Gastric Epithelium from BRCA1 and BRCA2 Carriers Harbors Increased Double-Stranded DNA Damage and Enhanced Growth Potential.

An accumulating body of evidence suggests that carriers of a pathogenic germline variant (PGV) in BRCA1 or BRCA2 have an increased gastric cancer risk. BRCA1 and BRCA2 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 (PDGO) between BRCA1 and BRCA2 carriers and noncarriers to determine if evidence of early gastric carcinogenesis exists among these carriers. First, using gastric epithelial biopsies, BRCA2 carriers were found to harbor higher expression of the proliferative marker Ki-67 within the antral gastric epithelium, and strikingly, biopsies from both BRCA1 and BRCA2 carriers displayed a marked increase in double-stranded DNA damage. These results were further explored using PDGOs, in which a growth advantage was observed for both BRCA1 and BRCA2 PDGOs compared with noncarrier PDGOs. Furthermore, both BRCA1 and BRCA2 PDGOs displayed a more pronounced enhancement of Ki-67 expression as well as increased double-stranded DNA damage compared with noncarrier PDGOs. Importantly, none of the PDGOs showed signs of BRCA1 or BRCA2 loss of heterozygosity, potentially indicating a haploinsufficient phenotype. Taken together, these novel findings suggest that haploinsufficiency in BRCA1 and BRCA2 carriers may lead to DNA damage in the gastric epithelium, which may serve as an early event contributing to gastric cancer development. The elevated risk of gastric cancer for BRCA1 and BRCA2 PGV carriers may be due to haploinsufficiency, which warrants further investigation into mechanisms of BRCA1- and BRCA2-associated gastric cancer.