Department of Molecular Neuropathology, Beijing Neurosurgical Institute; Chinese Glioma Genome Atlas Network (CGGA), Capital Medical University, Beijing 100070, China.
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.
Cancer Biol Med. 2021 Feb 15;18(1):272-282. doi: 10.20892/j.issn.2095-3941.2020.0179.
O6methylguanine-DNA methyltransferase () promoter methylation is a biomarker widely used to predict the sensitivity of -wildtype glioblastoma to temozolomide therapy. Given that the status has critical effects on the survival and epigenetic features of glioblastoma, we aimed to assess the role of promoter methylation in -mutant glioblastoma.
This study included 187 -mutant glioblastomas and used 173 -wildtype glioblastomas for comparison. Kaplan-Meier curves and multivariate Cox regression were used to study the predictive effects.
Compared with -wildtype glioblastomas, -mutant glioblastomas showed significantly higher ( < 0.0001) promoter methylation. We demonstrated that promoter methylation status, as determined by a high cutoff value (≥30%) in pyrosequencing, could be used to significantly stratify the survival of 50 -mutant glioblastomas receiving temozolomide therapy (cohort A); this result was validated in another cohort of 25 -mutant glioblastomas (cohort B). The median progression-free survival and median overall survival in cohort A were 9.33 and 13.76 months for unmethylated cases, and 18.37 and 41.61 months for methylated cases, and in cohort B were 6.97 and 9.10 months for unmethylated cases, and 23.40 and 26.40 months for methylated cases. In addition, we confirmed that the promoter methylation was significantly ( = 0.0001) correlated with longer OS in -mutant patients with GBM, independently of age, gender distribution, tumor type (primary or recurrent/secondary), and the extent of resection.
promoter methylation has predictive value in -mutant glioblastoma, but its cutoff value should be higher than that for -wildtype glioblastoma.
O6-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）启动子甲基化是广泛用于预测野生型胶质母细胞瘤对替莫唑胺治疗敏感性的生物标志物。鉴于 状态对胶质母细胞瘤的生存和表观遗传特征有重要影响，我们旨在评估 MGMT 启动子甲基化在 突变型胶质母细胞瘤中的作用。
本研究纳入了 187 例 突变型胶质母细胞瘤，并将 173 例 野生型胶质母细胞瘤用于比较。使用 Kaplan-Meier 曲线和多变量 Cox 回归来研究预测效果。
与 野生型胶质母细胞瘤相比， 突变型胶质母细胞瘤的 MGMT 启动子甲基化明显更高（<0.0001）。我们证明，通过焦磷酸测序确定的高截断值（≥30%）的 MGMT 启动子甲基化状态，可以显著分层 50 例接受替莫唑胺治疗的 突变型胶质母细胞瘤的生存情况（队列 A）；这一结果在另一组 25 例 突变型胶质母细胞瘤（队列 B）中得到了验证。在队列 A 中，未甲基化病例的中位无进展生存期和总生存期分别为 9.33 个月和 13.76 个月，甲基化病例分别为 18.37 个月和 41.61 个月；在队列 B 中，未甲基化病例的中位无进展生存期和总生存期分别为 6.97 个月和 9.10 个月，甲基化病例分别为 23.40 个月和 26.40 个月。此外，我们还证实，MGMT 启动子甲基化与 突变型胶质母细胞瘤患者的 OS 显著相关（=0.0001），独立于年龄、性别分布、肿瘤类型（原发性或复发性/继发性）以及切除程度。
MGMT 启动子甲基化在 突变型胶质母细胞瘤中具有预测价值，但其截断值应高于野生型胶质母细胞瘤。
