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Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study
Journal article   Open access   Peer reviewed

Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study

Jonine L Bernstein, Robert W Haile, Marilyn Stovall, John D Boice Jr, Roy E Shore, Bryan Langholz, Duncan C Thomas, Leslie Bernstein, Charles F Lynch, Jorgen H Olsen, …
JNCI : Journal of the National Cancer Institute, Vol.102(7), pp.475-483
04/07/2010
DOI: 10.1093/jnci/djq055
PMCID: PMC2902825
PMID: 20305132
url
https://doi.org/10.1093/jnci/djq055View
Published (Version of record) Open Access

Abstract

Ionizing 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. The Women's Environmental, Cancer, and Radiation Epidemiology Study is an international population-based case-control study nested within a cohort of 52,536 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. Among 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; > or =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; > or =1.0 Gy: RR = 5.8, 95% CI = 1.8 to 19.0; P(trend) = .044). Women 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.
 Age Factors Humans Middle Aged Neoplasms, Radiation-Induced - etiology Breast Neoplasms - etiology Mutation, Missense Case-Control Studies Time Factors Tumor Suppressor Proteins - genetics Cell Cycle Proteins - genetics Adult Female Neoplasms, Second Primary - genetics Odds Ratio Genetic Predisposition to Disease Risk Assessment Risk Factors Protein-Serine-Threonine Kinases - genetics International Cooperation Ataxia Telangiectasia Mutated Proteins Radiation Injuries - complications DNA-Binding Proteins - genetics Neoplasms, Second Primary - etiology Radiation Injuries - etiology Environmental Exposure - adverse effects Breast Neoplasms - radiotherapy Aged DNA Damage - radiation effects

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