Prognostic significance of O6-methylguanine-DNA methyltransferase determined by promoter hypermethylation and immunohistochemical expression in anaplastic gliomas
Prognostic significance of O6-methylguanine-DNA methyltransferase determined by promoter hypermethylation and immunohistochemical expression in anaplastic gliomas
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DOI：
10.1158/1078-0432.ccr-05-0230
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发表时间：
2005-07-15
影响因子：
11.5
通讯作者：
Graus, F
中科院分区：
文献类型：
--
作者：
Brell, M;Tortosa, A;Graus, F
目的：间变性胶质瘤构成了一组异质性肿瘤，对烷基化药物辅助化疗具有不同的治疗反应。O-6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）是一种DNA修复蛋白，是胶质瘤化疗耐药的相关因素之一。MGMT的预后价值仍然存在争议，部分原因是以前发表的研究包括不同肿瘤分级的异质性患者组。本研究的目的是评估MGMT在间变性胶质瘤患者的预后意义。实验设计：93例间变性胶质瘤患者进行了MGMT蛋白表达的免疫组化分析。此外，对于那些获得良好DNA产量的患者（n = 40），通过甲基化特异性PCR分析MGMT启动子甲基化谱。结果：51例（54.8%）肿瘤显示MGMT核染色，MGMT免疫染色阴性的患者总生存期有延长的趋势（危险比，1.66; P = 0.066）。在包括那些实际接受化疗的患者（n = 72）的次要分析中，MGMT表达的缺失与更好的生存独立相关（风险比，2.12; P = 0.027）。在50%的分析肿瘤中观察到MGMT启动子甲基化。MGMT表达和MGMT启动子甲基化之间无统计学相关性，observed.Conclusions：与以往的研究不同，我们没有发现MGMT启动子甲基化和生存之间的相关性。然而，我们在接受化疗的患者中观察到MGMT蛋白表达与生存之间的相关性，从而表明MGMT表达的缺失是间变性胶质瘤患者的阳性预测标志物。
Purpose: Anaplastic gliomas constitute a heterogeneous group of tumors with different therapeutic responses to adjuvant chemotherapy with alkylating agents. O-6-Methylguanine-DNA methyltransferase (MGMT), a DNA repair protein, is one of the implicated factors in glioma chemoresistance. The prognostic value of MGMT remains controversial due in part to the fact that previous published studies included heterogeneous groups of patients with different tumor grades. The aim of this study was to evaluate the prognostic significance of MGMT in patients with anaplastic glioma.Experimental Design: Ninety-three patients with anaplastic glioma were analyzed for MGMT protein expression by immunohistochemistry. In addition, for those patients from whom a good yield of DNA was obtained (n = 40), MGMT promoter methylation profile was analyzed by methylation-specific PCR. MGMT prognostic significance was evaluated together with other well-known prognostic factors.Results: Fifty-one tumors (54.8%) showed nuclear staining of MGMT There was a trend towards longer overall survival for those patients with negative MGMT immunostaining (hazard ratio, 1.66; P = 0.066). In a secondary analysis including those patients who actually received chemotherapy (n = 72), the absence of MGMT expression was independently associated with better survival (hazard ratio, 2.12; P = 0.027). MGMT promoter methylation was observed in 50% of the analyzed tumors. No statistical correlation between MGMT expression and MGMT promoter hype methylation was observed.Conclusions: Unlike previous studies, we did not find a correlation between MGMT promoter methylation and survival. However, we observed a correlation between MGMT protein expression and survival in those patients who received chemotherapy thus suggesting that the absence of MGMT expression is a positive predictive marker in patients with anaplastic glioma.