Breast Cancer-Associated Abraxas Mutation Disrupts Nuclear Localization and DNA Damage Response Functions
Breast Cancer-Associated Abraxas Mutation Disrupts Nuclear Localization and DNA Damage Response Functions
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DOI：
10.1126/scitranslmed.3003223
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发表时间：
2012-02-22
影响因子：
17.1
通讯作者：
Winqvist, Robert
中科院分区：
文献类型：
--
作者：
Solyom, Szilvia;Aressy, Bernadette;Winqvist, Robert
乳腺癌是发达国家妇女中最常见的癌症，具有公认的遗传成分。编码BRCA1、BRCA2及其相互作用伙伴的基因网络的种系突变赋予乳腺癌的遗传易感性。Abraxas直接与BRCA1 BRCT （BRCA1羧基末端）重复序列相互作用，并有助于BRCA1依赖性DNA损伤反应，使Abraxas成为尚未解释的疾病易感性的候选基因。在这里，我们筛选了125个北芬兰乳腺癌家族的编码区和剪接位点Abraxas突变，并从991例未选择的乳腺癌病例和868例女性对照中对基因内的三个标记单核苷酸多态性进行了基因分型，以发现常见的癌症相关变异。一种新的杂合变异，c. 1082G>A (Arg361Gln)，在三个乳腺癌家族和一个未选择的乳腺癌队列的另外一个家族病例中被发现，导致核定位和DNA应答活性被取消，但在健康对照组中没有（P = 0.002）。基于其在家族性癌症、疾病共分离、进化守恒和关键BRCA1功能破坏中的独家发生，复发性Abraxas c. 1082G>A突变与癌症易感性有关。这些发现有助于建立以brca为中心的肿瘤抑制网络的概念，并提供了Abraxas作为新的乳腺癌易感基因的身份。
Breast cancer is the most common cancer in women in developed countries and has a well-established genetic component. Germline mutations in a network of genes encoding BRCA1, BRCA2, and their interacting partners confer hereditary susceptibility to breast cancer. Abraxas directly interacts with the BRCA1 BRCT (BRCA1 carboxyl-terminal) repeats and contributes to BRCA1-dependent DNA damage responses, making Abraxas a candidate for yet unexplained disease susceptibility. Here, we have screened 125 Northern Finnish breast cancer families for coding region and splice-site Abraxas mutations and genotyped three tagging single-nucleotide polymorphisms within the gene from 991 unselected breast cancer cases and 868 female controls for common cancer-associated variants. A novel heterozygous alteration, c. 1082G>A (Arg361Gln), that results in abrogated nuclear localization and DNA response activities was identified in three breast cancer families and in one additional familial case from an unselected breast cancer cohort, but not in healthy controls (P = 0.002). On the basis of its exclusive occurrence in familial cancers, disease cosegregation, evolutionary conservation, and disruption of critical BRCA1 functions, the recurrent Abraxas c. 1082G>A mutation connects to cancer predisposition. These findings contribute to the concept of a BRCA-centered tumor suppressor network and provide the identity of Abraxas as a new breast cancer susceptibility gene.