The response of glioblastoma (GBM) patients to the alkylating agent temozolomide (TMZ) vitally depends on the expression level of the repair protein O6-methylguanine-DNA methyltransferase (MGMT). Since MGMT is strongly regulated by promoter methylation, the methylation status of theMGMTpromoter has emerged as a prognostic and predictive biomarker for GBM patients. By determining the methylation levels of the four enhancers located within or close to theMGMTgene, we recently found that enhancer methylation contributes toMGMTregulation. In this study, we investigated if methylation of the four enhancers is associated with SNP rs16906252,TERTpromoter mutations C228T and C250T,TERTSNP rs2853669, proliferation index Ki-67, overall survival (OS), age, and sex of the patients. In general, associations with genetic variants, clinical parameters, and demographic characteristics were caused by a complex interplay of multiple CpGs in theMGMTpromoter and of multiple CpGs in enhancer regions. The observed associations for intragenic enhancer 4, located in intron 2 ofMGMT, differed from associations observed for the three intergenic enhancers. Some findings were restricted to subgroups of samples with either methylated or unmethylatedMGMTpromoters, underpinning the relevance of theMGMTpromoter status in GBMs.
胶质母细胞瘤（GBM）患者对烷化剂替莫唑胺（TMZ）的治疗反应，关键取决于修复蛋白O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）的表达水平。由于MGMT的表达受其启动子甲基化的强烈调控，MGMT启动子的甲基化状态已成为GBM患者重要的预后和预测性生物标志物。通过测定位于MGMT基因内部或附近的四个增强子的甲基化水平，我们近期发现增强子甲基化也参与MGMT的调控。本研究旨在探讨这四个增强子的甲基化是否与SNP rs16906252、TERT启动子突变C228T和C250T、TERT SNP rs2853669、增殖指数Ki-67、患者总生存期（OS）、年龄及性别相关。总体而言，这些与遗传变异、临床参数及人口学特征之间的关联，是由MGMT启动子内多个CpG位点与增强子区域内多个CpG位点之间复杂的相互作用所导致。位于MGMT基因内含子2内的基因内增强子4所观察到的关联性，与三个基因间增强子的关联模式有所不同。部分研究结果仅限于MGMT启动子甲基化或未甲基化的样本亚组，这进一步证实了MGMT启动子状态在胶质母细胞瘤中的重要意义。
肿瘤(癌症)患者之家