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  • Loss-of-function variants i...
    Helgason, Hannes; Rafnar, Thorunn; Olafsdottir, Halla S; Jonasson, Jon G; Sigurdsson, Asgeir; Stacey, Simon N; Jonasdottir, Adalbjorg; Tryggvadottir, Laufey; Alexiusdottir, Kristin; Haraldsson, Asgeir; le Roux, Louise; Gudmundsson, Julius; Johannsdottir, Hrefna; Oddsson, Asmundur; Gylfason, Arnaldur; Magnusson, Olafur T; Masson, Gisli; Jonsson, Thorvaldur; Skuladottir, Halla; Gudbjartsson, Daniel F; Thorsteinsdottir, Unnur; Sulem, Patrick; Stefansson, Kari

    Nature genetics, 08/2015, Letnik: 47, Številka: 8
    Journal Article

    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.