Geddert Helene, Kiel Sibylle, Iskender Erol, Florl Andrea R, Krieg Thomas, Vossen Sandra, Gabbert Helmut E, Sarbia Mario
Institute of Pathology, Heinrich-Heine-University, Düsseldorf, Germany.
Int J Cancer. 2004 Jun 10;110(2):208-11. doi: 10.1002/ijc.20058.
Using methylation-specific real-time PCR, we determined the prevalence of aberrant methylation in the mismatch repair gene hMLH1 and in the recently described HPP1 gene among 50 esophageal, 50 cardiac and 50 gastric ADCs. Additionally, expression of hMLH1 protein was detected immunohistochemically and correlated with DNA MSI. Hypermethylation of hMLH1 was found in 14% of esophageal, 28% of cardiac and 32% of gastric ADCs, whereas HPP1 hypermethylation was found more frequently in the 3 tumor types (64% vs. 38% vs. 54%). In gastric ADC, HPP1 hypermethylation was found more frequently in tumors with concomitant hMLH1 hypermethylation (81%) than in those without hMLH1 hypermethylation (41%, p = 0.008). Complete loss of hMLH1 protein expression, which was present in 10 carcinomas (5 cardiac and 5 gastric), was invariably correlated with hMLH1 hypermethylation and MSI. In conclusion, our data indicate that MSI and loss of the mismatch repair protein hMLH1, which is mainly caused by hMLH1 gene hypermethylation, are more prevalent in stomach and cardia carcinogenesis than in that of the esophagus. Moreover, in gastric cancer, hMLH1 hypermethylation is correlated with hypermethylation of the HPP1 gene.
我们采用甲基化特异性实时聚合酶链反应，在50例食管腺癌、50例贲门腺癌和50例胃腺癌中，确定错配修复基因hMLH1和最近描述的HPP1基因异常甲基化的发生率。此外，采用免疫组织化学法检测hMLH1蛋白的表达，并与DNA微卫星不稳定性（MSI）进行关联分析。结果发现，14%的食管腺癌、28%的贲门腺癌和32%的胃腺癌存在hMLH1高甲基化，而HPP1高甲基化在这3种肿瘤类型中更为常见（分别为64%、38%和54%）。在胃腺癌中，伴有hMLH1高甲基化的肿瘤（81%）比无hMLH1高甲基化的肿瘤（41%，p = 0.008）更常出现HPP1高甲基化。10例癌（5例贲门癌和5例胃癌）中存在hMLH1蛋白表达完全缺失，这与hMLH1高甲基化和MSI始终相关。总之，我们的数据表明，MSI和错配修复蛋白hMLH1的缺失（主要由hMLH1基因高甲基化引起）在胃癌和贲门癌发生中比在食管癌发生中更为普遍。此外，在胃癌中，hMLH1高甲基化与HPP1基因高甲基化相关。
