Germline BRCA1 promoter deletions in UK and Australian familial breast cancer patients:: Identification of a novel deletion consistent with BRCA1:ψVBRCA1 recombination
Germline BRCA1 promoter deletions in UK and Australian familial breast cancer patients:: Identification of a novel deletion consistent with BRCA1:ψVBRCA1 recombination
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DOI：
10.1002/humu.10055
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发表时间：
2002-01-01
期刊：
影响因子：
3.9
通讯作者：
Solomon, E
中科院分区：
文献类型：
--
作者：
Brown, MA;Lo, LJ;Solomon, E
对乳腺癌的遗传易感性是由包括 BRCA1 在内的多种基因之一的种系突变引起的。然而，大量 BRCA1 相关家族性乳腺癌患者没有可检测到的 BRCA1 突变。这可能部分是由于常用的突变检测技术无法识别 BRCA1 编码区之外的突变。本文提出了这样的假设：非编码区突变（特别是 BRCA1 启动子中的突变）是其中一些病例的原因。我们描述了 BRCA1 基因 5' 区域的新的详细限制性图谱，包括附近的 NBR2、psiBRCA1 和 NBR1 基因，并分离了许多适合 Southern 分析的新的信息丰富的杂交探针。利用这些信息，我们从 114 名英国家族性乳腺癌患者的类淋巴母细胞系中筛选 DNA，并检测到 BRCA1 5' 区域的一个大缺失。我们发现该缺失的断点位于 BRCA1 内含子 2 以及 psiBRCA1 的 NBR2 和外显子 2 之间，这提高了该缺失通过涉及 BRCA1:psiBRCA1 重组的新机制产生的可能性。我们还使用我们小组之前描述的扩增阻滞突变系统 (ARMS) 技术，从澳大利亚人群中筛查了 60 名家族性乳腺癌患者，并发现了一名患者的基因型与 BRCA1 启动子缺失一致。这些发现表明，种系 BRCA1 启动子缺失是一种罕见但重要的突变事件，并且它们可能通过一种新的遗传机制产生。 Hum Mutat 19:435-442, 2002。(C) 2002 Wiley-Liss, Inc.
Inherited susceptibility to breast cancer results from germline mutations in one of a number of genes including BRCA1. A significant number of BRCA1-linked familial breast cancer patients, however, have no detectable BRCA1 mutation. This could be due in part to the inability of commonly used mutation-detection techniques to identify mutations outside the BRCA1 coding region. This paper addresses the hypothesis that non coding region mutations, specifically in the BRCA1 promoter, account for some of these cases. We describe a new and detailed restriction map of the 5' region of the BRCA1 gene including the nearby NBR2, psiBRCA1, and NBR1 genes and the isolation of a number of new informative hybridization probes suitable for Southern analysis. Using this information we screened DNA from lymphoblastoid cell-lines made from 114 UK familial breast cancer patients and detected one large deletion in the 5' region of BRCA1. We show that the breakpoints for this deletion are in BRCA1 intron 2 and between NBR2 and exon 2 of psiBRCA1, raising the possibility that this deletion arose via a novel mechanism involving BRCA1:psiBRCA1 recombination. We have also screened 60 familial breast cancer patients from the Australian population, using an amplification refractory mutation system (ARMS) technique described previously by our group, and found one patient with a genotype consistent with a BRCA1 promoter deletion. These findings indicate that germline BRCA1 promoter deletions are a rare and yet significant mutation event and that they could arise via a novel genetic mechanism. Hum Mutat 19:435-442, 2002. (C) 2002 Wiley-Liss, Inc.