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

Helgason, Hannes; Rafnar, Thorunn; Ólafsdóttir, Halla Sif; Jonasson, Jón G.; Sigurðsson, Ásgeir; Stacey, Simon; Jónasdóttir, Aðalbjörg; Tryggvadóttír, Laufey; Alexíusdóttir, Kristín; Haraldsson, Ásgeir; Roux, Louise le; Guðmundsson, Jūlı́us; Johannsdottir, Hrefna; Oddsson, Ásmundur; Gylfason, Arnaldur; Magnússon, Ólafur Þ.; Másson, Gísli; Jónsson, Þorvaldur; Skuladottir, Halla; Guðbjartsson, Daníel F.; Þorsteinsdóttir, Unnur; Sulem, Patrick; Stefánsson, Kāri

doi:10.1038/ng.3342

Cited by 147 publications

(131 citation statements)

References 38 publications

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“…A recent meta-analyses provided support for an association of this variant with gastric cancer in Asian populations (37), and a recent GWAS in the Icelandic population also suggested an association between this region and gastric cancer in European populations. These results lend further support for the etiological role of this region on cancer susceptibility in general (38). …”

Section: Discussionsupporting

confidence: 72%

Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

Kraft²,

et al. 2016

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Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-staged approach to conduct genome-wide association studies for lung, ovary, breast, prostate and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression.

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Section: Discussionsupporting

confidence: 72%

Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

Kraft²,

et al. 2016

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“…mutations that are usually A-T causing) and breast cancer (Renwick et al 2006). More recently, similar associations with germline ATM mutations have also been observed in familial gastric and pancreatic cancers (Helgason et al 2015, Roberts et al 2012). Given that the products of a number of genes already implicated in breast cancer risk such as BRCA1 , BRCA2 , TP53 , PALB2 , CHEK2 and NBN are either directly phosphorylated by ATM, or are dependent on ATM function for their radiation-induced phosphorylation, a role for ATM mutations in breast cancer risk, particularly in radiation exposed individuals, is highly plausible.…”

Section: Introductionsupporting

confidence: 59%

ATM, radiation, and the risk of second primary breast cancer

Bernstein

Concannon

2017

International Journal of Radiation Biology

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Purpose It was first suggested more than 40 years ago that heterozygous carriers for the human autosomal recessive disorder Ataxia-Telangiectasia (A-T) might also be at increased risk for cancer. Subsequent studies have identified the responsible gene, Ataxia-Telangiectasia Mutated (ATM), characterized genetic variation at this locus in A-T and a variety of different cancers, and described the functions of the ATM protein with respect to cellular DNA damage responses. However, an overall model of how ATM contributes to cancer risk, and in particular, the role of DNA damage in this process, remains lacking. This review considers these questions in the context of contralateral breast cancer (CBC). Conclusions Heterozygous carriers of loss of function mutations in ATM that are A-T causing, are at increased risk of breast cancer. However, examination of a range of genetic variants, both rare and common, across multiple cancers, suggests that ATM may have additional effects on cancer risk that are allele dependent. In the case of CBC, selected common alleles at ATM are associated with a reduced incidence of CBC, while other rare and predicted deleterious variants may act jointly with radiation exposure to increase risk. Further studies that characterize germline and somatic ATM mutations in breast cancer and relate the detected genetic changes to functional outcomes, particularly with regard to radiation responses, are needed to gain a complete picture of the complex relationship between ATM, radiation and breast cancer.

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“…Currently, there is only limited information on the genomes of the people inhabiting this portion of Iran and our study included multiple distinct ethnic groups, including Turkmen of central Asian descent and non-Turkmen that are primarily of Indo-European descent. We note that recent reports from GWAS studies have identified some differences in genetic predisposition for gastric cancer between Asian and Caucasian subjects (45) . We did not observe significant difference in H. pylori virulence factors between or cancer risk between ethnicities in our population, therefore it seems less likely that population differences are a primary reason of our findings with regard to H. pylori seropositivity and risk of gastric cardia adenocarcinoma.…”

Section: Discussionmentioning

confidence: 69%

Multiplex H. pylori Serology and Risk of Gastric Cardia and Noncardia Adenocarcinomas

et al. 2015

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The reported associations with gastric adenocarcinoma and seropositivity to different H. pylori antigens using multiplex serology have not been consistent across studies. We aimed to investigate the association between fifteen different multiplex serology antigens and the risk of gastric cardia (GCA) and gastric non-cardia (GNCA) adenocarcinomas in northeastern Iran, a population with high rates of gastric adenocarcinoma. We included 272 cases of gastric adenocarcinoma (142 GCA, 103 GNCA, and 27 unspecified) and 524 controls who were individually matched to cases for age, sex, and place of residence in a population-based case-control study. Seropositivity to H. pylori was assessed using both multiplex serology and H. pylori IgG ELISA. 95% of controls were seropositive to H. pylori. Of the 15 antibodies in the multiplex assay, 11 showed no significant association with gastric adenocarcinomas. CagA and VacA were associated with a significantly increased risk of all gastric adenocarcinoma and GNCA in multivariate models. Surprisingly, GroEL and NapA were significantly associated with a reduced risk of these tumors. Only CagA antigen was associated with significantly elevated risk of GCA. We found no associations between H. pylori seropositivity overall either by whole-cell ELISA test or multiplex serology, likely due to the high prevalence of seropositivity. Individual antigen testing showed that CagA positivity was associated with increased risk of both noncardia and cardia adenocarcinoma, which is similar to some other Asian populations, while two antigens were associated with lower risk of gastric cancer. This latter result was unexpected and should be re-tested in other populations.

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

Cited by 147 publications

References 38 publications

Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

ATM, radiation, and the risk of second primary breast cancer

Multiplex H. pylori Serology and Risk of Gastric Cardia and Noncardia Adenocarcinomas

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