Identification Of Tumor Microenvironment-related Prognostic Genes In Colorectal Cancer Based On Bioinformatic Methods

Objective:Colorectal cancer（CRC）is still a leading cause of cancer death worldwide.Since tumors only show symptoms in advanced stages,about80% of CRC patients relapse within the first three years.Therefore,the determination of reliable prognostic biomarkers is essential for exploring immunotherapy targets and improving the survival rate of CRC patients.In recent years,many studies have shown that the tumor microenvironment significantly affects tumor growth and progression and offers potential value in the diagnosis and prognosis prediction of tumors.Moreover,it has been reported that the tumor microenvironment highly influences the progression of colorectal cancer.Therefore,this study aims to explore the relationship between TME and colorectal cancer prognosis and identifies prognostic genes related to the CRC microenvironment.Methods:We collected gene expression data from The Cancer Genome Atlas（TCGA）.We calculated the score of stromal/immune cells and their relationship with the clinical outcome of CRC through the ESTIMATE algorithm.We screened differentially expressed genes（DEGs）by dividing colorectal cancer cases into high and low stromal/immune score groups.GO,KEGG enrichment analysis and protein-protein interaction（PPI）network are used to determine the potential enrichment functions and pathways of DEGs.K-M survival analysis is used to screen the DEGs related to prognosis.The expression levels of these genes were verified in two cohorts（GSE17538 and GSE161158）from the GEO database（Gene Expression Omnibus,GEO）.The TIMER（Tumor Immune Estimation Resource）database is used to evaluate the relationship between prognosticrelated DEGs and the level of immune cell infiltration.The HPA（Human Protein Atlas）database is used to study the expression levels of the proteins encoded by these DEGs.Results:The immune score of CRC patients in the TCGA database decreased with increasing tumor metastasis.The stromal score gradually increased with the increase of the size of the primary tumor.We identified 292 DEGs.GO,KEGG functional enrichment analysis and PPI showed that these DEGs were closely related to immune response,cytokine-cytokine receptor interaction and chemokine signalling pathway.We identified six differential genes（FABP4,MEOX2,MMP12,ERMN,TNFAIP6 and CHST11）with prognostic value through K-M survival analysis and verified them in two independent cohorts（GSE17538 and GSE161158）.According to TIMER,these six differential genes are positively correlated with the level of infiltration of different immune cells in CRC.Therefore,we speculated that the six prognostic-related DEGs might regulate the immune microenvironment of CRC by affecting the infiltration of immune cells.Conclusion:1.Lower immune score is significantly related to the malignant progression of CRC.2.292 differentially expressed genes are closely related to immune response,cytokine-cytokine receptor interaction and chemokine signalling pathway.3.6 prognostic-related DEGs（FABP4,MEOX2,MMP12,ERMN,TNFAIP6 and CHST11）are closely related to the prognosis of CRC patients.4.Six prognostic-related DEGs are significantly related to the level of immune cell infiltration in colorectal cancer.Our research provides new ideas for analyzing the complex relationship between colorectal cancer and the tumor microenvironment.The results might help discover new diagnostic and prognostic biomarkers and new treatment targets for colorectal cancer.