Rahner N, Friedrichs N, Steinke V, Aretz S, Friedl W, Buettner R, Mangold E, Propping P, Walldorf C
Institute of Human Genetics, University of Bonn, Germany.
J Pathol. 2008 Jan;214(1):10-6. doi: 10.1002/path.2263.
Somatic epimutations in the MLH1 promoter mimic the phenotype of Lynch syndrome. To date, no somatic hypermethylation of the MLH1 promoter in the carrier of a pathogenic MLH1 germline mutation has been identified, prompting the recommendation that a germline mutation in MLH1 should only be sought in the absence of tumour tissue methylation. We aimed to determine whether methylation of the MLH1 promoter may coexist in carriers of a pathogenic germline mutation in MLH1. We examined the methylation status of the MLH1 promoter in 123 tumour tissue samples, demonstrating high microsatellite instability and loss of expression of a mismatch repair protein (60 cases with MLH1 germline mutation, 25 cases without mutation, 38 cases with MSH2 mutations), using combined bisulphite restriction analysis (COBRA) and SNaPshot analysis. Methylation of the MLH1 promoter was found in two patients with pathogenic germline mutations, one a carrier of a MLH1 mutation and the other a carrier of a MSH2 mutation. Our results demonstrate that methylation of the MLH1 promoter region does not exclude the presence of a germline mutation in a mismatch repair (MMR) gene. Hypermethylation of the MLH1 promoter may be present in most cases of sporadic colorectal cancers, but this does not exclude a diagnosis of Lynch syndrome.
错配修复基因1（MLH1）启动子的体细胞表遗传突变可模拟林奇综合征的表型。迄今为止，尚未在携带致病性MLH1种系突变的个体中鉴定出MLH1启动子的体细胞高甲基化，这促使人们建议仅在肿瘤组织无甲基化的情况下才寻找MLH1种系突变。我们旨在确定MLH1启动子的甲基化是否可能与致病性MLH1种系突变携带者共存。我们使用联合亚硫酸氢盐限制分析（COBRA）和SNaPshot分析检测了123例肿瘤组织样本中MLH1启动子的甲基化状态，这些样本显示出高微卫星不稳定性和错配修复蛋白表达缺失（60例携带MLH1种系突变，25例无突变，38例携带MSH2突变）。在两名携带致病性种系突变的患者中发现了MLH1启动子的甲基化，其中一名是MLH1突变携带者，另一名是MSH2突变携带者。我们的结果表明，MLH1启动子区域的甲基化并不排除错配修复（MMR）基因中存在种系突变。MLH1启动子的高甲基化可能存在于大多数散发性结直肠癌病例中，但这并不排除林奇综合征的诊断。
