Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, No. 38 Guangji Rd., Banshanqiao District, 310022, Hangzhou, People's Republic of China.
Dig Dis Sci. 2011 Oct;56(10):2992-3004. doi: 10.1007/s10620-011-1774-z. Epub 2011 Jun 15.
DNA mismatch repair (MMR) deficiency results in a strong mutator phenotype and high-frequency microsatellite instability (MSI-H), which are the hallmarks of many tumors.
The objective of this study is to investigate the promoter CpG island methylation status of mismatch repair genes human mutL homolog 1 (hMLH1), human mutS homolog 2 (hMSH2), and O(6)-methylguanine-DNA methyltransferase (MGMT) in esophageal squamous cell carcinoma (ESCC) and its roles in alkylating agents chemotherapy.
Real-time methylation-specific polymerase chain reaction (PCR) (real-time MSP) was employed to detect promoter CpG island methylation of the hMLH1, hMSH2, as well as MGMT genes in 235 surgical tumor tissue samples from ESCC patients and their corresponding normal tissue samples.
Promoter CpG island methylation of hMLH1, hMSH2, and MGMT were detectable in 43.4, 28.9, and 40.4% of ESCC tumor DNA, respectively, and the loss rates of hMLH1, hMSH2, and MGMT protein expression were 48.6, 34.5, and 40.9% in tumor tissues, respectively. For the entire population of 235 ESCC patients who were enrolled in operating treatment combined with radiotherapy and chemotherapy with alkylating agents, there was a significant difference in the overall survival between patients with methylated MGMT promoter and those with an unmethylated MGMT promoter (P < 0.05).
Promoter CpG island methylation may be a frequent event in ESCC carcinogenesis. Detection of the methylated sequences of hMLH1, hMSH2, and MGMT appears to be promising as a predictive factor in primary ESCC.
DNA 错配修复 (MMR) 缺陷导致强烈的突变表型和高频微卫星不稳定 (MSI-H)，这是许多肿瘤的标志。
本研究旨在探讨错配修复基因人 mutL 同源物 1 (hMLH1)、人 mutS 同源物 2 (hMSH2) 和 O(6)-甲基鸟嘌呤-DNA 甲基转移酶 (MGMT) 的启动子 CpG 岛甲基化状态在食管鳞状细胞癌 (ESCC) 及其在烷化剂化疗中的作用。
采用实时甲基化特异性聚合酶链反应 (PCR) (实时 MSP) 检测 235 例 ESCC 患者手术肿瘤组织及其相应正常组织中 hMLH1、hMSH2 及 MGMT 基因启动子 CpG 岛甲基化。
ESCC 肿瘤 DNA 中 hMLH1、hMSH2 和 MGMT 的启动子 CpG 岛甲基化分别为 43.4%、28.9%和 40.4%，肿瘤组织中 hMLH1、hMSH2 和 MGMT 蛋白表达缺失率分别为 48.6%、34.5%和 40.9%。对于接受手术治疗联合放疗和烷化剂化疗的 235 例 ESCC 患者，整个队列中，MGMT 启动子甲基化患者与非甲基化患者的总生存期有显著差异 (P<0.05)。
启动子 CpG 岛甲基化可能是 ESCC 癌变的一个常见事件。检测 hMLH1、hMSH2 和 MGMT 的甲基化序列似乎有望成为原发性 ESCC 的预测因子。
