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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




Journal article



Publication Date





983 - 986.e6


Genome Center and Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, California.


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