Follow-up study confirms the presence of gastric cancer DNA Methylation Hallmarks in high-risk precursor lesions
To adopt prevention strategies in gastric cancer, it is imperative to develop robust biomarkers with acceptable costs and feasibility in clinical practice to stratified populations according to risk scores. With this aim, we applied an unbiased genome-wide CpG methylation approach to a discovery cohort composed of gastric cancer (n = 24), and non-malignant precursor lesions (n = 64). Then, candidate-methylation approaches were performed in a validation cohort of precursor lesions obtained from an observational longitudinal study (n = 264), with a 12-year follow-up to identify repression or progression cases. H. pylori stratification and histology were considered to determine their influence on the methylation dynamics. As a result, we ascertained that intestinal metaplasia partially recapitulates patterns of aberrant methylation of intestinal type of gastric cancer, independently of the H. pylori status. Two epigenetically regulated genes in cancer, RPRM and ZNF793, consistently showed increased methylation in intestinal metaplasia with respect to earlier precursor lesions. In summary, our result supports the need to investigate the practical utilities of the quantification of DNA methylation in candidate genes as a marker for disease progression. In addition, the H. pylori-dependent methylation in intestinal metaplasia suggests that pharmacological treatments aimed at H. pylori eradication in the late stages of precursor lesions do not prevent epigenome reprogramming toward a cancer signature ; This study was supported by grants from the Instituto de Salud Carlos III co-funded by European Regional Development Funds (ERDF/FEDER) a way to build Europe (PI10/02267 to M.B.; PI10/01089 to C.A.G.; PI10/01203 to S.L.) and COST CM1406 (to M.B.). D.J.H. has received funding from the People Program (MSCA-ITN-2014-ETN) of the European Union's Horizon 2020 Program under Chromatin 3D project (nº SEP-210147404), and O.C. has received funding from Institut d'Investigació Biomèdica de Bellvitge (IDIBELL) (Ph.D. scholarship to O.C.)