恶性脑胶质瘤MGMT基因启动子甲基化状态与患者临床预后的相关性

Correlation between promoter methylation of O（6）-methylguanine-DNA-methyltransferase gene in malignant brain gliomas and clinical prognosis of these patients

目的探讨恶性脑胶质瘤组织O6-甲基鸟嘌呤-DNA-甲基转移酶（MGMT）基因启动子甲基化状态及MGMT蛋白表达与患者生存预后的关系，评价MS-MLPA技术检测MGMT基因启动子甲基化状态对脑胶质瘤化疗的意义。方法选择自2006至2010年南方医科大学珠江医院神经外科手术治疗且病理证实为恶性脑胶质瘤（WHOII级、Ⅳ级）的39例患者为研究对象，应用免疫组化染色法检测肿瘤组织MGMT蛋白表达，应用MS-MLPA技术检测MGMT基因启动子甲基化状态，并观察患者化疗后总生存时间。结果肿瘤组织中MGMT蛋白表达阳性、弱阳性者与表达阴性者生存时间比较差异有统计学意义（P=-O．0031，MGMT蛋白表达阳性者比表达阴性者预后更差。肿瘤组织中MGMT基因启动子未甲基化者、低度过甲基化者、中度过甲基化者、高度过甲基化者生存时间两两比较差异均有统计学意义（P〈0．05），MGMT基因启动子过甲基化率越高者预后越好。MGMT蛋白表达与MGMT基因启动子甲基化状态存在统计学相关性（r==0．697，P=-0．000），基因甲基化程度越高者蛋白表达越低。结论MGMT蛋白表达与MGMT基因启动子甲基化状态均可以作为接受烷化剂化疗的恶性胶质瘤患者生存期的预测指标。MS-MLPA技术是一种可靠的检测MGMT基因启动子甲基化状态的方法。

Objective To study the correlations between O （6） -methylguanine-DNA-methyltransferase （MGMT） gene promoter methylation status in malignant glioma tissues and both MGMT protein expression and survival prognosis in these patients, and evaluate the significance of MGMT gene methylation status analyzing with methylation-specific multiplex ligation-dependent probe amplification （MS-MLPA） method in chemotherapy of brain glioma. Methods Thirty-nine patients with gliomas confirmed by pathology （WHO grade III and grade IV） were collected in our study; the patient＇s overall survival （OS） after chemotherapy was tracked. MGMT protein expression of glioma tissues was detected by immunohistochemical staining, and MGMT promoter methylation status was detected by MS-MLPA method. Results Statistical difference of OS time was noted between patients with MGMT-negative and patients with MGMT-positive/-weak-positive （P=- 0.003）. The prognosis in patients with positive MGMT protein expression was obviously poorer than that in patients with negative expression. In the groups of MGMT promoter un-methylation, mild hypermethylation, moderate hypermethylation and extensive hypermethylation, significant statisticaldifference of OS time was noted between each 2 groups （P〈0.05）; the higher degree of methylation, the better prognosis. Statistical correlation was noted between MGMT protein expression and promoter methylation status （r=0.697, P=0.000）; the higher degree ofmethylation, the lower protein exression of MGMT. Conclusion Both MGMT protein expression and promoter methylation status can be regarded as prognostic indicator of OS in patients with malignant glioma accepted alkylating agent chemotherapy; MS-MLPA is a reliable method to detect MGMT gene promoter methylation status.