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在113,000多名女性中进行的乳腺癌风险基因关联分析
Breast Cancer Risk Genes — Association Analysis in More than 113,000 Women


Breast Cancer Association Consortium* 肿瘤 • 2021.02.04
相关阅读
• 对之前发现的乳腺癌相关基因进行的人群研究

关于乳腺癌风险基因的两项人群研究

 

杜小莉

Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

 

大约1/8的女性在其一生中会罹患乳腺癌1,而大约5%~10%的乳腺癌为遗传性。及时发现高危个体的生殖细胞系致病突变,让我们可以监测高位人群,尽早实施预防性手术以降低患癌风险,以及实施靶向治疗。

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摘要


背景

乳腺癌易感性的基因检测已被广泛应用,但其中许多基因与乳腺癌之间的关联证据薄弱,基础风险估计值不精确,而且缺乏可靠的亚型特异的风险估计值。

 

方法

我们应用由34个推测的易感基因构成的基因面板,对60,466例乳腺癌女性患者和53,461例对照女性的样本进行了测序。在对这些基因的蛋白质截短变异体和罕见错义变异体分别进行的分析中,我们估算了对于总体乳腺癌和乳腺癌亚型的比值比。我们根据结构域和致病性分类结果评估了错义变异体相关性。

 

结果

5个基因(ATMBRCA1BRCA2CHEK2PALB2)的蛋白质截短变异体与总体乳腺癌风险相关且P值小于0.0001。另外4个基因(BARD1RAD51CRAD51DTP53)的蛋白质截短变异体与总体乳腺癌风险相关且P值小于0.05,贝叶斯错误发现概率小于0.05。在其余25个基因中,对于19个基因的蛋白质截短变异体,总体乳腺癌的比值比的95%置信区间(CI)的上限小于2.0。对于ATMCHEK2的蛋白质截短变异体,雌激素受体(ER)阳性乳腺癌的比值比大于ER阴性乳腺癌;对于BARD1BRCA1BRCA2PALB2RAD51CRAD51D的蛋白质截短变异体,ER阴性乳腺癌的比值比大于ER阳性乳腺癌。ATMCHEK2TP53的罕见错义变异体(汇总结果)与总体乳腺癌风险相关且P值小于0.001。对于BRCA1BRCA2TP53,根据标准归类为致病性的错义变异体(汇总结果)与总体乳腺癌风险相关,且风险与蛋白质截短变异体相似。

 

结论

本研究的结果确定了在临床上可纳入基因面板,用于预测乳腺癌风险的最有用基因,并提供了与蛋白质截短变异体相关的风险估计值,这些结果可以指导遗传咨询(由欧盟地平线2020[European Union Horizon 2020]计划等资助)。





作者信息

Breast Cancer Association Consortium*
Address reprint requests to Dr. Easton at the University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, United Kingdom, or at dfe20@medschl.cam.ac.uk. The authors’ full names, academic degrees, and affiliations are listed in the Appendix. *A complete list of collaborators and investigators is provided in the Supplementary Appendix, available at NEJM.org.

 

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