Molecular and clinical characteristics of MSH6 variants:: An analysis of 25 index carriers of a germline variant
Molecular and clinical characteristics of MSH6 variants:: An analysis of 25 index carriers of a germline variant
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DOI：
10.1086/337944
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发表时间：
2002-01-01
影响因子：
9.8
通讯作者：
Kleibeuker, JH
中科院分区：
文献类型：
--
作者：
Berends, MJW;Wu, Y;Kleibeuker, JH
MSH6基因是遗传性非息肉病性结直肠癌(HNPCC)的错配修复基因之一。对已知或怀疑患有HNPCC的316名个体进行了MSH6种系突变分析。对25例先证者和8例MSH6变异家系的分子和临床特征进行了描述。在微卫星不稳定性(MSI)分析中，使用了5个共识标记。进行MLH1、MSH2和MSH6蛋白的免疫组织化学分析。在12例INDEX患者中发现5个MSH6截短突变，其中1例被检测到7次；在13例INDEX患者中发现10个MSH6变异，其致病性未知。在26例结直肠癌和子宫内膜癌中，14例(54%)没有或仅有微弱的微血管密度。18例截短突变携带者中12例和17例错义突变携带者中3例MSH6染色缺失。我们研究的家庭中有六个符合最初的阿姆斯特丹标准；然而，大多数患有MSH6的家庭只被怀疑患有HNPCC。在不符合修订的阿姆斯特丹标准的家庭中，MSH6变异的患病率与MLH1/MSH2的患病率大致相同。在12名携带MSH6基因突变的女性携带者中，有8人被诊断为子宫内膜癌和/或不典型增生。多数癌细胞定位于结肠远端。虽然在分子上，错义变异被标记为可疑的致病，但临床数据显示错义变异携带者和截断突变携带者之间有很大的相似之处。我们的结论是，在所有怀疑患有HNPCC的患者中，应该考虑进行MSH6突变分析。MSI和免疫组织化学都不应成为MSH6突变分析的明确选择标准。
The MSH6 gene is one of the mismatch-repair genes involved in hereditary nonpolyposis colorectal cancer (HNPCC). Three hundred sixteen individuals who were known or suspected to have HNPCC were analyzed for MSH6 germline mutations. For 25 index patients and 8 relatives with MSH6 variants, molecular and clinical features are described. For analysis of microsatellite instability (MSI), the five consensus markers were used. Immunohistochemical analysis of the MLH1, MSH2, and MSH6 proteins was performed. Five truncating MSH6 mutations, of which one was detected seven times, were found in 12 index patients, and 10 MSH6 variants with unknown pathogenicity were found in 13 index patients. Fourteen (54%) of 26 colorectal cancers (CRCs) and endometrial cancers showed no, or only weak, MSI. Twelve of 18 tumors of truncating-mutation carriers and 3 of 17 tumors of missense-mutation carriers showed loss of MSH6 staining. Six of the families that we studied fulfilled the original Amsterdam criteria; most families with MSH6, however, were only suspected to have HNPCC. In families that did not fulfill the revised Amsterdam criteria, the prevalence of MSH6 variants is about the same as the prevalence of those in MLH1/MSH2. Endometrial cancer and/or atypical hyperplasia were diagnosed in 8 of 12 female carriers of MSH6 truncating mutations. Most CRCs were localized distally in the colon. Although, molecularly, missense variants are labeled as doubtfully pathogenic, clinical data disclose a great resemblance between missense-variant carriers and truncating-mutation carriers. We conclude that, in all patients suspected to have HNPCC, MSH6-mutation analysis should be considered. Neither MSI nor immunohistochemistry should be a definitive selection criterion for MSH6-mutation analysis.