Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 german families suspected of hereditary nonpolyposis colorectal cancer
Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 german families suspected of hereditary nonpolyposis colorectal cancer
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DOI：
10.1002/ijc.20863
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发表时间：
2005-09-20
影响因子：
6.4
通讯作者：
Propping, P
中科院分区：
文献类型：
--
作者：
Mangold, E;Pagenstecher, C;Propping, P
DNA MMR基因的突变，主要是MSH 2和MLH 1，占HNPCC的大多数，HNPCC是结直肠癌和其他恶性肿瘤的常染色体显性遗传易感性。对HNPCC的许多问题的评价需要临床和遗传学特征良好的合理规模的HNPCC患者队列。这项多中心研究的一个主要重点是评价德国一个大型HNPCC队列的突变谱和突变频率;研究纳入了1,721例符合Bethesda标准的无关患者，主要是德国血统。在1,377例患者的肿瘤样本中，成功进行了微卫星分析，并将结果用于选择符合突变分析条件的患者。在符合HNPCC严格的阿姆斯特丹标准（AC）的患者中，72%的肿瘤表现出高微卫星不稳定性（MSI-H），而符合不太严格标准的患者中只有37%的肿瘤显示出NISI-H; 454名索引患者（406名MSI-H和48名符合AC的患者，其中没有肿瘤样本）进行了小突变筛查。在134名指示患者中发现了致病性MSH 2突变，在118名患者中发现了致病性MLH 1突变（致病性突变的总体检测率为56%）。检测到160个不同的突变，其中86个是新的突变。值得注意的是，在我们的患者系列中有2种突变过度出现：MSH 2，c.942 +3A > T和MLH 1，c.1489_1490insC，分别占MSH 2和MLH 1突变的11%和18%。对238名患者的子集进行大基因组缺失筛查。在24例（10%）患者中，缺失被发现。在72例患者中，只有未指明的变异被发现。我们的研究结果表明，预选微卫星分析大大提高突变检测率在患者不符合AC。作为德国HNPCC患者的突变检测策略，我们建议首先筛查大基因组缺失，然后继续筛查MSH 2外显子5和MLH 1外显子13中的常见突变，然后再搜索其余外显子中的小突变。(c)2005 Wiley-Liss，Inc.
Mutations in DNA MMR genes, mainly MSH2 and MLH1, account for the majority of HNPCC, an autosomal dominant predisposition to colorectal cancer and other malignancies. The evaluation of many questions regarding HNPCC requires clinically and genetically well-characterized HNPCC patient cohorts of reasonable size. One main focus of this multicenter study is the evaluation of the mutation spectrum and mutation frequencies in a large HNPCC cohort in Germany; 1,721 unrelated patients, mainly of German descent, who met the Bethesda criteria were included in the study. In tumor samples of 1,377 patients, microsatellite analysis was successfully performed and the results were applied to select patients eligible for mutation analysis. In the patients meeting the strict Amsterdam criteria (AC) for HNPCC, 72% of the tumors exhibited high microsatellite instability (MSI-H) while only 37% of the tumors from patients fulfilling the less stringent criteria showed NISI-H; 454 index patients (406 MSI-H and 48 meeting the AC of whom no tumor samples were available) were screened for small mutations. In 134 index patients, a pathogenic MSH2 mutation, and in 118 patients, a pathogenic MLH1 mutation was identified (overall detection rate for pathogenic mutations 56%). One hundred sixty distinct mutations were detected, of which 86 are novel mutations. Noteworthy is that 2 mutations were over-represented in our patient series: MSH2,c.942+3A > T and MLH1,c.1489_1490insC, which account for 11% and 18% of the MSH2 and MLH1 mutations, respectively. A subset of 238 patients was screened for large genomic deletions. In 24 (10%) patients, a deletion was found. In 72 patients, only unspecified variants were found. Our findings demonstrate that preselection by microsatellite analysis substantially raises mutation detection rates in patients not meeting the AC. As a mutation detection strategy for German HNPCC patients, we recommend to start with screening for large genomic deletions and to continue by screening for common mutations in exon 5 of MSH2 and exon 13 of MLH1 before searching for small mutations in the remaining exons. (c) 2005 Wiley-Liss, Inc.