Laboratory of Cancer Genetics, Department of Clinical Genetics, Institute of Clinical Medicine and Biocenter Oulu, University of Oulu, Oulu University Hospital, Aapistie 5A, FI-90220 Oulu, Finland.
Sci Transl Med. 2012 Feb 22;4(122):122ra23. doi: 10.1126/scitranslmed.3003223.
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.
在发达国家，乳腺癌是女性最常见的癌症，并且具有明确的遗传成分。BRCA1、BRCA2 及其相互作用伙伴的基因网络中的种系突变赋予了乳腺癌的遗传易感性。Abraxas 与 BRCA1 BRCT（BRCA1 羧基末端）重复序列直接相互作用，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者。在这里，我们筛选了 125 个来自北芬兰的乳腺癌家族，以寻找编码区和剪接位点 Abraxas 突变，并对来自 991 例未经选择的乳腺癌病例和 868 例女性对照的基因内三个标记单核苷酸多态性进行了基因分型，以寻找常见的癌症相关变体。在三个乳腺癌家族和一个来自未经选择的乳腺癌队列的家族性病例中发现了一种新的杂合性改变，c.1082G>A（Arg361Gln），导致核定位和 DNA 反应活性丧失，但在健康对照中没有发现（P = 0.002）。基于其仅在家族性癌症中发生、疾病共分离、进化保守性以及对关键 BRCA1 功能的破坏，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 为中心的肿瘤抑制器网络的概念，并为 Abraxas 作为新的乳腺癌易感性基因提供了依据。
