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

Nature Genetics volume 47, pages 906–910 (2015)Cite this article

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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.

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Acknowledgements

We thank the individuals who participated in the study and whose contribution made this work possible. We also thank the personnel at the recruitment center. We acknowledge the Icelandic Cancer Registry (ICR) for assistance in the ascertainment of patients with cancer.

Author information

Author notes

  1. Hannes Helgason and Thorunn Rafnar: These authors contributed equally to this work.

Authors and Affiliations

  1. deCODE Genetics/Amgen, Reykjavik, Iceland

    Hannes Helgason, Thorunn Rafnar, Asgeir Sigurdsson, Simon N Stacey, Adalbjorg Jonasdottir, Louise le Roux, Julius Gudmundsson, Hrefna Johannsdottir, Asmundur Oddsson, Arnaldur Gylfason, Olafur T Magnusson, Gisli Masson, Daniel F Gudbjartsson, Unnur Thorsteinsdottir, Patrick Sulem & Kari Stefansson

  2. School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland

    Hannes Helgason & Daniel F Gudbjartsson

  3. Department of Medicine, Landspitali-University Hospital, Reykjavik, Iceland

    Halla S Olafsdottir & Kristin Alexiusdottir

  4. Department of Pathology, Landspitali-University Hospital, Reykjavik, Iceland

    Jon G Jonasson

  5. Icelandic Cancer Registry, Reykjavik, Iceland

    Jon G Jonasson & Laufey Tryggvadottir

  6. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    Jon G Jonasson, Laufey Tryggvadottir, Asgeir Haraldsson, Thorvaldur Jonsson, Unnur Thorsteinsdottir & Kari Stefansson

  7. Children's Hospital Iceland, Landspitali-University Hospital, Reykjavik, Iceland

    Asgeir Haraldsson

  8. Department of Surgery, Landspitali-University Hospital, Reykjavik, Iceland

    Thorvaldur Jonsson

  9. Department of Oncology, Regional Hospital West Jutland, Herning, Denmark

    Halla Skuladottir

Authors
  1. Hannes Helgason
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  2. Thorunn Rafnar
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Contributions

H.H., T.R., P.S. and K.S. designed the study and interpreted the results. H.S.O., J.G.J., L.T., K.A., A.H., T.J. and H.S. carried out the subject ascertainment, recruitment and collection of clinical data. H.H., T.R., A.S., S.N.S., A.J., L.l.R., J.G., H.J., A.O., O.T.M., G.M. and U.T. performed the sequencing, genotyping and expression analyses. H.H., A.G., D.F.G. and P.S. performed the statistical and bioinformatics analyses. H.H., T.R., P.S. and K.S. drafted the manuscript. All authors contributed to the final version of the manuscript.

Corresponding authors

Correspondence to Hannes Helgason or Kari Stefansson.

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Competing interests

H.H., T.R., A.S., S.N.S., A.J., L.l.R., J.G., H.J., A.O., A.G., O.T.M., G.M., D.H.G., U.T., P.S. and K.S. are all employees of deCODE Genetics/Amgen, Inc.

Integrated supplementary information

Supplementary Figure 1 Manhattan plots showing genome-wide association results for gastric cancer.

Results are shown for all variants with significance level P < 0.05 and imputation information greater than 0.8. The associations are based on two overlapping sets: (a) 2,500 gastric cancer patients and 205,652 controls (GC all) and (b) 2,043 verified gastric cancer adenocarcinomas and 202,533 controls (GC verified adenocarcinomas).

Supplementary Figure 2 Q-Q plots of the gastric cancer GWAS results.

The plots show uncorrected (red crosses) and corrected (using the method of genomic control; blue circles) χ2 statistics from the gastric cancer GWAS. The associations are based on two overlapping sets: (a) 2,500 gastric cancer patients and 205,652 controls (GC all; correction factor λg = 1.13) and (b) 2,043 verified gastric cancer adenocarcinomas and 202,533 controls (GC verified adenocarcinomas; correction factor λg = 1.11). Results are shown for variants that reached P < 0.05.

Supplementary Figure 3 Overview of associations in the region around ATM.

Black circles show –log10 P as a function of Build 36 coordinates for associations with gastric cancer for imputed SNPs and indels in Iceland. The associations are based on 2,500 gastric cancer patients and 205,652 controls (GC all). The vertical broken lines indicate the LoF variants p.Ser644* (P = 2.7 × 10−6) and p.Gln852* (P = 5.5 × 10−7). Genes are shown in blue, and recombination rates are reported in cM/Mb.

Supplementary Figure 4 Overview of associations in the ATM gene.

Black circles show –log10 P as a function of Build 36 coordinates for associations with gastric cancer for imputed SNPs and indels in Iceland. The associations are based on 2,500 gastric cancer patients and 205,652 controls (GC all). The vertical dashed lines indicate the LoF variants p.Tyr103* (P = 0.19), p.Ser644* (P = 2.7 × 10−6) and p.Gln852* (P = 5.5 × 10-7). Genes are shown in blue, and recombination rates are reported in cM/Mb.

