Macdonald G A, Greenson J K, Saito K, Cherian S P, Appelman H D, Boland C R
Department of Internal Medicine, University of Michigan, Ann Arbor, USA.
Hepatology. 1998 Jul;28(1):90-7. doi: 10.1002/hep.510280114.
DNA mismatch repair is an important mechanism involved in maintaining the fidelity of genomic DNA. Defective DNA mismatch repair is implicated in a variety of gastrointestinal and other tumors; however, its role in hepatocellular carcinoma (HCC) has not been assessed. Formalin-fixed, paraffin-embedded archival pathology tissues from 46 primary liver tumors were studied by microdissection and microsatellite analysis of extracted DNA to assess the degree of microsatellite instability, a marker of defective mismatch repair, and to determine the extent and timing of allelic loss of two DNA mismatch repair genes, human Mut S homologue-2 (hMSH2) and human Mut L homologue-1 (hMLH1), and the tumor suppressor genes adenomatous polyposis coli gene (APC), p53, and DPC4. Microsatellite instability was detected in 16 of the tumors (34.8%). Loss of heterozygosity at microsatellites linked to the DNA mismatch repair genes, hMSH2 and/or hMLH1, was found in 9 cases (19.6%), usually in association with microsatellite instability. Importantly, the pattern of allelic loss was uniform in 8 of these 9 tumors, suggesting that clonal loss had occurred. Moreover, loss at these loci also occurred in nonmalignant tissue adjacent to 4 of these tumors, where it was associated with marked allelic heterogeneity. There was relatively infrequent loss of APC, p53, or DPC4 loci that appeared unrelated to loss of hMSH2 or hMLH1 gene loci. Loss of heterozygosity at hMSH2 and/or hMLH1 gene loci, and the associated microsatellite instability in premalignant hepatic tissues suggests a possible causal role in hepatic carcinogenesis in a subset of hepatomas.
DNA错配修复是维持基因组DNA保真度的重要机制。DNA错配修复缺陷与多种胃肠道及其他肿瘤相关；然而，其在肝细胞癌（HCC）中的作用尚未得到评估。通过对46例原发性肝肿瘤的福尔马林固定、石蜡包埋存档病理组织进行显微切割，并对提取的DNA进行微卫星分析，以评估微卫星不稳定性的程度（错配修复缺陷的标志物），并确定两个DNA错配修复基因人类Mut S同源物2（hMSH2）和人类Mut L同源物1（hMLH1）以及肿瘤抑制基因腺瘤性息肉病 coli基因（APC）、p53和DPC4的等位基因缺失的范围和时间。在16例肿瘤中检测到微卫星不稳定性（34.8%）。在9例（19.6%）中发现与DNA错配修复基因hMSH2和/或hMLH1相关的微卫星杂合性缺失，通常与微卫星不稳定性相关。重要的是，这9例肿瘤中有8例的等位基因缺失模式是一致的，表明发生了克隆性缺失。此外，在其中4例肿瘤相邻的非恶性组织中也出现了这些位点的缺失，且与明显的等位基因异质性相关。APC、p53或DPC4位点的缺失相对较少，且似乎与hMSH2或hMLH1基因位点的缺失无关。hMSH2和/或hMLH1基因位点的杂合性缺失以及癌前肝组织中相关的微卫星不稳定性表明，在一部分肝癌的肝致癌过程中可能起因果作用。
