Peltomäki Päivi
Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, P.O. Box 63, Haartmaninkatu 8, 00014, Finland.
Fam Cancer. 2005;4(3):227-32. doi: 10.1007/s10689-004-7993-0.
Since the discovery of the major human genes with DNA mismatch repair (MMR) function in 1993-1995, mutations in four, MSH2, MLH1, MSH6, and PMS2, have been convincingly linked to susceptibility of hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome. Among these, PMS2 mutations are associated with diverse clinical features, including those of the Turcot syndrome. Two additional MMR genes, MLH3 and PMS1, have also been proposed to play a role in Lynch syndrome predisposition, but the clinical significance of mutations in these genes is less clear. According to the database maintained by the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer (ICG-HNPCC), current InSiGHT (International Society for Gastrointestinal Hereditary Tumors), approximately 500 different HNPCC-associated MMR gene mutations are known that primarily involve MLH1 (approximately 50%), MSH2 (approximately 40%), and MSH6 (approximately 10%). Examination of HNPCC/Lynch syndrome-associated MMR genes and their mutations has revealed several other important functions for their protein products beyond postreplicative mismatch repair as well as many alternative mechanisms of pathogenicity. Despite these advances, much is yet to be learned about the molecular basis of correlations between genetic changes and clinical features of the disease.
自1993年至1995年发现具有DNA错配修复（MMR）功能的主要人类基因以来，已确凿证实MSH2、MLH1、MSH6和PMS2这四个基因中的突变与遗传性非息肉病性结直肠癌（HNPCC）/林奇综合征的易感性相关。其中，PMS2突变与多种临床特征相关，包括Turcot综合征的特征。另外两个MMR基因，MLH3和PMS1，也被认为在林奇综合征易感性中起作用，但这些基因中突变的临床意义尚不清楚。根据遗传性非息肉病性结直肠癌国际协作组（ICG-HNPCC）维护的数据库，即目前的国际胃肠道遗传性肿瘤学会（InSiGHT），已知大约500种不同的与HNPCC相关的MMR基因突变，主要涉及MLH1（约50%）、MSH2（约40%）和MSH6（约10%）。对HNPCC/林奇综合征相关的MMR基因及其突变的研究揭示了其蛋白质产物除复制后错配修复之外的其他几个重要功能，以及许多致病性的替代机制。尽管有这些进展，但关于该疾病基因变化与临床特征之间相关性的分子基础仍有许多有待了解。
