Donson Andrew M, Addo-Yobo Steven O, Handler Michael H, Gore Lia, Foreman Nicholas K
University of Colorado at Denver and Health Sciences Center and Denver Children's Hospital, Denver, Colorado, USA.
Pediatr Blood Cancer. 2007 Apr;48(4):403-7. doi: 10.1002/pbc.20803.
Methylation of the DNA-repair gene O6-methylguanine-DNA methyltransferase (MGMT) causes gene silencing. This epigenetic modification has been associated with a favorable prognosis in adult patients with glioblastoma (GBM) who receive temozolomide and other alkylating agents. We explored MGMT promoter methylation in pediatric GBM and its relationship to survival and temozolomide sensitivity.
We performed a retrospective study of MGMT promoter methylation in 10 pediatric GBM. The methylation status of the MGMT was determined using a 2-stage methylation specific PCR analysis on DNA extracted from tumor specimens which had been snap frozen at surgery. The relationships between MGMT promoter methylation and patient outcome and response to temozolomide were evaluated.
Four of our 10 pediatric patients with GBM were found to have methylation of the MGMT gene promoter. Methylation of the MGMT promoter was shown to correlate (P = 0.0005) with survival. The average survival time for patients with methyltated MGMT was 13.7 months as compared to 2.5 months for the 6 patients with unmethylated MGMT promoter. Of the seven patients that received temozolomide, those patients that had the methylated MGMT gene promoter responded better to treatment (P = 0.007).
As in adults, pediatric GBM patients with methylated MGMT promoter benefited from temozolomide. However, a stronger correlation with overall survival, regardless of treatment, was observed in this group of patients. These data suggest that MGMT methylation may be a prognostic factor for survival in pediatric GBM, as well as a marker for temozolomide sensitivity.
DNA修复基因O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）的甲基化会导致基因沉默。这种表观遗传修饰与接受替莫唑胺和其他烷化剂治疗的成胶质母细胞瘤（GBM）成年患者的良好预后相关。我们探讨了儿童GBM中MGMT启动子甲基化及其与生存和替莫唑胺敏感性的关系。
我们对10例儿童GBM中的MGMT启动子甲基化进行了回顾性研究。使用两阶段甲基化特异性PCR分析从手术时速冻的肿瘤标本中提取的DNA，以确定MGMT的甲基化状态。评估了MGMT启动子甲基化与患者预后及对替莫唑胺反应之间的关系。
我们的10例儿童GBM患者中有4例被发现具有MGMT基因启动子甲基化。MGMT启动子甲基化与生存相关（P = 0.0005）。MGMT甲基化患者的平均生存时间为13.7个月，而MGMT启动子未甲基化的6例患者为2.5个月。在接受替莫唑胺治疗的7例患者中，MGMT基因启动子甲基化的患者对治疗反应更好（P = 0.007）。
与成人一样，MGMT启动子甲基化的儿童GBM患者从替莫唑胺中获益。然而，在这组患者中观察到与总生存的更强相关性，无论是否接受治疗。这些数据表明，MGMT甲基化可能是儿童GBM生存的预后因素，也是替莫唑胺敏感性的标志物。
