A founder mutation of the MSH2 gene and hereditary nonpolyposis colorectal cancer in the United States
A founder mutation of the MSH2 gene and hereditary nonpolyposis colorectal cancer in the United States
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DOI：
10.1001/jama.291.6.718
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发表时间：
2004-02-11
影响因子：
120.7
通讯作者：
de la Chapelle, A
中科院分区：
文献类型：
--
作者：
Lynch, HT;Coronel, SM;de la Chapelle, A
遗传性非息肉病性结直肠癌（HNPCC），也被称为Lynch综合征，是由错配修复基因突变引起的，并赋予结直肠癌、子宫内膜癌和其他癌症的极高风险。然而，虽然这些突变的携带者应该被识别，咨询，并提供临床监测，目前的突变没有测试在突变analysis.Objective描述的患病率大基因组缺失涵盖外显子1至6的MSH 2基因，这是广泛存在于美国人口作为一个创始人效应的结果。和历史的研究进行评估的起源和传播的MSH 2突变先前确定在9个明显无关的家庭与假定的HNPCC和生活在广泛不同的地理位置在美国。主要结果测量分类的家庭成员作为载体或非载体的MSH 2突变;结果到目前为止，9个先证者的566个家庭成员已被确定为处于危险之中，并进行了咨询;其中137人进行了测试，61人携带创始人突变。有三个家庭的家谱显示，他们来自一个德国移民家庭，该家庭于18世纪初抵达并首次定居在宾夕法尼亚州。该家族分支从宾夕法尼亚州到北卡罗来纳州、亚拉巴马、肯塔基州、密苏里州、爱荷华州、内布拉斯加州、犹他州、德克萨斯州和加州的迁徙已被记录下来，并且该突变的携带者已在14个州被诊断出来。与此相反，在407个欧洲和澳大利亚的HNPCC家系中未发现该缺失。结论在一个大型远交种中，MSH 2基因的癌症易感创始者突变的假设频率高，分布在整个大陆。（与遗传隔离相反）群体，以及突变可以被检测到的容易程度，建议在美国对有HNPCC风险的个体进行常规检测时应包括对这种突变的检测，直到更多地了解其发生。
Context Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is caused by mutations in the mismatch repair genes and confers an extraordinarily high risk of colorectal, endometrial, and other cancers. However, while carriers of these mutations should be identified, counseled, and offered clinical surveillance, at present the mutations are not tested for in mutation analyses.Objective To describe the prevalence of a large genomic deletion encompassing exons 1 to 6 of the MSH2 gene that is widespread in the US population as a result of a founder effect.Design, Setting, and Patients Ongoing genealogical, and historical study conducted to assess the origin and spread of an MSH2 mutation previously identified in 9 apparently unrelated families with putative HNPCC and living in widely different geographic locations in the United States.Main Outcome Measures Classification of family members as carriers or noncarriers of the MSH2 mutation; spread of the mutation across the continental United States.Results To date, 566 family members of the 9 probands have been identified to be at risk and counseled; 137 of these have been tested, and 61 carry the founder mutation. Three families have been genealogically shown to descend from a German immigrant family that arrived and first settled in Pennsylvania in the early 1700s. Movements of branches of the family from Pennsylvania through North Carolina, Alabama, Kentucky, Missouri, Iowa, Nebraska, Utah, Texas, and California have been documented, and carriers of the mutation have already been diagnosed in 14 states. In contrast, the deletion was not found among 407 European and Australian families with HNPCC.Conclusion The postulated high frequency and continent-wide geographic distribution of a cancer-predisposing founder mutation of the MSH2 gene in a large, outbred (as opposed to genetically isolated) population, and the ease with which the mutation can be detected, suggest that the routine testing of individuals at risk for HNPCC in the United States should include an assay for this mutation until more is learned about its occurrence.