DNA methylation accumulation and its predetermination of future cancer phenotypes

Aberant DNA methylation is a common epigenomic alteration in carcinogenesis. Comprehensive analyses of DNA methylation have stratified gastrointestinal cancer into several subgroups according to specific DNA methylation accumulation. In gastric cancer, Helicobacter pylori infection is a cause of methylation accumulation in apparently normal mucosa. Epstein-Barr virus infection is another methylation inducer that causes more genome-wide methylation, resulting in the formation of unique epigenotype with extensive methylation. In colorectal carcinogenesis, accumulation of high levels of methylation in combination with BRAF mutation is characteristic of the serrated pathway, but not of the adenoma-carcinoma sequence through conventional adenoma. In a de novo pathway, laterally spreading tumours generate intermediate- and low-methylation epigenotypes, accompanied by different genetic features and different macroscopic morphologies. These methylation epigenotypes, with specific genomic aberrations, are mostly completed by the adenoma stage, and additional molecular aberration, such as TP53 mutation, is suggested to lead to cancer development with the corresponding epigenotype. Accumulation of DNA methylation and formation of the epigenotype is suggested to occur during the early stages of carcinogenesis and predetermines the future cancer type.