Germline Mutations in PALB2, BRCA1, and RAD51C, Which Regulate DNA Recombination Repair, in Patients With Gastric Cancer

Gastroenterology. 2017 Apr;152(5):983-986.e6. doi: 10.1053/j.gastro.2016.12.010. Epub 2016 Dec 23.

Abstract

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.

Keywords: Interaction; Stomach; Tumor; WES.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • DNA-Binding Proteins
  • Fanconi Anemia Complementation Group N Protein
  • Nuclear Proteins
  • PALB2 protein, human
  • RAD51C protein, human
  • Tumor Suppressor Proteins