Sun Jie, Wang Yuxia, Xia Yisui, Xu Ye, Ouyang Tao, Li Jinfeng, Wang Tianfeng, Fan Zhaoqing, Fan Tie, Lin Benyao, Lou Huiqiang, Xie Yuntao
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Breast Center, Peking University Cancer Hospital & Institute, Beijing, the People's Republic of China.
State Key Laboratory of Agro-Biotechnology, College of Biological Sciences, China Agricultural University, Beijing, the People's Republic of China.
PLoS Genet. 2015 May 6;11(5):e1005228. doi: 10.1371/journal.pgen.1005228. eCollection 2015 May.
The genetic cause for approximately 80% of familial breast cancer patients is unknown. Here, by sequencing the entire exomes of nine early-onset familial breast cancer patients without BRCA1/2 mutations (diagnosed with breast cancer at or before the age of 35) we found that two index cases carried a potentially deleterious mutation in the RECQL gene (RecQ helicase-like; chr12p12). Recent studies suggested that RECQL is involved in DNA double-strand break repair and it plays an important role in the maintenance of genomic stability. Therefore, we further screened the RECQL gene in an additional 439 unrelated familial breast cancer patients. In total, we found three nonsense mutations leading to a truncated protein of RECQL (p.L128X, p.W172X, and p.Q266X), one mutation affecting mRNA splicing (c.395-2A>G), and five missense mutations disrupting the helicase activity of RECQL (p.A195S, p.R215Q, p.R455C, p.M458K, and p.T562I), as evaluated through an in vitro helicase assay. Taken together, 9 out of 448 BRCA-negative familial breast cancer patients carried a pathogenic mutation of the RECQL gene compared with one of the 1,588 controls (P = 9.14×10-6). Our findings suggest that RECQL is a potential breast cancer susceptibility gene and that mutations in this gene contribute to familial breast cancer development.
约80%的家族性乳腺癌患者的遗传病因尚不清楚。在此，通过对9例无BRCA1/2突变的早发性家族性乳腺癌患者（35岁及以前被诊断为乳腺癌）的全外显子组进行测序，我们发现两名索引病例在RECQL基因（类RecQ解旋酶；12号染色体短臂12区）中携带一个潜在有害突变。最近的研究表明，RECQL参与DNA双链断裂修复，并且在维持基因组稳定性方面发挥重要作用。因此，我们在另外439例无亲缘关系的家族性乳腺癌患者中进一步筛查了RECQL基因。通过体外解旋酶分析评估，我们总共发现了三个导致RECQL截短蛋白的无义突变（p.L128X、p.W172X和p.Q266X）、一个影响mRNA剪接的突变（c.395-2A>G）以及五个破坏RECQL解旋酶活性的错义突变（p.A195S、p.R215Q、p.R455C、p.M458K和p.T562I）。在448例BRCA阴性的家族性乳腺癌患者中，有9例携带RECQL基因的致病突变，而1588例对照中仅有1例携带该突变（P = 9.14×10-6）。我们的研究结果表明，RECQL是一个潜在的乳腺癌易感基因，该基因的突变促成家族性乳腺癌的发生。
