DNA methylation signatures and the contribution of age-associated methylomic drift to carcinogenesis in early-onset colorectal cancer

BackgroundThe role of DNA methylation (DNAm) in the carcinogenesis of colorectal cancer (CRC) diagnosed 70 years; 318 tumour and 40 normal). CpGs associated with age-related methylation drift were identified using a public dataset of 231 normal mucosa samples from people without CRC. DNAm-age was estimated using epiTOC2. ResultsCommon to all three age-of-onset groups, 88,385 (20% of all CpGs) CpGs were differentially methylated between tumour and normal mucosa. We identified 234 differentially methylated genes that were unique to the EOCRC group. In normal mucosa from people without CRC, we identified 28,154 CpGs that undergo ageing-related DNAm drift and of those, 65% were aberrantly methylated in EOCRC tumours. Based on the mitotic-based DNAm clock epiTOC2, we identified age acceleration in normal mucosa of people with EOCRC compared with normal mucosa from the IOCRC, LOCRC groups (p=3.7x10-16) and young people without CRC (p=5.8x10-6). ConclusionEOCRC acquires unique DNAm alterations at 234 loci. CpGs associated with ageing-associated drift were widely affected in EOCRC without needing the decades-long accrual of DNAm drift as commonly seen in intermediate- and late-onset CRCs. We found accelerated ageing in normal mucosa from people with EOCRC, as evidenced by a faster stem-cell division rate, potentially contributing to EOCRC carcinogenesis.