Unraveling epigenetic heterogeneity across gastrointestinal adenocarcinomas through a standardized analytical framework.

In this study, we propose an alternative approach for stratifying genome-scale DNA methylation profiles of gastrointestinal (GI) adenocarcinomas based on a robust analytical framework. A set of 978 GI adenocarcinomas and 120 adjacent normal tissues from public repositories was quality controlled and analyzed. Hierarchical consensus clustering of the tumors, based on differential epigenetic variability between malignant and normal samples, identified six distinct subtypes defined either by a pan-GI or a lower GI-specific phenotype. In addition to methylation levels, aberrant methylation frequencies and the degree of DNA methylation instability contributed to the characterization of each subtype. We found significant differences in the outcome of patients, with the poorest overall survival seen for those belonging to a pan-GI subtype with infrequent aberrant methylation. In conclusion, our standardized approach contributes to a refined characterization of the epigenetic heterogeneity in GI adenocarcinomas, offering insights into subtype-specific methylation with the potential to support prognostication.