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Background:  Colorectal cancer (CRC) is the third most frequently diagnosed malignancy and the fourth leading cause of cancer-related death among common tumors in the world. We aimed to establish and validate a risk assessment model to predict overall survival (OS) for the CRC patients.   Methods:  DNA methylation-driven genes were identified by integrating DNA methylation profile and transcriptome data from The Cancer Genome Atlas (TCGA) CRC cohort. Then, a risk score model was built based on LASSO, univariable Cox and multivariable Cox regression analysis. After analyzing the clinicopathological factors, a nomogram was constructed and assessed. Another cohort from GEO was used for external validation. Afterward, the molecular and immune characteristics in the two risk score groups were analyzed.   Results:  In total, 705 methylation-driven genes were identified. Based on the LASSO and Cox regression analyses, nine genes, i.e.,  LINC01555 ,  GSTM1 ,  HSPA1A ,  VWDE ,  MAGEA12 ,  ARHGAP ,  PTPRD ,  ABHD12B  and  TMEM88 , were selected for the development of a risk score model. The Kaplan–Meier curve indicated that patients in the low-risk group had considerably better OS ( P  = 2e-08). The verification performed in subgroups demonstrated the validity of the model. Then, we established an OS-associated nomogram that included the risk score and significant clinicopathological factors. The concordance index of the nomogram was 0.81. A comprehensive molecular and immune characteristics analysis showed that the high-risk group was associated with tumor invasion, infiltration of immune cells executing pro-tumor suppression (such as myeloid-derived suppressor cells, regulatory T cells, immature dendritic cells) and higher expression of common inhibitory checkpoint molecules (ICPs).   Conclusion:  Our nine-gene associated risk assessment model is a promising signature to distinguish the prognosis for CRC patients. It is expected to serve as a predictive tool with high sensitivity and specificity for individualized prediction of OS in the patients with CRC.

A Prognostic Model Based on Nine DNA Methylation-Driven Genes Predicts Overall Survival for Colorectal Cancer