Rare Mutations in XRCC2 Increase the Risk of Breast Cancer
Rare Mutations in XRCC2 Increase the Risk of Breast Cancer
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DOI：
10.1016/j.ajhg.2012.02.027
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发表时间：
2012-04-06
影响因子：
9.8
通讯作者：
Southey, M. C.
中科院分区：
文献类型：
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作者：
Park, D. J.;Lesueur, F.;Southey, M. C.
一项对多个乳腺癌患者家族的外显子组测序研究发现了两个具有XRCC 2突变的家族，一个具有蛋白质截短突变，另一个具有可能有害的错义突变。我们进行了一项基于人群的病例对照突变筛查研究，在1,308例早发性乳腺癌患者中发现了6种可能致病的编码变异，而在1,120例对照中没有发现变异（严重程度分级为p < 0.02）。我们还对689个多病例家族进行了额外的突变筛查。我们确定了10个乳腺癌受影响的家庭与蛋白质截短或可能有害的罕见的XRCC 2错义变异。因此，我们将XRCC 2鉴定为乳腺癌易感基因增加了与同源重组DNA修复功能障碍和范可尼贫血相关的乳腺癌的比例，因此可以从PARP（聚ADP核糖聚合酶）抑制剂等特异性靶向治疗中获益。这项研究证明了大规模平行测序在发现常见复杂疾病易感基因方面的作用。
An exome-sequencing study of families with multiple breast-cancer-affected individuals identified two families with XRCC2 mutations, one with a protein-truncating mutation and one with a probably deleterious missense mutation. We performed a population-based case-control mutation-screening study that identified six probably pathogenic coding variants in 1,308 cases with early-onset breast cancer and no variants in 1,120 controls (the severity grading was p < 0.02). We also performed additional mutation screening in 689 multiple-case families. We identified ten breast-cancer-affected families with protein-truncating or probably deleterious rare missense variants in XRCC2. Our identification of XRCC2 as a breast cancer susceptibility gene thus increases the proportion of breast cancers that are associated with homologous recombination-DNA-repair dysfunction and Fanconi anemia and could therefore benefit from specific targeted treatments such as PARP (poly ADP ribose polymerase) inhibitors. This study demonstrates the power of massively parallel sequencing for discovering susceptibility genes for common, complex diseases.