Leung S Y, Yuen S T, Chung L P, Chu K M, Chan A S, Ho J C
Department of Pathology, The University of Hong Kong, Queen Mary Hospital.
Cancer Res. 1999 Jan 1;59(1):159-64.
Mutation of DNA mismatch repair genes has rarely been documented in sporadic gastric carcinoma with microsatellite instability (MSI). In sporadic colorectal carcinoma, hMLH1 promoter methylation associated with protein loss is found in the majority of high-frequency MSI cases. We investigated a series of 35 sporadic gastric carcinomas stratified into high-frequency MSI (MSI-H), low-frequency MSI (MSI-L) and microsatellite stable (MSS) groups and found that hypermethylation of the CpG island in the hMLH1 promoter region was present in 100% of MSI-H sporadic gastric carcinomas. In 90% of cases, there was an associated complete loss of hMLH1 protein, as detected by immunohistochemistry, and a markedly lowered hMLH1 mRNA level. This loss of hMLH1 protein occurred in the MSI-H invasive tumor but not in the adjacent carcinoma-in situ or dysplastic components that were MSS. The MSI-L and MSS forms of gastric carcinoma all showed predominantly unmethylated hMLH1 promoter, positive hMLH1 protein and high hMLH1 mRNA level. On the other hand, hMSH2 protein was expressed in all of the tumors irrespective of the MSI status. Our results suggest that high-frequency MSI in sporadic gastric cancer is mostly due to epigenetic inactivation of hMLH1 in association with promoter methylation, and the loss of hMLH1 protein is a significant event in the development of invasive tumor.
DNA错配修复基因的突变在伴有微卫星不稳定性（MSI）的散发性胃癌中鲜有报道。在散发性结直肠癌中，大多数高频MSI病例中发现了与蛋白缺失相关的hMLH1启动子甲基化。我们研究了35例散发性胃癌，将其分为高频MSI（MSI-H）、低频MSI（MSI-L）和微卫星稳定（MSS）组，发现hMLH1启动子区域的CpG岛甲基化在100%的MSI-H散发性胃癌中存在。在90%的病例中，免疫组化检测显示hMLH1蛋白完全缺失，且hMLH1 mRNA水平显著降低。hMLH1蛋白的缺失发生在MSI-H浸润性肿瘤中，而在相邻的原位癌或发育异常成分（MSS）中未发生。胃癌的MSI-L和MSS形式均主要表现为hMLH1启动子未甲基化、hMLH1蛋白阳性和hMLH1 mRNA水平高。另一方面，无论MSI状态如何，所有肿瘤中均表达hMSH2蛋白。我们的结果表明，散发性胃癌中的高频MSI主要是由于hMLH1的表观遗传失活与启动子甲基化有关，hMLH1蛋白的缺失是浸润性肿瘤发生发展中的一个重要事件。
