Prognostic Effect of Inflammatory Genes on Stage I–III Colorectal Cancer—Integrative Analysis of TCGA Data

SIMPLE SUMMARY: Research interest in the role of inflammation in the progression and prognosis of colorectal cancer (CRC) is growing. In this study, we evaluated the expression and DNA methylation levels of inflammation-related genes in CRC tissues using the TCGA-COREAD dataset by integratively combining multi-omics features using machine learning. Statistical analysis was additionally performed to allow for interpretable, understandable, and clinically practical results. An integrative model combining expression, methylation, and clinical features had the highest performance. In multivariate analysis, the methylation levels of CEP250, RAB21, and TNPO3 were significantly associated with overall survival. Our study results implicate the importance of integrating expression and methylation information along with clinical information in the prediction of survival. CEP250, RAB21, and TNPO3 in the prediction model might have a crucial role in CRC prognosis and further improve our understanding of potential mechanisms linking inflammatory reactions and CRC progression. ABSTRACT: Background inflammatory status indicators have been reported as prognostic biomarkers of colorectal cancer (CRC). However, since inflammatory interactions with the colon involve various modes of action, the biological mechanism linking inflammation and CRC prognosis has not been fully elucidated. We comprehensively evaluated the predictive roles of the expression and methylation levels of inflammation-related genes for CRC prognosis and their pathophysiological associations. Method. An integrative analysis of 247 patients with stage I-III CRC from The Cancer Genome Atlas was conducted. Lasso-penalized Cox proportional hazards regression (Lasso-Cox) and statistical Cox proportional hazard regression (CPH) were used for the analysis. Results. Models to predict overall survival were designed with respective combinations of clinical variables, including age, sex, stage, gene expression, and methylation. An integrative model combining expression, methylation, and clinical features performed better (median C-index = 0.756) than the model with clinical features alone (median C-index = 0.726). Based on multivariate CPH with features from the best model, the methylation levels of CEP250, RAB21, and TNPO3 were significantly associated with overall survival. They did not share any biological process in functional networks. The 5-year survival rate was 29.8% in the low methylation group of CEP250 and 79.1% in the high methylation group (p < 0.001). Conclusion. Our study results implicate the importance of integrating expression and methylation information along with clinical information in the prediction of survival. CEP250, RAB21, and TNPO3 in the prediction model might have a crucial role in CRC prognosis and further improve our understanding of potential mechanisms linking inflammatory reactions and CRC progression.