Abnormal epigenetic aging of epigenetic outliers in normal colon mucosa from colorectal cancer patients.

A subset of colorectal cancer (CRC) patients displays abnormal DNA methylation patterns (“Outlier Methylation Phenotype” (OMP)) in normal adjacent tissue (NAT). We analyzed the impact of OMP status on epigenetic age and tumor progression using published aging and mitotic clocks and colonic epigenetic clock (EpiAge) developed on controls, with equal representation from Black and Caucasian populations. Three aging clocks (including EpiAge) showed “significantly lower” epigenetic age in CRC. Mitotic clocks suggested significantly fewer stem cell divisions in CRC versus controls. A binomial model using inactive X chromosome CpGs suggested that NAT of CRC patients had fewer stem cells compared with controls. On comparing NAT and tumor methylome, the OMP group showed the fewest epigenetic differences. In conclusion, our study demonstrates that NAT of OMP-CRC patients undergoes epigenetic age deceleration and have fewer epigenetic differences with tumor tissues, suggesting that NAT of OMPs had progressed toward a tumor identity.