Supplementary Figure 5 Age at diagnosis based on imputed genotype of ATM LoF mutations for all cancers except BCC.

The plot shows the distribution of age at diagnosis for chip-typed individuals for all cancers except basal cell carcinoma. The dashed blue line corresponds to chip-typed individuals who are not imputed carriers of ATM LoF variants; the solid red line corresponds to chip-typed individuals who are imputed carriers of ATM LoF variants.

Supplementary Figure 6 Age at diagnosis based on imputed genotype of ATM LoF mutations for prostate cancer.

The plot shows the distribution of age at diagnosis for chip-typed individuals with prostate cancer. The dashed blue line corresponds to chip-typed individuals who are not imputed carriers of ATM LoF variants; the solid red line corresponds to chip-typed individuals who are imputed carriers of ATM LoF variants.

Supplementary Figure 7 Age at diagnosis based on imputed genotype of ATM LoF mutations for breast cancer.

The plot shows the distribution of age at diagnosis for chip-typed individuals with breast cancer. The dashed blue line corresponds to chip-typed individuals who are not imputed carriers of ATM LoF variants; the solid red line corresponds to chip-typed individuals who are imputed carriers of ATM LoF variants.

Supplementary Figure 8 Age at diagnosis based on imputed genotype of ATM LoF mutations for gastric cancer.

The plot shows the distribution of age at diagnosis for chip-typed individuals with gastric cancer (2,500 gastric cancer patients and 205,652 controls (GC all)). The dashed blue line corresponds to chip-typed individuals who are not imputed carriers of ATM LoF variants; the solid red line corresponds to chip-typed individuals who are imputed carriers of ATM LoF variants.

Supplementary Figure 9 Age at diagnosis based on imputed genotype of ATM LoF mutations for pancreatic cancer.

The plot shows the distribution of age at diagnosis for chip-typed individuals with pancreatic cancer. The dashed blue line corresponds to chip-typed individuals who are not imputed carriers of ATM LoF variants; the solid red line corresponds to chip-typed individuals who are imputed carriers of ATM LoF variants.

Supplementary Figure 10 Age at diagnosis based on imputed genotype of ATM LoF mutations for colorectal cancer.

The plot shows the distribution of age at diagnosis for chip-typed individuals with colorectal cancer. The dashed blue line corresponds to chip-typed individuals who are not imputed carriers of ATM LoF variants; the solid red line corresponds to chip-typed individuals who are imputed carriers of ATM LoF variants.

Supplementary Figure 11 Regional plot and conditional analysis at the reported PSCA locus at 8q24 that replicates in Iceland.

Vertical dashed lines indicate the most significant variant at the locus, rs2920295[G] (P = 1.0 × 10−7, OR = 1.21), and the previously reported 5′ UTR variant rs2294008[T] in PSCA that associates with gastric cancer in Iceland (P = 2.4 × 10−7, OR = 1.21). The horizontal dashed line shows the P-value threshold for the locus. Black circles correspond to unadjusted P values; red crosses correspond to P values adjusted for rs2920295. The associations are based on 2,500 gastric cancer patients and 205,652 controls (GC all).

Supplementary Figure 12 Regional plot and conditional analysis at the reported PTGER4-PRKAA1 locus at 5p13.1 that replicates in Iceland.

Vertical dashed lines indicate the most significant variant at the locus, rs10036575[C] (P = 4.8 × 10−6, OR = 0.81), and the variant rs13361707[C] in PRKAA1 that was previously reported in the Han Chinese population and associated with gastric cancer in Iceland (P = 2.7 × 10−4, OR = 1.16). The horizontal dashed line shows the P-value threshold for the locus. Black circles correspond to unadjusted P values; red crosses correspond to P values adjusted for rs10036575. The associations are based on 2,500 gastric cancer patients and 205,652 controls (GC all).

Supplementary Figure 13 Regional plot and conditional analysis at the reported MUC1 locus at 1q22 that replicates in Iceland.

The vertical dashed line indicates the missense variant rs760077[A] in MTX1 (P = 1.1 × 10−9, OR = 0.79, AF = 35.1%, p.Thr63Ser). The horizontal dashed line shows the P-value threshold for the locus. Black circles correspond to unadjusted P values; red crosses correspond to P values adjusted for rs760077. The associations are based on 2,500 gastric cancer patients and 205,652 controls (GC all).

Supplementary Figure 14 eQTL analysis for rs2294008 and the expression of PSCA in stomach.

The alternative allele of rs2294008 is the risk allele for gastric cancer; thus, the risk allele associates significantly with increased expression of PSCA (P = 3 × 10−13). The plot and data are taken from GTEx (http://www.gtexportal.org/home/eqtls/calc?tissueName=Stomach&geneId=ENSG00000167653.4&snpId=rs2294008; accessed 28 October 2014).

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Helgason, H., Rafnar, T., Olafsdottir, H. et al. Loss-of-function variants in ATM confer risk of gastric cancer. Nat Genet 47, 906–910 (2015). https://doi.org/10.1038/ng.3342

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