Integrative Clinical and DNA Methylation Analyses in a Population-Based Cohort Identifies CDH17 and LRP2 as Risk Recurrence Factors in Stage II Colon Cancer

Abstract

Stage II colon cancer (CC), although diagnosed early, accounts for 16% of CC deaths. Predictors of recurrence risk could mitigate this but are currently lacking. By using a DNA methylation-based clinical screening in real-world (<i>n</i> = 383) and in TCGA-derived cohorts of stage II CC (<i>n</i> = 134), we have devised a novel 40 CpG site-based classifier that can segregate stage II CC into four previously undescribed disease sub-classes that are characterised by distinct molecular features, including activation of MYC/E2F-dependant proliferation signatures. By multivariate analyses, hypermethylation of 2 CpG sites at genes <i>CDH17</i> and <i>LRP2</i>, respectively, was found to independently confer either significantly increased (<i>CDH17</i>; <i>p</i>-value, 0.0203) or reduced (<i>LRP2</i>; <i>p</i>-value, 0.0047) risk of CC recurrence. Functional enrichment and immune cell infiltration analyses, on RNAseq data from the TCGA cohort, revealed cases with hypermethylation at <i>CDH17</i> to be enriched for <i>KRAS</i>, epithelial-mesenchymal transition and inflammatory functions (via IL2/STAT5), associated with infiltration by 'exhausted' T cells. By contrast, <i>LRP2</i> hypermethylated cases showed enrichment for mTORC1, DNA repair pathways and activated B cell signatures. These findings will be of value for improving personalised care paths and treatment in stage II CC patients.