Radiation exposure, the ATM gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study Journal Article
| Authors: | Bernstein, J. L.; Haile, R. W.; Stovall, M.; Boice, J. D. Jr; Shore, R. E.; Langholz, B.; Thomas, D. C.; Bernstein, L.; Lynch, C. F.; Olsen, J. H.; Malone, K. E.; Mellemkjaer, L.; Borresen-Dale, A. L.; Rosenstein, B. S.; Teraoka, S. N.; Diep, A. T.; Smith, S. A.; Capanu, M.; Reiner, A. S.; Liang, X.; Gatti, R. A.; Concannon, P. |
| Article Title: | Radiation exposure, the ATM gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study |
| Abstract: | BackgroundIonizing radiation is a known mutagen and an established breast carcinogen. The ATM gene is a key regulator of cellular responses to the DNA damage induced by ionizing radiation. We investigated whether genetic variants in ATM play a clinically significant role in radiation-induced contralateral breast cancer in women.MethodsThe Women's Environmental, Cancer, and Radiation Epidemiology Study is an international population-based case-control study nested within a cohort of 52536 survivors of unilateral breast cancer diagnosed between 1985 and 2000. The 708 case subjects were women with contralateral breast cancer, and the 1397 control subjects were women with unilateral breast cancer matched to the case subjects on age, follow-up time, registry reporting region, and race and/or ethnicity. All women were interviewed and underwent full mutation screening of the entire ATM gene. Complete medical treatment history information was collected, and for all women who received radiotherapy, the radiation dose to the contralateral breast was reconstructed using radiotherapy records and radiation measurements. Rate ratios (RRs) and corresponding 95% confidence intervals (CIs) were estimated by using multivariable conditional logistic regression. All P values are two-sided.ResultsAmong women who carried a rare ATM missense variant (ie, one carried by <1% of the study participants) that was predicted to be deleterious, those who were exposed to radiation (mean radiation exposure = 1.2 Gy, SD = 0.7) had a statistically significantly higher risk of contralateral breast cancer compared with unexposed women who carried the wild-type genotype (0.01-0.99 Gy: RR = 2.8, 95% CI = 1.2 to 6.5; ≥1.0 Gy: RR = 3.3, 95% CI = 1.4 to 8.0) or compared with unexposed women who carried the same predicted deleterious missense variant (0.01-0.99 Gy: RR = 5.3, 95% CI = 1.6 to 17.3; ≥1.0 Gy: RR = 5.8, 95% CI = 1.8 to 19.0; Ptrend =. 044).ConclusionsWomen who carry rare deleterious ATM missense variants and who are treated with radiation may have an elevated risk of developing contralateral breast cancer. However, the rarity of these deleterious missense variants in human populations implies that ATM mutations could account for only a small portion of second primary breast cancers. © 2010. Published by Oxford University Press. |
| Keywords: | adult; controlled study; aged; middle aged; dna binding protein; gene mutation; major clinical study; case control study; genetics; missense mutation; case-control studies; dna-binding proteins; mutation, missense; clinical trial; cancer risk; comparative study; cell cycle protein; cell cycle proteins; dna damage; gene; genetic predisposition to disease; breast cancer; genetic variability; odds ratio; risk factors; age factors; protein serine threonine kinase; radiation injury; breast neoplasms; risk factor; high risk patient; radiation exposure; time; time factors; age; risk assessment; risk; protein-serine-threonine kinases; neoplasms, radiation-induced; multicenter study; breast tumor; tumor suppressor proteins; radiation injuries; atm protein; ionizing radiation; cancer registry; neoplasms, second primary; second cancer; tumor suppressor protein; genetic predisposition; ethnicity; environmental exposure; race; international cooperation; radiation induced neoplasm; atm gene |
| Journal Title: | JNCI: Journal of the National Cancer Institute |
| Volume: | 102 |
| Issue: | 7 |
| ISSN: | 0027-8874 |
| Publisher: | Oxford University Press |
| Date Published: | 2010-04-07 |
| Start Page: | 475 |
| End Page: | 483 |
| Language: | English |
| DOI: | 10.1093/jnci/djq055 |
| PUBMED: | 20305132 |
| PROVIDER: | scopus |
| PMCID: | PMC2902825 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 6" - "Export Date: 20 April 2011" - "CODEN: JNCIA" - "Source: Scopus" |
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