Concurrent hypermethylation of CpG islands and hypomethylation of CpG-poor regions are associated with gastric cancer risk after Helicobacter pylori eradication.

Background and aim: Aberrant DNA methylation persists in the gastric mucosa after Helicobacter pylori (H. pylori) eradication and may contribute to the development of post-eradication gastric cancer (PEGC). We aimed to comprehensively investigate both DNA hypermethylation and hypomethylation and their relevance to cancer risk.

Methods: Genome-wide DNA methylation profiling was performed using Infinium MethylationEPIC BeadChips with tumor tissue and non-cancerous mucosa from PEGC patients. Public datasets, including The Cancer Genome Atlas (TCGA)-STAD and H. pylori-negative controls, were integrated to identify recurrently hyper- and hypomethylated loci. Representative gene methylation levels were validated using bisulfite pyrosequencing. Correlation analyses were conducted to link DNA methylation with gene expression.

Results: Non-cancerous mucosa from PEGC patients exhibited substantial CpG island (CGI) hypermethylation. In parallel, we detected 4081 CpG sites recurrently hypomethylated in GC, many of which were also hypomethylated in non-cancerous mucosa from PEGC patients. The majority of hypomethylated sites were located outside of CGIs, often near oncogenes such as CDH17, HNF4A and CD44, and showed inverse correlations with gene expression. CGI hypermethylation and CpG hypomethylation were positively correlated across samples.

Conclusions: CGI hypermethylation and non-CGI hypomethylation are tightly linked and may co-emerge during the early stages of gastric carcinogenesis. Their concurrent presence in non-cancerous mucosa from PEGC patients suggests a coordinated epigenetic landscape contributing to residual cancer risk after H. pylori eradication.