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

Loss-of-function variants in ATM confer risk of gastric cancer.

Author information

1
1] deCODE Genetics/Amgen, Reykjavik, Iceland. [2] School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
2
deCODE Genetics/Amgen, Reykjavik, Iceland.
3
Department of Medicine, Landspitali-University Hospital, Reykjavik, Iceland.
4
1] Department of Pathology, Landspitali-University Hospital, Reykjavik, Iceland. [2] Icelandic Cancer Registry, Reykjavik, Iceland. [3] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
5
1] Icelandic Cancer Registry, Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
6
1] Faculty of Medicine, University of Iceland, Reykjavik, Iceland. [2] Children's Hospital Iceland, Landspitali-University Hospital, Reykjavik, Iceland.
7
1] Faculty of Medicine, University of Iceland, Reykjavik, Iceland. [2] Department of Surgery, Landspitali-University Hospital, Reykjavik, Iceland.
8
Department of Oncology, Regional Hospital West Jutland, Herning, Denmark.
9
1] deCODE Genetics/Amgen, Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

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.

PMID:
26098866
DOI:
10.1038/ng.3342
[Indexed for MEDLINE]

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