Department of Neurosurgery, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Int J Mol Sci. 2023 Mar 24;24(7):6184. doi: 10.3390/ijms24076184.
Glioblastoma is the most common malignant brain tumor in adults. Standard treatment includes tumor resection, radio-chemotherapy and adjuvant chemotherapy with temozolomide (TMZ). TMZ methylates DNA, whereas O6-methylguanine DNA methyltransferase (MGMT) counteracts TMZ effects by removing the intended proteasomal degradation signal. Non-functional MGMT mediates the mismatch repair (MMR) system, leading to apoptosis after futile repair attempts. This study investigated the associations between promoter methylation, MGMT and MMR protein expression, and their effect on overall survival (OS) and progression-free survival (PFS) in patients with glioblastoma. promoter methylation was assessed in 42 treatment-naïve patients with glioblastoma WHO grade IV by pyrosequencing. MGMT and MMR protein expression was analyzed using immunohistochemistry. promoter methylation was present in 52%, whereas patients <70 years of age revealed a significantly longer OS using a log-rank test and a significance threshold of ≤ 0.05. MGMT protein expression and methylation status showed no correlation. MMR protein expression was present in all patients independent of MGMT status and did not influence OS and PFS. Overall, promoter methylation implicates an improved OS in patients with glioblastoma aged <70 years. In the elderly, the extent of surgery has an impact on OS rather than the promoter methylation or protein expression.
胶质母细胞瘤是成年人中最常见的恶性脑肿瘤。标准治疗包括肿瘤切除术、放化疗和替莫唑胺（TMZ）辅助化疗。TMZ 使 DNA 甲基化，而 O6-甲基鸟嘌呤 DNA 甲基转移酶（MGMT）通过去除预期的蛋白酶体降解信号来抵消 TMZ 的作用。无功能的 MGMT 介导错配修复（MMR）系统，导致无效修复尝试后的细胞凋亡。本研究探讨了胶质母细胞瘤患者中启动子甲基化、MGMT 和 MMR 蛋白表达之间的关联，以及它们对总生存期（OS）和无进展生存期（PFS）的影响。通过焦磷酸测序评估了 42 名未经治疗的胶质母细胞瘤 WHO 分级 IV 患者的启动子甲基化。使用免疫组织化学分析 MGMT 和 MMR 蛋白表达。52%的患者存在启动子甲基化，而年龄<70 岁的患者使用对数秩检验和 ≤0.05 的显著性阈值显示出显著更长的 OS。MGMT 蛋白表达和甲基化状态之间没有相关性。无论 MGMT 状态如何，所有患者均存在 MMR 蛋白表达，且不影响 OS 和 PFS。总体而言，在年龄<70 岁的胶质母细胞瘤患者中，启动子甲基化暗示 OS 得到改善。在老年人中，手术范围对 OS 有影响，而不是启动子甲基化或蛋白表达。
