Loss-of-function Variants in ATM Confer Risk of Gastric Cancer

Nat Genet. 2015 Aug;47(8):906-10. doi: 10.1038/ng.3342. Epub 2015 Jun 22.

Abstract

Gastric cancer is a serious health problem worldwide, with particularly high prevalence in eastern Asia. Genome-wide association studies (GWAS) in Asian populations have identified several loci that associate with gastric cancer risk. Here we report a GWAS of gastric cancer in a European population, using information on 2,500 population-based gastric cancer cases and 205,652 controls. We found a new gastric cancer association with loss-of-function mutations in ATM (gene test, P = 8.0 × 10(-12); odds ratio (OR) = 4.74). The combination of the loss-of-function variants p.Gln852*, p.Ser644* and p.Tyr103* (combined minor allele frequency (MAF) = 0.3%) also associates with pancreatic and prostate cancers (OR = 3.81 and 2.18, respectively) and gives an indication of risk of breast and colorectal cancers (OR = 1.82 and 1.97, respectively). Cancers in those carrying loss-of-function ATM mutations are diagnosed at a significantly earlier age than in non-carriers. Our results confirm an association between gastric cancer in Europeans and three loci previously reported in Asians, MUC1, PRKAA1 and PSCA, refine the association signal at PRKAA1 and support a pathogenic role for the tandem repeat identified in MUC1.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Algorithms
  • Ataxia Telangiectasia Mutated Proteins / genetics*
  • Europe
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study / methods
  • Genotype
  • Humans
  • Logistic Models
  • Male
  • Middle Aged
  • Models, Genetic
  • Odds Ratio
  • Polymorphism, Single Nucleotide*
  • Risk Factors
  • Sequence Analysis, DNA / methods
  • Stomach Neoplasms / genetics*

Substances

  • Ataxia Telangiectasia Mutated Proteins