Metellus Philippe, Coulibaly Bema, Nanni Isabelle, Fina Frederic, Eudes Nathalie, Giorgi Roch, Barrie Marylin, Chinot Olivier, Fuentes Stephane, Dufour Henry, Ouafik L'houcine, Figarella-Branger Dominique
Department of Neurosurgery, Timone Hospital, Marseille, France.
Cancer. 2009 Oct 15;115(20):4783-94. doi: 10.1002/cncr.24546.
O(6)-methylguanine-DNA methyltransferase (MGMT) is a key enzyme in the DNA repair process after alkylating agent action. Epigenetic silencing of the MGMT gene by promoter methylation has been associated with longer survival in patients with newly diagnosed glioblastoma multiforme (GBM) who receive alkylating agents. In this study, the authors evaluated the prognostic value of different biomarkers in recurrent GBM and analyzed the changes in MGMT status between primary tumors and recurrent tumors.
Twenty-two patients who had recurrent GBM and who underwent surgery with carmustine wafer implantation were enrolled prospectively between 2005 and 2007. The authors investigated the correlation between MGMT silencing in the tumor at recurrence and survival taking into account other clinically recognized prognostic factors. MGMT status was determined by using methylation-specific polymerase chain reaction analysis, a high-throughput quantitative methylation assay, and immunohistochemistry. In addition, expression analyses of human mutL homolog 1, human mutS homolog 2, and tumor necrosis factor alpha-induced protein 3 at recurrence were conducted with regard to their prognostic impact.
The median progression-free survival (PFS) and overall survival (OS) rates after recurrence were 3.6 months and 9.9 months, respectively, and the 6-month PFS rate after recurrence was 27.2%. On multivariate analysis, only age (P=.04) and MGMT promoter hypermethylation at recurrence, as determined by MethyLight technology (P=.0012) and methylation-specific polymerase chain reaction (MSP) analysis (P=.004), were correlated with better PFS. On multivariate analysis, only MGMT promoter hypermethylation at recurrence, as determined by using MethyLight technology (P=.019) and MSP analysis (P=.046), was associated with better OS.
MGMT methylation status was an important prognostic factor in patients with recurrent GBM who underwent surgery plus carmustine wafer implantation; therefore, it was useful in predicting the outcome of GBM therapy at recurrence.
O(6)-甲基鸟嘌呤-DNA甲基转移酶（MGMT）是烷化剂作用后DNA修复过程中的关键酶。MGMT基因启动子甲基化导致的表观遗传沉默与接受烷化剂治疗的新诊断多形性胶质母细胞瘤（GBM）患者的较长生存期相关。在本研究中，作者评估了不同生物标志物在复发性GBM中的预后价值，并分析了原发性肿瘤与复发性肿瘤之间MGMT状态的变化。
2005年至2007年期间前瞻性纳入了22例复发性GBM且接受卡莫司汀晶片植入手术的患者。作者在考虑其他临床公认的预后因素的情况下，研究了复发时肿瘤中MGMT沉默与生存之间的相关性。MGMT状态通过甲基化特异性聚合酶链反应分析、高通量定量甲基化检测和免疫组织化学来确定。此外，还对复发时人mutL同源物1、人mutS同源物2和肿瘤坏死因子α诱导蛋白3进行了表达分析，以评估它们的预后影响。
复发后的中位无进展生存期（PFS）和总生存期（OS）分别为3.6个月和9.9个月，复发后6个月的PFS率为27.2%。多因素分析显示，只有年龄（P = 0.04）以及通过MethyLight技术确定的复发时MGMT启动子高甲基化（P = 0.0012）和甲基化特异性聚合酶链反应（MSP）分析（P = 0.004）与更好的PFS相关。多因素分析显示，只有通过MethyLight技术（P = 0.019）和MSP分析（P = 0.046）确定的复发时MGMT启动子高甲基化与更好的OS相关。
MGMT甲基化状态是接受手术加卡莫司汀晶片植入的复发性GBM患者的重要预后因素；因此，它有助于预测GBM复发时的治疗结果。
