker combination at the gene level and / or protein level; Preferably, the substance comprises a substance for one or more detection techniques or methods selected from the group consisting of: 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, immunological PCR technology, biotin-avidin technology; Preferably, the immunohistochemistry comprises 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; Preferably, the substance for detecting the biomarker combination is selected from one or more of: a substance specific for the biomarker, a biomarker-specific probe, a gene chip, a protein chip, a PCR primer; Preferably, the substance specific for the biomarker comprises any one of h1)-h4): h1) An antibody specifically binding to the biomarker; h2) A ligand protein or polypeptide specifically binding to the biomarker; h3) A non-protein compound specifically recognizing the biomarker; h4) A nucleic acid aptamer specifically recognizing the biomarker; Preferably, the antibody comprises at least one of polyclonal antibody, monoclonal antibody, single-chain antibody, functional antibody fragment, Fab region of antibody, nanobody, chimeric antibody, multispecific antibody; Preferably, the product comprises at least one of a reagent, a kit, a test strip, a chip, a device, a system; Preferably, the product further comprises a substance for detecting other biomarkers for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer; Preferably, the product further comprises a reagent for assisting in detecting gene expression level, and the reagent for assisting in detecting gene expression level includes at least one of 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 for preparing a standard curve, a positive control; Preferably, the product further comprises a reagent for assisting in detecting protein expression level, and the reagent for assisting in detecting protein expression level 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, a positive control.

9. A method for constructing a model, the method comprising the step of constructing a model using the biomarker described in any one of claims 1 - 4.

10. The construction method according to claim 9, wherein: The method comprises the step of constructing a model using the biomarker combination described in claim 5 or 6; Preferably, the algorithm for constructing the model includes at least one of logistic regression, linear discriminant analysis, linear discriminant analysis of characteristic genes, support vector machine, random forest, recursive partitioning tree, XGBoost, ShrunkenCentroids, StepAIC, Kth-Nearest Neighbor, Boosting, neural network, Bayesian network, and hidden Markov model.

11. An apparatus or system, comprising: a detection module: configured to detect the content, activity, and / or expression level of the biomarker according to any one of claims 1-4 in a test sample; and an analysis module: configured to input the data obtained by the detection module into a model constructed according to the construction method of claim 9 or 10 for analysis.

12. The apparatus or system according to claim 11, wherein: the detection module is configured to detect the content, activity, and / or expression level of the biomarker combination according to claim 5 or 6 in a test sample; Preferably, the test sample is the test sample according to claim 4; Preferably, the apparatus or system further comprises: an output module, configured to output information according to the analysis result obtained by the analysis module.

13. A computer device, the computer device includes a memory and a processor, the memory stores a program, and when the processor executes the program, it implements any one of the following methods i1)-i2): i1) The model construction method according to claim 9 or 10; i2) S1: Obtain the content, activity, and / or expression level of the biomarker according to any one of claims 1-4 in a test sample; and S2: Input the data obtained in S1 into a model constructed according to the construction method of claim 9 or 10 for analysis.

14. The computer device according to claim 13, wherein: In i2), S1 is to obtain the content, activity, and / or expression level of the biomarker combination according to claim 5 or 6 in a test sample; Preferably, the test sample is the test sample according to claim 4; Preferably, i2) further includes the following step: Output information according to the obtained analysis result.

15. A computer-readable storage medium, the computer-readable storage medium including a stored computer program; wherein, When the computer program runs, it controls the computer-readable storage medium to implement any one of i1)-i2) in claim 13 or 14.

16. A method for early screening, diagnosis, staging, monitoring, efficacy evaluation, or prognosis evaluation of colorectal cancer, comprising the step of detecting the content, expression level, and / or activity of the biomarker according to any one of claims 1-4 in a test sample.

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