Heikkinen Katri, Rapakko Katrin, Karppinen Sanna-Maria, Erkko Hannele, Knuutila Sakari, Lundán Tuija, Mannermaa Arto, Børresen-Dale Anne-Lise, Borg Ake, Barkardottir Rosa B, Petrini John, Winqvist Robert
Department of Clinical Genetics, University of Oulu/Oulu University Hospital, Oulu, Finland.
Carcinogenesis. 2006 Aug;27(8):1593-9. doi: 10.1093/carcin/bgi360. Epub 2006 Feb 12.
The Mre11 complex, composed of RAD50, NBS1 and MRE11, has an essential role in the maintenance of genomic integrity and preventing cells from malignancy. Here we report the association of three Mre11 complex mutations with hereditary breast cancer susceptibility, studied by using a case-control design with 317 consecutive, newly diagnosed Northern Finnish breast cancer patients and 1000 geographically matched healthy controls (P = 0.0004). RAD50 687delT displayed significantly elevated frequency in the studied patients (8 out of 317, OR 4.3, 95% CI 1.5-12.5, P= 0.008), which indicates that it is a relatively common low-penetrance risk allele in this cohort. Haplotype analysis and the screening of altogether 512 additional breast cancer cases from Sweden, Norway and Iceland suggest that RAD50 687delT is a Finnish founder mutation, not present in the other Nordic cohorts. The RAD50 IVS3-1G>A splicing mutation leading to translational frameshift was observed in one patient, and the NBS1 Leu150Phe missense mutation affecting a conserved residue in the functionally important BRCA1 carboxy-terminal (BRCT) domain in two patients, both being absent from 1000 controls. Microsatellite marker analysis showed that loss of the wild-type allele was not involved in the tumorigenesis in any of the studied mutation carriers, but they all showed increased genomic instability assessed by cytogenetic analysis of peripheral blood T-lymphocytes (P = 0.006). In particular, the total number of chromosomal rearrangements was significantly increased (P = 0.002). These findings suggest an effect for RAD50 and NBS1 haploinsufficiency on genomic integrity and susceptibility to cancer.
由RAD50、NBS1和MRE11组成的Mre11复合物在维持基因组完整性和防止细胞发生恶性转化方面起着至关重要的作用。在此，我们报告了通过病例对照研究设计，对317例连续新诊断的芬兰北部乳腺癌患者和1000例地理匹配的健康对照进行研究后，发现三种Mre11复合物突变与遗传性乳腺癌易感性相关（P = 0.0004）。在研究的患者中，RAD50 687delT的频率显著升高（317例中有8例，比值比4.3，95%可信区间1.5 - 12.5，P = 0.008），这表明它是该队列中相对常见的低外显率风险等位基因。单倍型分析以及对来自瑞典、挪威和冰岛的另外512例乳腺癌病例的筛查表明，RAD50 687delT是芬兰的一个始祖突变，在其他北欧队列中不存在。在一名患者中观察到导致翻译移码的RAD50 IVS3 - 1G>A剪接突变，在两名患者中观察到影响功能重要的BRCA1羧基末端（BRCT）结构域中保守残基的NBS1 Leu150Phe错义突变，在1000例对照中均未出现。微卫星标记分析表明，在所研究的任何突变携带者中，野生型等位基因的缺失均未参与肿瘤发生，但通过外周血T淋巴细胞的细胞遗传学分析评估，他们均显示基因组不稳定性增加（P = 0.006）。特别是，染色体重排总数显著增加（P = 0.002）。这些发现提示RAD50和NBS1单倍体不足对基因组完整性和癌症易感性有影响。
