Department of Pathology, Chonnam National University Medical School, 8, Hak-dong, Dong-gu, Gwangju 501-757, South Korea.
Langenbecks Arch Surg. 2011 Oct;396(7):1017-26. doi: 10.1007/s00423-011-0812-9. Epub 2011 Jun 25.
Epigenetic silencing of the DNA mismatch repair genes has been poorly described in colorectal carcinomas showing the classic adenoma-carcinoma pathway of carcinogenesis. The aim of this study was to investigate the methylation status of MutL homolog 1 (hMLH1), MutS homolog 2 (hMSH2), and O-6-methylguanine-DNA methyltransferase (MGMT) in a series of colorectal carcinomas that contain both adenomas and carcinomas.
Promoter methylation of hMLH1, hMSH2, and MGMT was evaluated in normal mucosa, adenoma, and carcinoma samples from 112 colorectal cancer patients. Methylation was assessed by bisulfite modification and methylation-specific PCR. Expression of the gene products was also examined by immunohistochemistry.
Of the 112 adenomas, methylation was detected for hMLH1 (2, 1.8%), hMSH2 (9, 8.0%), and MGMT (38, 33.9%). In the carcinoma samples, methylation was seen in hMLH1 (2, 1.8%), hMSH2 (15, 13.4%), and MGMT (53, 47.3%). In normal mucosa, hMSH2 (6, 5.4%) and MGMT (12, 10.7%) were methylated, whereas hMLH1 was not. Immunohistochemical analysis revealed abnormal hMLH1 (14, 12.5%), hMSH2 (11, 9.8%), and MGMT (53, 47.3%) expression with a significant correlation between aberrant MGMT methylation and a loss of MGMT expression.
These data suggest that CpG island methylation in hMSH2 and MGMT, but not hMLH1, is closely related to carcinogenesis in colorectal carcinomas presenting with a conventional adenoma-carcinoma sequence. Therefore, the detection of hMSH2 and MGMT methylation may have clinical significance in the evaluation of colon cancer patients and in tumor-specific management of the disease.
在显示经典腺瘤-癌发生途径的结直肠癌中，DNA 错配修复基因的表观遗传沉默描述甚少。本研究旨在研究一系列同时含有腺瘤和癌的结直肠癌中 MutL 同源物 1(hMLH1)、MutS 同源物 2(hMSH2)和 O-6-甲基鸟嘌呤-DNA 甲基转移酶(MGMT)的甲基化状态。
在 112 例结直肠癌患者的正常黏膜、腺瘤和癌样本中，评估 hMLH1、hMSH2 和 MGMT 的启动子甲基化情况。通过亚硫酸氢盐修饰和甲基化特异性 PCR 评估甲基化。还通过免疫组织化学检查基因产物的表达情况。
在 112 个腺瘤中，检测到 hMLH1(2 个，1.8%)、hMSH2(9 个，8.0%)和 MGMT(38 个，33.9%)的甲基化。在癌样本中，检测到 hMLH1(2 个，1.8%)、hMSH2(15 个，13.4%)和 MGMT(53 个，47.3%)的甲基化。在正常黏膜中，hMSH2(6 个，5.4%)和 MGMT(12 个，10.7%)发生甲基化，而 hMLH1 则没有。免疫组织化学分析显示，异常 hMLH1(14 个，12.5%)、hMSH2(11 个，9.8%)和 MGMT(53 个，47.3%)的表达，MGMT 异常甲基化与 MGMT 表达缺失之间存在显著相关性。
这些数据表明，结直肠癌中 hMSH2 和 MGMT 的 CpG 岛甲基化与传统腺瘤-癌序列中的肿瘤发生密切相关，但 hMLH1 除外。因此，检测 hMSH2 和 MGMT 甲基化可能对评估结肠癌患者和肿瘤特异性管理疾病具有临床意义。
