Department of Oncology, Odense University Hospital.
Department of Epidemiology, Biostatistics and Biodemography, University of Southern Denmark.
J Neuropathol Exp Neurol. 2019 Jul 1;78(7):633-640. doi: 10.1093/jnen/nlz032.
The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) removes temozolomide-induced alkylation, thereby preventing DNA damage and cytotoxicity. We investigated the prognostic effect of different MGMT methylation levels on overall and progression-free survival in 327 patients with primary glioblastoma undergoing standard treatment. We obtained MGMT methylation level in 4 CpG sites using pyrosequencing. The association between MGMT methylation level and survival was investigated using Cox proportional hazards model and an extension to detect time-varying effects. We found an association between MGMT methylation level and overall survival (OS) from around 9 months after the diagnosis, with no association between MGMT methylation level and OS before that. For patients surviving at least 9 months even small increases in MGMT methylation level are significantly beneficial (HR = 0.97, 95% CI [0.96, 0.98]). The predictive ability of MGMT methylation level on OS from 9 months after diagnosis has a Harrel's C of 66%. We conclude that the MGMT methylation level is strongly associated with survival only for patients surviving beyond 9 months with considerable effects for levels much lower than previously reported. Prognostic evaluation of cut-points of MGMT methylation levels and of CpG island site selection should take the time-varying effect on overall survival into account.
DNA 修复蛋白 O6-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）可去除替莫唑胺诱导的烷基化，从而防止 DNA 损伤和细胞毒性。我们研究了在接受标准治疗的 327 名原发性胶质母细胞瘤患者中，不同 MGMT 甲基化水平对总生存期和无进展生存期的预后影响。我们使用焦磷酸测序法在 4 个 CpG 位点获得 MGMT 甲基化水平。使用 Cox 比例风险模型和扩展模型来检测时变效应，研究了 MGMT 甲基化水平与生存之间的关联。我们发现 MGMT 甲基化水平与总生存期（OS）之间存在关联，从诊断后约 9 个月开始，在此之前，MGMT 甲基化水平与 OS 之间没有关联。对于至少存活 9 个月的患者，即使 MGMT 甲基化水平略有增加，也有显著的获益（HR=0.97，95%CI[0.96,0.98]）。从诊断后 9 个月开始，MGMT 甲基化水平对 OS 的预测能力具有 Harrell 的 C 值为 66%。我们得出结论，只有在存活时间超过 9 个月的患者中，MGMT 甲基化水平与生存密切相关，并且与以前报道的水平相比，低得多的水平也有显著的效果。MGMT 甲基化水平的预后评估和 CpG 岛位点选择应考虑到对总生存期的时变效应。
