Downs Bradley, Kim Yeong C, Xiao Fengxia, Snyder Carrie, Chen Peixian, Fleissner Elizabeth A, Becirovic Dina, Wen Hongxiu, Sherman Simon, Cowan Kenneth H, Lynch Henry T, Wang San Ming
Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE, 68198, USA.
Breast Cancer Res Treat. 2015 May;151(1):219-24. doi: 10.1007/s10549-015-3358-7. Epub 2015 Apr 2.
Partner and localizer of BRCA2 (PALB2), plays an important functional role in DNA damage repair. Recent studies indicate that germline mutations in PALB2 predispose individuals to a high risk of developing familial breast cancer. Therefore, comprehensive identification of PALB2 germline mutations is potentially important for understanding their roles in tumorigenesis and for testing their potential utility as clinical targets. Most of the previous studies of PALB2 have focused on familial breast cancer cases with normal/wild-type BRCA1 and BRCA2 (BRCAx). We hypothesize that PALB2 genetic mutations also exist in individuals with BRCA mutations (BRCA+). To test this hypothesis, PALB2 germline mutations were screened in 107 exome data sets collected from familial breast cancer families who were either BRCA1+ or BRCAx. Two novel heterozygous mutations predicted to alter the function of PALB2 were identified (c.2014G>C, p.E672Q and c.2993G>A, p.G998E). Notably, both of these mutations co-existed in BRCA1+ and BRCA1x families. These studies show that mutations in PALB2 can occur independent of the status of BRCA1 mutations, and they highlight the importance to include BRCA1+ families in PALB2 mutation screens.
BRCA2的伴侣和定位因子（PALB2）在DNA损伤修复中发挥重要功能作用。最近的研究表明，PALB2的种系突变使个体易患家族性乳腺癌的风险增加。因此，全面鉴定PALB2种系突变对于理解其在肿瘤发生中的作用以及测试其作为临床靶点的潜在效用可能具有重要意义。先前大多数关于PALB2的研究都集中在BRCA1和BRCA2为正常/野生型（BRCAx）的家族性乳腺癌病例上。我们推测BRCA突变（BRCA+）个体中也存在PALB2基因突变。为了验证这一假设，我们在从BRCA1+或BRCAx的家族性乳腺癌家族收集的107个外显子组数据集中筛选了PALB2种系突变。鉴定出两个预测会改变PALB2功能的新型杂合突变（c.2014G>C，p.E672Q和c.2993G>A，p.G998E）。值得注意的是，这两个突变在BRCA1+和BRCA1x家族中均共存。这些研究表明，PALB2突变可独立于BRCA1突变状态而发生，并且它们强调了在PALB2突变筛查中纳入BRCA1+家族的重要性。
