Kowalski L D, Mutch D G, Herzog T J, Rader J S, Goodfellow P J
Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri, USA.
Genes Chromosomes Cancer. 1997 Mar;18(3):219-27. doi: 10.1002/(sici)1098-2264(199703)18:3<219::aid-gcc8>3.0.co;2-4.
Mutations in the DNA mismatch repair (MMR) genes MLH1 and MSH2 have been linked to several human cancers which display the replication error (RER) phenotype. Germline mutations in these two genes have been implicated in about 90% of families with hereditary nonpolyposis colorectal cancer (HNPCC). A significant proportion of endometrial cancers, the second most common malignancy of the HNPCC syndrome, also exhibit RER. We screened 125 primary endometrial adenocarcinomas with seven microsatellite markers and identified 25 specimens with RER (20%). We used single-strand conformation variant analysis to search for mutations in MLH1 and MSH2. Direct sequencing of variants revealed only one germline mutation in MLH1 and a single somatic mutation in MSH2. However, six previously unreported sequence polymorphisms in MLH1 were identified. Four of these polymorphisms show clear population-based differences in allele frequency. In addition, a highly informative marker for MLH1 was characterized. The low frequency of mutations in MLH1 and MSH2 in this large series of cancers suggests that other MMR genes are responsible for the RER phenotype in endometrial cancers.
DNA错配修复（MMR）基因MLH1和MSH2中的突变与几种表现出复制错误（RER）表型的人类癌症相关。这两个基因的种系突变与约90%的遗传性非息肉病性结直肠癌（HNPCC）家族有关。HNPCC综合征的第二大常见恶性肿瘤——相当一部分子宫内膜癌也表现出RER。我们用7个微卫星标记物筛选了125例原发性子宫内膜腺癌，鉴定出25例具有RER的标本（20%）。我们采用单链构象变异分析来寻找MLH1和MSH2中的突变。对变异体进行直接测序仅发现MLH1中有一个种系突变和MSH2中有一个体细胞突变。然而，在MLH1中鉴定出6个以前未报道的序列多态性。其中4种多态性在等位基因频率上显示出明显的基于人群的差异。此外，还鉴定出一个信息量丰富的MLH1标记物。在这一大系列癌症中MLH1和MSH2的低突变频率表明，其他MMR基因是子宫内膜癌RER表型的原因。
