MSH6 Mutations are Frequent in Hereditary Nonpolyposis Colorectal Cancer Families With Normal pMSH6 Expression as Detected by Immunohistochemistry
MSH6 Mutations are Frequent in Hereditary Nonpolyposis Colorectal Cancer Families With Normal pMSH6 Expression as Detected by Immunohistochemistry
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DOI：
10.1097/pai.0b013e318249739b
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发表时间：
2012-10-01
影响因子：
1.6
通讯作者：
Krarup, Henrik Bygum
中科院分区：
文献类型：
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作者：
Okkels, Henrik;Lindorff-Larsen, Karen;Krarup, Henrik Bygum
简介：遗传性非息肉病性结直肠癌（HNPCC）是一种常染色体显性遗传疾病，占全球所有结直肠癌病例的2%至4%。在6个错配修复基因中的1个中具有生殖系突变的家族被称为Lynch综合征家族。错配修复基因MLH 1和MSH 2中检测到的突变数量最多，但MSH 6中的几个突变也已被证明。Aim：HNPCC家族是否筛查错配修复基因突变往往依赖于其免疫组化谱。本研究的目的是在携带MSH 6突变的Lynch家系中评估这种方法。材料和方法：在HNPCC家系中筛选MSH 6基因的结果与免疫组织化学蛋白分析的结果进行比较。在815个家族中，56个（7%）家族中至少有1个MSH 6突变，23个明确的致病突变和38个错义突变或未分类的变体，并检测到MSH 6基因的多个多态性。在携带致病性MSH 6突变的家族中，69.6%的23例结肠腺癌的肿瘤组织中通过免疫组织化学分析显示pMSH 6缺失。在34.5%，所有的蛋白都可以检测到，而在34.5%的pMSH 6存在和pMLH 1/pPMS2.Conclusions：如果遗传筛查HNPCC家庭依赖于免疫组化结果，大量的家庭窝藏致病突变的MSH 6和绝大多数家庭窝藏MSH 6未分类的变异将无法检测到。
Introduction: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant condition accounting for 2% to 4% of all colorectal cancer cases worldwide. Families with germ line mutations in 1 of 6 mismatch repair genes are known as Lynch syndrome families. The largest number of mutations has been detected in the mismatch repair genes MLH1 and MSH2, but several mutations in MSH6 have also been demonstrated.Aim: Whether HNPCC families are screened for mutations in mismatch repair genes often relies on their immunohistochemical profile. The aim of the present study was to evaluate this approach in Lynch families carrying mutations in MSH6.Materials and Methods: Results of the screening of the MSH6 gene in HNPCC families were compared with those obtained on immunohistochemical protein analysis.Results: In 56 (7%) of 815 families, at least 1 MSH6 mutation, 23 definitively pathogenic mutations and 38 missense mutations or unclassified variants, and several polymorphisms in the MSH6 gene were detected. In families carrying a pathogenic MSH6 mutation, 69.6% of 23 colon adenocarcinomas showed absence of pMSH6 in tumor tissue by immunohistochemical analysis. In 34.5%, all proteins could be detected, whereas in 34.5% pMSH6 was present and pMLH1/pPMS2 was absent.Conclusions: If genetic screening of HNPCC families depended on immunohistochemical results, a substantial number of families harboring a pathogenic mutation in MSH6 and the vast majority of families harboring an MSH6 unclassified variant would not be detected.