Tischkowitz Marc, Xia Bing, Sabbaghian Nelly, Reis-Filho Jorge S, Hamel Nancy, Li Guilan, van Beers Erik H, Li Lili, Khalil Tayma, Quenneville Louise A, Omeroglu Atilla, Poll Aletta, Lepage Pierre, Wong Nora, Nederlof Petra M, Ashworth Alan, Tonin Patricia N, Narod Steven A, Livingston David M, Foulkes William D
Program in Cancer Genetics, Departments of Oncology and Human Genetics and Departments of Medicine and Human Genetics, McGill University, Montréal, QC, Canada.
Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6788-93. doi: 10.1073/pnas.0701724104. Epub 2007 Apr 9.
No more than approximately 30% of hereditary breast cancer has been accounted for by mutations in known genes. Most of these genes, such as BRCA1, BRCA2, TP53, CHEK2, ATM, and FANCJ/BRIP1, function in DNA repair, raising the possibility that germ line mutations in other genes that contribute to this process also predispose to breast cancer. Given its close relationship with BRCA2, PALB2 was sequenced in affected probands from 68 BRCA1/BRCA2-negative breast cancer families of Ashkenazi Jewish, French Canadian, or mixed ethnic descent. The average BRCAPRO score was 0.58. A truncating mutation (229delT) was identified in one family with a strong history of breast cancer (seven breast cancers in three female mutation carriers). This mutation and its associated breast cancers were characterized with another recently reported but unstudied mutation (2521delA) that is also associated with a strong family history of breast cancer. There was no loss of heterozygosity in tumors with either mutation. Moreover, comparative genomic hybridization analysis showed major similarities to that of BRCA2 tumors but with some notable differences, especially loss of 18q, a change that was previously unknown in BRCA2 tumors and less common in sporadic breast cancer. This study supports recent observations that PALB2 mutations are present, albeit not frequently, in breast cancer families. The apparently high penetrance noted in this study suggests that at least some PALB2 mutations are associated with a substantially increased risk for the disease.
已知基因的突变仅占遗传性乳腺癌的约30%。这些基因中的大多数，如BRCA1、BRCA2、TP53、CHEK2、ATM和FANCJ/BRIP1，在DNA修复中发挥作用，这增加了以下可能性：参与这一过程的其他基因中的种系突变也易患乳腺癌。鉴于PALB2与BRCA2关系密切，对来自68个阿什肯纳兹犹太人、法裔加拿大人或混合族裔血统的BRCA1/BRCA2阴性乳腺癌家族的患病先证者进行了PALB2测序。BRCAPRO评分的平均值为0.58。在一个有强烈乳腺癌家族史（三名女性突变携带者中有七例乳腺癌）的家族中发现了一个截短突变（229delT）。该突变及其相关的乳腺癌与另一个最近报道但未研究的突变（2521delA）进行了特征分析，该突变也与强烈的乳腺癌家族史相关。两种突变的肿瘤均未出现杂合性缺失。此外，比较基因组杂交分析显示与BRCA2肿瘤有主要相似之处，但也有一些显著差异，特别是18q的缺失，这一变化在BRCA2肿瘤中以前未知，在散发性乳腺癌中也较少见。这项研究支持了最近的观察结果，即PALB2突变在乳腺癌家族中存在，尽管并不常见。本研究中观察到的明显高外显率表明，至少一些PALB2突变与该疾病风险的大幅增加有关。
