Variants in activators and downstream targets of ATM, radiation exposure, and contralateral breast cancer risk in the WECARE study |
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Authors: | Brooks Jennifer D,Teraoka Sharon N,Reiner Anne S,Satagopan Jaya M,Bernstein Leslie,Thomas Duncan C,Capanu Marinela,Stovall Marilyn,Smith Susan A,Wei Shan,Shore Roy E,Boice John D,Lynch Charles F,Mellemkjaer Lene,Malone Kathleen E,Liang Xiaolin Wecare Study Collaborative Group,Haile Robert W,Concannon Patrick,Bernstein Jonine L |
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Affiliation: | Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. brooksj@mskcc.org |
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Abstract: | Ionizing radiation (IR) is a breast carcinogen that induces DNA double-strand breaks (DSBs), and variation in genes involved in the DNA DSB response has been implicated in radiation-induced breast cancer. The Women's Environmental, Cancer, and Radiation Epidemiology (WECARE) study is a population-based study of cases with contralateral breast cancer (CBC) and matched controls with unilateral breast cancer. The location-specific radiation dose received by the contralateral breast was estimated from radiotherapy records and mathematical models. One hundred fifty-two SNPs in six genes (CHEK2, MRE11A, MDC1, NBN, RAD50, TP53BP1) involved in the DNA DSBs response were genotyped. No variants or haplotypes were associated with CBC risk (649 cases and 1,284 controls) and no variants were found to interact with radiation dose. Carriers of a RAD50 haplotype exposed to ≥1 gray (Gy) had an increased risk of CBC compared with unexposed carriers (Rate ratios [RR] = 4.31 [95% confidence intervals [CI] 1.93-9.62]); with an excess relative risk (ERR) per Gy = 2.13 [95% CI 0.61-5.33]). Although the results of this study were largely null, carriers of a haplotype in RAD50 treated with radiation had a greater CBC risk than unexposed carriers. This suggests that carriers of this haplotype may be susceptible to the DNA-damaging effects of radiation therapy associated with radiation-induced breast cancer. |
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Keywords: | DNA repair haplotypes polymorphisms radiation contralateral breast cancer |
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