A recurrent mutation in PALB2 in Finnish cancer families
A recurrent mutation in PALB2 in Finnish cancer families
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DOI：
10.1038/nature05609
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发表时间：
2007-03-15
期刊：
影响因子：
64.8
通讯作者：
Winqvist, Robert
中科院分区：
文献类型：
--
作者：
Erkko, Hannele;Xia, Bing;Winqvist, Robert
BRCA 1，BRCA 2和其他已知的易感基因占不到一半的可检测的遗传易感性乳腺癌（1-3）。因此，其他相关基因仍有待发现。最近发现了一种新的BRCA 2结合蛋白PALB 2（4）。BRCA 2-PALB 2相互作用对于某些关键的BRCA 2 DNA损伤反应功能及其肿瘤抑制活性至关重要（4）。在这里，我们显示，通过筛选PALB 2突变在芬兰的移码突变，c.1592delT，是目前在家族性乳腺癌的情况下，与祖先匹配的人群对照组相比，在显着升高的频率。由该突变引起的截短的PALB 2蛋白保留了很少的BRCA 2结合能力，并且在同源重组和交联修复中存在缺陷。进一步筛选c.1592delT在乳腺癌患者中发现，与对照组相比，患者中这种突变的富集程度约为4倍。大多数突变阳性的乳腺癌病例具有家族性疾病发展模式。此外，一个多代的前列腺癌家族分离的c.1592delT截断等位基因进行了观察。这些结果表明，PALB 2是一个乳腺癌易感基因，在适当的突变形式，也可能有助于家族性前列腺癌的发展。
BRCA1, BRCA2 and other known susceptibility genes account for less than half of the detectable hereditary predisposition to breast cancer(1-3). Other relevant genes therefore remain to be discovered. Recently a new BRCA2-binding protein, PALB2, was identified(4). The BRCA2-PALB2 interaction is crucial for certain key BRCA2 DNA damage response functions as well as its tumour suppression activity(4). Here we show, by screening for PALB2 mutations in Finland that a frameshift mutation, c.1592delT, is present at significantly elevated frequency in familial breast cancer cases compared with ancestry-matched population controls. The truncated PALB2 protein caused by this mutation retained little BRCA2-binding capacity and was deficient in homologous recombination and crosslink repair. Further screening of c.1592delT in unselected breast cancer individuals revealed a roughly fourfold enrichment of this mutation in patients compared with controls. Most of the mutation-positive unselected cases had a familial pattern of disease development. In addition, one multigenerational prostate cancer family that segregated the c.1592delT truncation allele was observed. These results indicate that PALB2 is a breast cancer susceptibility gene that, in a suitably mutant form, may also contribute to familial prostate cancer development.