remodeler SMARCA4/BRG1. Loss of MSH2 in advanced gastric cancers was accompanied by deficient cell adhesion pathway expression, epithelial-mesenchymal transition, and enhanced tumorigenesis in vitro and in vivo. However, MSH2-deficient gastric cancers also displayed addiction to BAZ1B, a bromodomain- containing family member, and consequent synthetic lethality to bromodomain and extraterminal motif (BET) inhibition. Our results reveal a role for MSH2 in gastric cancer epigenomic regu- lation and identify BET inhibition as a potential therapy in MSH2-deficient gastric malignancies.

Mutations in the DNA mismatch repair gene MSH2 are causative discovered that besides its well-established role in DNA repair, MSH2 exerts a novel epigenomic function in gastric cancer. Unbiased CRISPR-based mass spectrometry combined with genomewide CRISPR functional screening revealed that in early-stage but rather is associated specifically with tumor-associated superenhancers controlling the expression of cell adhesion genes. At these loci, MSH2 genomic binding was required for chromatin rewiring, de novo enhancer-promoter interactions, maintenance of histone acetylation levels, and regulation of cell adhesion pathway expression. The chromatin function of MSH2 was independent of its DNA repair catalytic activity but required MSH6, another DNA repair gene, and recruitment to gene loci by the SWI/SNF chromatin remodeler SMARCA4/BRG1. Loss of MSH2 in advanced gastric cancers was accompanied by deficient cell adhesion pathway expression, epithelial-mesenchymal transition, and enhanced tumorigenesis in vitro and in vivo. However, MSH2-deficient gastric cancers also displayed addiction to BAZ1B, a bromodomain- containing family member, and consequent synthetic lethality to bromodomain and extraterminal motif (BET) inhibition. Our results reveal a role for MSH2 in gastric cancer epigenomic regu- lation and identify BET inhibition as a potential therapy in MSH2- deficient gastric malignancies.

Automated summary

Mutations in the MSH2 gene are causative in gastric cancer, and MSH2 has a novel epigenomic function in regulating gene expression. MSH2 binds to tumor-associated superenhancers in early-stage gastric cancer, playing a role in chromatin rewiring and cell adhesion pathway expression. Loss of MSH2 in advanced gastric cancer leads to deficient cell adhesion pathway expression and enhanced tumorigenesis. Additionally, MSH2-deficient gastric cancer cells show addiction to BET inhibition.