Is MSH2 a breast cancer susceptibility gene?
Is MSH2 a breast cancer susceptibility gene?
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DOI：
10.1007/s10689-007-9162-8
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发表时间：
2008-06-01
期刊：
影响因子：
2.2
通讯作者：
Southey, Melissa C.
中科院分区：
文献类型：
--
作者：
Wong, E. E. Ming;Tesoriero, Andrea A.;Southey, Melissa C.
DNA 错配修复基因 MSH2 的突变导致复制错误和微卫星不稳定性增加，并在遗传性非息肉病性结直肠癌（林奇综合征）中占很大比例。最近一项针对乳腺癌易感位点的国际协作全基因组连锁扫描（GWS）发现了一些证据，表明在染色体 2p 上靠近 MSH2 的基因组区域中存在乳腺癌易感基因。我们试图调查 MSH2 突变是否可以解释国际 GWS 中一些家庭中出现的多例乳腺癌病例。来自 59 个多病例乳腺癌家族受影响先证者的 DNA 样本（其中许多人在 MSH2 区域的 LOD 评分 >0.5）通过多重连接依赖性探针扩增 (MLPA) 测定筛选 MSH2 中的大基因组改变，并通过外显子测序筛选编码区突变。除了乳腺癌之外，其中几个家庭还存在结直肠癌病例，并且已被纳入 GWS，该 GWS 已在 2p 染色体上发现了阳性 LOD 评分。使用 MLPA，在一个先证者中鉴定出 c.1236C > T，但使用计算机分析预测该变异不会在外显子 7 MSH2 内创建替代受体/供体位点。通过外显子测序在第二个先证者中鉴定出 c.1734T > C，但在其他家庭成员中测试该变异并不支持该变异与疾病的分离。对 59 个多病例乳腺癌家族的广泛筛查并未发现 MSH2 中任何编码区突变或较大的基因组改变可能表明 MSH2 是乳腺癌易感基因。
Mutations in the DNA mismatch repair gene MSH2 lead to increased replication error and microsatellite instability and account for a substantial proportion of hereditary non-polyposis colorectal cancer (Lynch syndrome). A recent international collaborative genome-wide linkage scan (GWS) for breast cancer susceptibility loci found some evidence for there being a breast cancer susceptibility gene in a genomic region on chromosome 2p close to MSH2. We sought to investigate the possibility that mutations in MSH2 might explain the multiple cases of breast cancer in some families that were included in the international GWS. DNA samples from the affected probands of 59 multiple-case breast cancer families, many of whom gave LOD scores >0.5 in the MSH2 region, were screened for large genomic alterations in MSH2 via the Multiplex Ligation-dependant Probe Amplification (MLPA) assay and for coding region mutations via exonic sequencing. Several of the families also contained cases of colorectal cancer in addition to breast cancer and had been included in the GWS that had identified a positive LOD score on chromosome 2p. Using MLPA, c.1236C > T was identified in one proband but this variant was not predicted to create an alternate acceptor/donor site within exon 7 MSH2 using in silico analyses. A c.1734T > C was identified in a second proband via exonic sequencing but testing of the variant in other family members did not support segregation of this variant with disease. Extensive screening of 59 multiple-case breast cancer families did not identify any coding region mutations or larger genomic alterations in MSH2 that might implicate MSH2 as a breast cancer susceptibility gene.