Deciphering the Role of DNA Methylation-Driven Genes in Rectal Cancer: Insights into Prognostic Modeling and Mechanistic Pathways

Background DNA methylation alterations play a crucial role in rectal cancer development. This study identifies and characterizes DNA methylation-driven genes in the TCGA-READ cohort, exploring their association with rectal cancer development and the underlying mechanism. Methods DNA methylation-driven genes were identified using MethylMix package and subjected to gene ontology (GO) enrichment analysis via cluster profiler package. Prognostic model development involved Lasso regression and ten-fold cross-validation, followed by performance evaluation using Kaplan-Meier survival curves, time-dependent ROC curves, calibration curves, and decision curve analysis. Cancer-promoting mechanism underlying high risk score group was clarified through gene set enrichment analysis (GSEA) and multi-algorithm-based immune infiltration analyses. Results GO enrichment analysis highlighted significant functional terms based on 490 DNA methylation-driven genes, implicating Wnt signaling and cell fate commitment in rectal cancer development. The developed prognostic model, consisting of CCNI2, LINC00899, and ST6GALNAC1, exhibited high predictive accuracy. Differential gene expression analysis identified 89 underexpressed genes in the high-risk score group, with SULF1 identified as a hub gene. The negative regulation process of malignant tumor-associated pathways is suppressed, and the decreased infiltration abundance of cytotoxic cells, such as NK cells, may represent a potential mechanism for the poor prognosis observed in the high-risk score group. Conclusions Our findings elucidate the landscape of DNA methylation-driven genes in rectal cancer. These insights contribute to a deeper understanding of rectal cancer progression and provide potential targets for therapeutic intervention.