Departments of Pathology and Radiation-Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit-0097, Houston, TX 77030, USA.
Neuro Oncol. 2010 Feb;12(2):116-21. doi: 10.1093/neuonc/nop020. Epub 2009 Dec 14.
Hypermethylation of the O(6)-methylguanine-DNA-methyltransferase (MGMT) gene has been shown to be associated with improved outcome in glioblastoma (GBM) and may be a predictive marker of sensitivity to alkylating agents. However, the predictive utility of this marker has not been rigorously tested with regard to sensitivity to other therapies, namely radiation. To address this issue, we assessed MGMT methylation status in a cohort of patients with GBM who underwent radiation treatment but did not receive chemotherapy as a component of adjuvant treatment. Formalin-fixed, paraffin-embedded tumor samples from 225 patients with newly diagnosed GBM were analyzed via methylation-specific, quantitative real-time polymerase chain reaction following bisulfite treatment on isolated DNA to assess MGMT promoter methylation status. In patients who received radiotherapy alone following resection, methylation of the MGMT promoter correlated with an improved response to radiotherapy. Unmethylated tumors were twice as likely to progress during radiation treatment. The median time interval between resection and tumor progression of unmethylated tumors was also nearly half that of methylated tumors. Promoter methylation was also found to confer improved overall survival in patients who did not receive adjuvant alkylating chemotherapy. Multivariable analysis demonstrated that methylation status was independent of age, Karnofsky performance score, and extent of resection as a predictor of time to progression and overall survival. Our data suggest that MGMT promoter methylation appears to be a predictive biomarker of radiation response. Since this biomarker has also been shown to predict response to alkylating agents, perhaps MGMT promoter methylation represents a general, favorable prognostic factor in GBM.
MGMT 基因的过度甲基化已被证明与胶质母细胞瘤（GBM）的预后改善有关，并且可能是对烷化剂敏感性的预测标志物。然而，该标志物对其他治疗方法（即放射治疗）的敏感性的预测效用尚未经过严格测试。为了解决这个问题，我们评估了接受放射治疗但未接受化疗作为辅助治疗一部分的 GBM 患者队列中的 MGMT 甲基化状态。对 225 名新诊断为 GBM 的患者的福尔马林固定、石蜡包埋的肿瘤样本进行了分析，方法是在分离的 DNA 上进行亚硫酸氢盐处理后，通过甲基化特异性、定量实时聚合酶链反应来评估 MGMT 启动子甲基化状态。在接受手术后单独接受放射治疗的患者中，MGMT 启动子的甲基化与对放射治疗的反应改善相关。未甲基化的肿瘤在放射治疗过程中进展的可能性是甲基化肿瘤的两倍。未甲基化肿瘤的切除后至肿瘤进展的中位时间间隔也几乎是甲基化肿瘤的一半。未接受辅助烷化化疗的患者中，启动子甲基化也可改善总生存率。多变量分析表明，甲基化状态是独立于年龄、Karnofsky 表现评分和切除范围的预测进展时间和总生存率的因素。我们的数据表明，MGMT 启动子甲基化似乎是放射反应的预测生物标志物。由于该生物标志物也已被证明可预测对烷化剂的反应，因此 MGMT 启动子甲基化可能代表 GBM 中的一般有利预后因素。
