title: Loss-of-function variants in ATM confer risk of gastric cancer.
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.
authors.affiliation: 1] deCODE Genetics/Amgen, Reykjavik, Iceland. [2] School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Hannes
authors.initials: H
authors.lastname: Helgason
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Thorunn
authors.initials: T
authors.lastname: Rafnar
authors.affiliation: Department of Medicine, Landspitali-University Hospital, Reykjavik, Iceland.
authors.forename: Halla S
authors.initials: HS
authors.lastname: Olafsdottir
authors.affiliation: 1] Department of Pathology, Landspitali-University Hospital, Reykjavik, Iceland. [2] Icelandic Cancer Registry, Reykjavik, Iceland. [3] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Jon G
authors.initials: JG
authors.lastname: Jonasson
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Asgeir
authors.initials: A
authors.lastname: Sigurdsson
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Stacey
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Adalbjorg
authors.initials: A
authors.lastname: Jonasdottir
authors.affiliation: 1] Icelandic Cancer Registry, Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Laufey
authors.initials: L
authors.lastname: Tryggvadottir
authors.affiliation: Department of Medicine, Landspitali-University Hospital, Reykjavik, Iceland.
authors.forename: Kristin
authors.initials: K
authors.lastname: Alexiusdottir
authors.affiliation: 1] Faculty of Medicine, University of Iceland, Reykjavik, Iceland. [2] Children's Hospital Iceland, Landspitali-University Hospital, Reykjavik, Iceland.
authors.forename: Asgeir
authors.initials: A
authors.lastname: Haraldsson
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Louise
authors.initials: L
authors.lastname: le Roux
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Julius
authors.initials: J
authors.lastname: Gudmundsson
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Hrefna
authors.initials: H
authors.lastname: Johannsdottir
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Asmundur
authors.initials: A
authors.lastname: Oddsson
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Arnaldur
authors.initials: A
authors.lastname: Gylfason
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Olafur T
authors.initials: OT
authors.lastname: Magnusson
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Gisli
authors.initials: G
authors.lastname: Masson
authors.affiliation: 1] Faculty of Medicine, University of Iceland, Reykjavik, Iceland. [2] Department of Surgery, Landspitali-University Hospital, Reykjavik, Iceland.
authors.forename: Thorvaldur
authors.initials: T
authors.lastname: Jonsson
authors.affiliation: Department of Oncology, Regional Hospital West Jutland, Herning, Denmark.
authors.forename: Halla
authors.initials: H
authors.lastname: Skuladottir
authors.affiliation: 1] deCODE Genetics/Amgen, Reykjavik, Iceland. [2] School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Daniel F
authors.identifier: 0000000252229857
authors.initials: DF
authors.lastname: Gudbjartsson
authors.affiliation: 1] deCODE Genetics/Amgen, Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: Patrick
authors.identifier: 0000000171236123
authors.initials: P
authors.lastname: Sulem
authors.affiliation: 1] deCODE Genetics/Amgen, Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D005060:Europe; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D017422:Sequence Analysis, DNA / Q000379:methods; D013274:Stomach Neoplasms / Q000235:genetics*
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins