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Up to 10% of cases of gastric cancer are familial, but so far, only mutations in CDH1 have been associated with gastric cancer risk. To identify genetic variants that affect risk for gastric cancer, we collected blood samples from 28 patients with hereditary diffuse gastric cancer (HDGC) not associated with mutations in CDH1 and performed whole-exome sequence analysis. We then analyzed sequences of candidate genes in 333 independent HDGC and non-HDGC cases. We identified 11 cases with mutations in PALB2, BRCA1, or RAD51C genes, which regulate homologous DNA recombination. We found these mutations in 2 of 31 patients with HDGC (6.5%) and 9 of 331 patients with sporadic gastric cancer (2.8%). Most of these mutations had been previously associated with other types of tumors and partially co-segregated with gastric cancer in our study. Tumors that developed in patients with these mutations had a mutation signature associated with somatic homologous recombination deficiency. Our findings indicate that defects in homologous recombination increase risk for gastric cancer.

Original publication

DOI

10.1053/j.gastro.2016.12.010

Type

Journal article

Journal

Gastroenterology

Publication Date

04/2017

Volume

152

Pages

983 - 986.e6

Keywords

Interaction, Stomach, Tumor, WES, Aged, Aged, 80 and over, BRCA1 Protein, DNA-Binding Proteins, Fanconi Anemia Complementation Group N Protein, Female, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Male, Middle Aged, Mutation, Nuclear Proteins, Recombinational DNA Repair, Stomach Neoplasms, Tumor Suppressor Proteins