Radiation Exposure, the ATM Gene, and Contralateral Breast Cancer in the Women's Environmental Cancer and Radiation Epidemiology Study
Radiation Exposure, the ATM Gene, and Contralateral Breast Cancer in the Women's Environmental Cancer and Radiation Epidemiology Study
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DOI：
10.1093/jnci/djq055
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发表时间：
2010-04-07
期刊：
影响因子：
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通讯作者：
Concannon, Patrick
中科院分区：
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作者：
Bernstein, Jonine L.;Haile, Robert W.;Concannon, Patrick
电离辐射是一种已知的诱变剂，也是一种确定的乳腺癌致癌物。ATM基因是细胞对电离辐射引起的DNA损伤反应的关键调节因子。我们研究了ATM的遗传变异是否在女性辐射诱导的对侧乳腺癌中发挥临床重要作用。妇女环境、癌症和辐射流行病学研究是一项以国际人群为基础的病例对照研究，研究对象是1985年至2000年间诊断为单侧乳腺癌的52536名幸存者。708例受试者为对侧乳腺癌女性，1397例对照受试者为单侧乳腺癌女性，与病例受试者年龄、随访时间、登记报告地区、种族和/或民族相匹配。所有女性都接受了采访，并对整个ATM基因进行了全面的突变筛查。收集完整的医疗史信息，并对所有接受放射治疗的妇女，利用放射治疗记录和辐射测量重建对侧乳房的辐射剂量。采用多变量条件logistic回归估计各指标的发病率比（rr）和相应的95%置信区间（ci）。所有P值都是双面的。在携带一种罕见的ATM错义变异（即，在< 1%的研究参与者中携带的一种变异）的女性中，那些暴露于辐射（平均辐射暴露= 1.2 Gy, SD = 0.7）的女性患对侧乳腺癌的风险显著高于未暴露的携带野生型基因型的女性(0.01-0.99 Gy: RR = 2.8, 95% CI = 1.2 - 6.5；>= 1.0 Gy: RR = 3.3, 95% CI = 1.4 ~ 8.0)或与携带相同预测有害错义变异的未暴露妇女相比（0.01 ~ 0.99 Gy: RR = 5.3, 95% CI = 1.6 ~ 17.3; >= 1.0 Gy: RR = 5.8, 95% CI = 1.8 ~ 19.0； P（趋势）= 0.044）。携带罕见的有害的ATM错义变体并接受放射治疗的妇女患对侧乳腺癌的风险可能会增加。然而，这些有害的错义变异在人类群体中的罕见性表明，ATM突变可能只占第二原发性乳腺癌的一小部分。
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; >= 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; 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.