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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 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.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; > 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).ConclusionsWomen who carry rare del

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 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.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; > 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).ConclusionsWomen who carry rare del

IntroductionDeficiencies in cellular responses to DNA damage can predispose to cancer. Ionizing radiation can cause cluster damage and double-strand breaks (DSBs) that pose problems for cellular repair processes. Three genes (ATM, BRCA1, and BRCA2) encode products that are essential for the normal cellular response to DSBs, but predispose to breast cancer when mutated.DesignTo examine the joint roles of radiation exposure and genetic susceptibility in the etiology of breast cancer, we designed a case-control study nested within five population-based cancer registries. We hypothesized that a woman carrying a mutant allele in one of these genes is more susceptible to radiation-induced breast cancer than is a non-carrier. In our study, 700 women with asynchronous bilateral breast cancer were individually matched to 1400 controls with unilateral breast cancer on date and age at diagnosis of the first breast cancer, race, and registry region, and counter-matched on radiation therapy. Each triplet comprised two women who received radiation therapy and one woman who did not. Radiation absorbed dose to the contralateral breast after initial treatment was estimated with a comprehensive dose reconstruction approach that included experimental measurements in anthropomorphic and water phantoms applying patient treatment parameters. Blood samples were collected from all participants for genetic analyses.ConclusionsOur study design improves the potential for detecting gene-environment interactions for diseases when both gene mutations and the environmental exposures of interest are rare in the general population. This is particularly applicable to the study of bilateral breast cancer because both radiation dose and genetic susceptibility have important etiologic roles, possibly by interactive mechanisms. By using counter-matching, we optimized the informativeness of the collected dosimetry data by increasing the variability of radiation dose within the case-control sets and enhan

IntroductionDeficiencies in cellular responses to DNA damage can predispose to cancer. Ionizing radiation can cause cluster damage and double-strand breaks (DSBs) that pose problems for cellular repair processes. Three genes (ATM, BRCA1, and BRCA2) encode products that are essential for the normal cellular response to DSBs, but predispose to breast cancer when mutated.DesignTo examine the joint roles of radiation exposure and genetic susceptibility in the etiology of breast cancer, we designed a case-control study nested within five population-based cancer registries. We hypothesized that a woman carrying a mutant allele in one of these genes is more susceptible to radiation-induced breast cancer than is a non-carrier. In our study, 700 women with asynchronous bilateral breast cancer were individually matched to 1400 controls with unilateral breast cancer on date and age at diagnosis of the first breast cancer, race, and registry region, and counter-matched on radiation therapy. Each triplet comprised two women who received radiation therapy and one woman who did not. Radiation absorbed dose to the contralateral breast after initial treatment was estimated with a comprehensive dose reconstruction approach that included experimental measurements in anthropomorphic and water phantoms applying patient treatment parameters. Blood samples were collected from all participants for genetic analyses.ConclusionsOur study design improves the potential for detecting gene-environment interactions for diseases when both gene mutations and the environmental exposures of interest are rare in the general population. This is particularly applicable to the study of bilateral breast cancer because both radiation dose and genetic susceptibility have important etiologic roles, possibly by interactive mechanisms. By using counter-matching, we optimized the informativeness of the collected dosimetry data by increasing the variability of radiation dose within the case-control sets and enhan