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Background  CIMP (CpG island methylator phenotype) is an epigenetic molecular subtype, observed in multiple malignancies and associated with the epigenetic silencing of tumor suppressors. Currently, for most cancers including gastric cancer (GC), mechanisms underlying CIMP remain poorly understood. We sought to discover molecular contributors to CIMP in GC, by performing global DNA methylation, gene expression, and proteomics profiling across 14 gastric cell lines, followed by similar integrative analysis in 50 GC cell lines and 467 primary GCs.    Results  We identify the cystathionine beta-synthase enzyme (CBS) as a highly recurrent target of epigenetic silencing in CIMP GC. Likewise, we show that  CBS  epimutations are significantly associated with CIMP in various other cancers, occurring even in premalignant gastroesophageal conditions and longitudinally linked to clinical persistence. Of note, CRISPR deletion of  CBS  in normal gastric epithelial cells induces widespread DNA methylation changes that overlap with primary GC CIMP patterns. Reflecting its metabolic role as a gatekeeper interlinking the methionine and homocysteine cycles,  CBS  loss in vitro also causes reductions in the anti-inflammatory gasotransmitter hydrogen sulfide (H 2 S), with concomitant increase in NF-κB activity. In a murine genetic model of  CBS  deficiency, preliminary data indicate upregulated immune-mediated transcriptional signatures in the stomach.    Conclusions  Our results implicate  CBS  as a bi-faceted modifier of aberrant DNA methylation and inflammation in GC and highlights H 2 S donors as a potential new therapy for  CBS -silenced lesions.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13059-021-02375-2.

Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation