DNA-methylation variability in normal mucosa: a field cancerization marker in patients with adenomatous polyps.

Abstract

The phenomenon of field cancerization reflects the transition of normal cells into those predisposed to cancer. Assessing the scope and intensity of this process in the colon may support risk prediction and colorectal cancer prevention. The SWEPIC study, encompassing 1,111 participants for DNA methylation analysis and a subset of 84 for RNA-seq, was employed to detect field cancerization in individuals with adenomatous polyps (AP). Methylation variations were evaluated for their discriminative capability, including in external cohorts, genomic localization, clinical correlations, and associated RNA expression patterns. Normal cecal tissue of individuals harboring an AP in the proximal colon manifested dysregulated DNA methylation compared to tissue from healthy individuals at 558 unique loci. Leveraging these adenoma-related differentially variable and methylated CpGs (aDVMCs), our classifier discerned between healthy and AP-adjacent tissues across SWEPIC datasets (cross-validated ROC AUC [0.63-0.81]), including within age-stratified cohorts. This discriminative capacity was validated in three external sets, differentiating healthy from cancer-adjacent tissue (ROC AUC: [0.82-0.88]). Notably, aDVMC dysregulation correlated with polyp multiplicity. More than 50% of aDVMCs were significantly associated with age. These aDVMCs were enriched in active regions of the genome (p < .001), and associated genes exhibited altered expression in AP-adjacent tissues. Our findings underscore the early onset of field cancerization in the right colon during the neoplastic transformation process. A more extensive validation of aDVMC dysregulation as a stratification tool could pave the way for enhanced surveillance approaches, especially given its linkage to adenoma emergence.