Risk of cancer by ATM missense mutations in the general population

Research output: Contribution to journalJournal articleResearchpeer-review

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

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.
Original languageEnglish
JournalJournal of Clinical Oncology
Volume26
Issue number18
Pages (from-to)3057-62
Number of pages5
ISSN0732-183X
DOIs
Publication statusPublished - 2008

Bibliographical note

Keywords: Adult; Breast Neoplasms; Cell Cycle Proteins; DNA-Binding Proteins; Denmark; Female; Genetic Predisposition to Disease; Heterozygote; Humans; Male; Middle Aged; Mutation, Missense; Neoplasms; Prospective Studies; Protein-Serine-Threonine Kinases; Tumor Suppressor Proteins

ID: 10479939