Germline whole-exome sequencing identifies CTNND1 as a candidate gene for hereditary gastric cancer in a large Brazilian cohort.

Gastric cancer is the fifth most commonly diagnosed cancer. Although 10% of cases show familial clustering, a monogenic hereditary cause is rarely observed. Little is known about the molecular profile of familial gastric cancer cases in Brazil. Thus, we aimed to characterize the germline genomic profile of patients with potentially hereditary gastric cancer in the Brazilian population. DNA from peripheral blood or buccal swab was obtained for whole-exome sequencing of 126 patients with gastric cancer with suspected hereditary cancer predisposition syndrome from the Mendelics laboratory. Results from our initial analyses using an exome-derived multigene panel showed that, among the 11 cases identified as having hereditary cancer predisposing syndrome, BRCA2 gene was the most frequently mutated (n = 3, 27.3%). Whole exome sequencing showed candidate genes, such as FBXO24 and CTNND1. Among the candidates, CTNND1 has emerging evidence of association with gastric cancer predisposition. Analysis of somatic data from The Cancer Genome Atlas showed that diffuse gastric tumors and signet ring cell adenocarcinomas with somatic mutations in CTNND1 exhibited high microsatellite instability and high mutation count. A rare germline variant identified in CTNND1 may expand understanding of hereditary gastric cancer predisposition. This is the first study to evaluate, through germline whole exome sequencing, candidate genes for gastric cancer predisposition in a large Brazilian population. The novel candidate genes identified may be associated with gastric cancer and have potential to improve surveillance and management of individuals at increased risk of developing this tumor.