Gastric epithelium from and carriers harbors increased double-stranded DNA damage and augmented growth.

An accumulating body of evidence suggests carriers of a pathogenic germline variant (PGV) in or have increased gastric cancer (GC) risk. and are tumor suppressor genes involved in promoting homologous recombination to repair double-stranded DNA breaks. The aim of this investigation was to identify differences within the gastric epithelium and in patient-derived gastric organoids (PDGOs) between and carriers and non-carriers to determine if evidence of early gastric carcinogenesis exists amongst these carriers. First, using gastric epithelial biopsies, carriers were found to harbor higher expression of the proliferative marker Ki-67 within the antral gastric epithelium and strikingly, biopsies from both and carriers displayed a marked increase in double-stranded DNA damage. These results were further explored using PDGOs, where a growth advantage was observed for both and PDGOs compared to non-carrier PDGOs. Furthermore, both and PDGOs displayed a more pronounced enhancement of Ki-67 expression as well as increased double stranded DNA damage compared to non-carrier PDGOs. Importantly, none of the PDGOs showed signs of or loss of heterozygosity, potentially indicating a haploinsufficient phenotype. Taken together, these novel findings suggest that haploinsufficiency in and carriers may lead to DNA damage in the gastric epithelium, which may serve as an early event contributing to GC development.