Gastric Cancer Risk and Pathogenesis in BRCA1 and BRCA2 Carriers

SIMPLE SUMMARY: Germline BRCA1 and BRCA2 pathogenic variant carriers are recognized to be at increased risk for multiple cancers including breast, ovarian, pancreatic, and prostate cancer, with risk management recommendations for these cancers included in BRCA1/2 guidelines. Currently, it is remains uncertain whether BRCA1/2 carriers are also at an increased risk for gastric cancer. Herein, we review the accumulating evidence that suggests BRCA1/2 carriers are at increased risk for gastric cancer, particularly among BRCA2 carriers. We also review existing literature addressing BRCA1/2-associated gastric carcinogenesis and potential avenues for therapeutic intervention. Lastly, we present gastric cancer risk management considerations for BRCA1/2 carriers as currently no such recommendations exist. ABSTRACT: Carriers of a pathogenic germline variant (PV) in BRCA1 or BRCA2 are at increased risk for a number of malignancies, including breast, ovarian, pancreatic, and prostate cancer. In this review, we discuss emerging evidence that BRCA2 PV carriers, and likely also BRCA1 PV carriers, are also at increased risk for gastric cancer (GC), highlighting that GC may be part of the BRCA1/2 cancer risk spectrum. While the pathogenesis of GC among BRCA1/2 PV carriers remains unclear, increasing evidence reveals that GCs are often enriched with mutations in homologous recombination-associated genes such as BRCA1/2, and that GC prognosis and response to certain therapies can depend on BRCA1/2 expression. Given the strength of data published to date, a risk management strategy for GC among BRCA1/2 PV carriers is needed, and herein we also propose a potential strategy for GC risk management in this population. Moving forward, further study is clearly warranted to define the mechanistic relationship between BRCA1/2 PVs and development of GC as well as to determine how GC risk management should be factored into the clinical care of BRCA1/2 carriers.