Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
J Med Genet. 2009 Dec;46(12):793-802. doi: 10.1136/jmg.2009.068122. Epub 2009 Jun 29.
Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome characterised by a predisposition to early onset colorectal, endometrial and other cancers. The tumours typically exhibit microsatellite instability due to defective mismatch repair. HNPCC is classically caused by heterozygous loss-of-function mutations within the mismatch repair genes MLH1, MSH2, MSH6 and PMS2, but no pathogenic mutations are identified in a third of cases. In recent years, constitutional epimutations of the MLH1 gene, characterised by soma-wide allele specific promoter methylation and transcriptional silencing, have been identified in a handful of mutation negative HNPCC cases. In contrast to genetic mutations, MLH1 epimutations are reversible between generations and thus display non-Mendelian inheritance. This review focuses on the aetiological role of constitutional MLH1 epimutations in the development of HNPCC related cancers. The molecular characteristics, clinical ramifications and potential mechanism underlying this defect are discussed. Recommendations for the selection of cases warranting screening for MLH1 epimutations are proffered.
遗传性非息肉病性结直肠癌（HNPCC）是一种常染色体显性综合征，其特征是易患早发性结直肠、子宫内膜和其他癌症。由于错配修复缺陷，肿瘤通常表现出微卫星不稳定性。HNPCC 经典地由错配修复基因 MLH1、MSH2、MSH6 和 PMS2 中的杂合功能丧失突变引起，但在三分之一的病例中未发现致病突变。近年来，在少数突变阴性的 HNPCC 病例中，已鉴定出 MLH1 基因的组成性表观突变，其特征是广泛的等位基因特异性启动子甲基化和转录沉默。与遗传突变不同，MLH1 表观突变在代际之间是可逆的，因此表现出非孟德尔遗传。本综述重点讨论了组成性 MLH1 表观突变在 HNPCC 相关癌症发展中的病因作用。讨论了这种缺陷的分子特征、临床后果和潜在机制。提出了针对需要筛查 MLH1 表观突变的病例选择的建议。
