Viel A, Genuardi M, Capozzi E, Leonardi F, Bellacosa A, Paravatou-Petsotas M, Pomponi M G, Fornasarig M, Percesepe A, Roncucci L, Tamassia M G, Benatti P, Ponz de Leon M, Valenti A, Covino M, Anti M, Foletto M, Boiocchi M, Neri G
Division of Experimental Oncology I, Centro Riferimento Oncologico, Aviano, Italy.
Genes Chromosomes Cancer. 1997 Jan;18(1):8-18. doi: 10.1002/(sici)1098-2264(199701)18:1<8::aid-gcc2>3.0.co;2-7.
Mismatch repair genes MSH2 and MLH1 are considered to be the two major genes that are responsible for hereditary nonpolyposis colorectal cancer (HNPCC). Germline heterozygous inactivating mutations of MSH2 and MLH1 have been identified previously in a substantial fraction of individuals who are predisposed genetically to colorectal carcinoma (CRC) and other tumors of the HNPCC spectrum. With the aim of determining the relevance of these two genes in the Italian population, we submitted to mutational analysis a set of 17 HNPCC families, all of which fulfilled the "Amsterdam criteria." A combination of different techniques, including reverse transcription-polymerase chain reaction (RT-PCR) of long fragments and single-strand conformation polymorphism (SSCP) on cDNA and genomic DNA, allowed the identification of ten molecular variants, seven of which are predicted to inactivate mismatch repair function. The mutated predisposing gene was MSH2 in two families and MLH1 in five other families. All of the mutations were characterized by DNA sequencing and appeared to involve different molecular mechanisms, such as short in-frame and out-of-frame deletions, splicing errors, and nonsense mutations. This study also demonstrates that, in the Italian population, a considerable fraction of HNPCC families (at least 41%) is linked to MSH2 and MLH1 mutations.
错配修复基因MSH2和MLH1被认为是导致遗传性非息肉病性结直肠癌（HNPCC）的两个主要基因。此前，在很大一部分遗传易患结直肠癌（CRC）及HNPCC谱系中其他肿瘤的个体中，已鉴定出MSH2和MLH1的种系杂合失活突变。为了确定这两个基因在意大利人群中的相关性，我们对一组17个HNPCC家族进行了突变分析，所有这些家族均符合“阿姆斯特丹标准”。通过包括长片段逆转录-聚合酶链反应（RT-PCR）以及对cDNA和基因组DNA进行单链构象多态性（SSCP）分析在内的多种技术组合，共鉴定出10种分子变异，其中7种预计会使错配修复功能失活。两个家族中突变的易感基因是MSH2，另外五个家族中是MLH1。所有突变均通过DNA测序进行了表征，并且似乎涉及不同的分子机制，如框内和框外短缺失、剪接错误和无义突变。这项研究还表明，在意大利人群中，相当一部分HNPCC家族（至少41%）与MSH2和MLH1突变有关。
