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Risk of Cancer by ATM Missense Mutations in the General Population

Sarah Louise Dombernowsky, Maren Weischer, Kristine Højgaard Allin, Stig Egil Bojesen, Anne Tybjjrg-Hansen, Børge Grønne Nordestgaard

From the Department of Clinical Biochemistry, Herlev University Hospital, Herlev; the Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, and the Copenhagen City Heart Study, Bispebjerg University Hospital, University of Copenhagen, Denmark

Corresponding author: Børge G. Nordestgaard, MD, DMSc, Department of Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark; e-mail: brno{at}heh.regionh.dk

Purpose: Truncating and missense mutations in the ATM gene, which cause insufficient DNA damage surveillance, allow damaged cells to proceed into mitosis, which eventually results in increased cancer susceptibility. We tested the hypotheses that ATM Ser49Cys and ATM Ser707Pro heterozygosity increase the risk of cancer overall, of breast cancer, and of 26 other cancer subtypes in the general population.

Patients and Methods: We genotyped 10,324 individuals from the Danish general population who were observed prospectively for 36 years, during which 2,056 developed cancer.

Results: Multifactorially adjusted hazard ratios for ATM Ser49Cys heterozygotes versus noncarriers were 1.2 (95% CI, 0.9 to 1.5) for cancer overall, 0.8 (95% CI, 0.3 to 2.0) for breast cancer, 4.8 (95% CI, 2.2 to 11) for melanoma, 2.3 (95% CI, 1.1 to 5.0) for prostate cancer, and 3.4 (95% CI, 1.1 to 11) for cancer of the oral cavity/pharynx. Multifactorially adjusted hazard ratios for ATM Ser707Pro heterozygotes versus noncarriers were 0.8 (95% CI, 0.6 to 1.2) for cancer overall, 0.6 (95% CI, 0.2 to 1.6) for breast cancer, 10 (95% CI, 1.1 to 93) for thyroid/other endocrine tumors, and 2.7 (95% CI, 1.0 to 7.6) for cancer of corpus uteri.

Conclusion: ATM missense mutations do not increase the risk of cancer overall or of breast cancer in the general population; however, we observed in exploratory analyses that ATM missense mutations may be associated with an increased risk of other cancer subtypes. As we did multiple comparisons, some of these findings could represent chance findings rather than real phenomena.

B.G.N. was supported by the Danish Medical Research Council, the Copenhagen County Foundation, and the Danish Heart Foundation.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.