胶质母细胞瘤中高影响 CpG 位点和区域的系统评价 [胶质母细胞瘤中 MGMT 甲基化的系统评价]。
A systematic review of high impact CpG sites and regions for MGMT methylation in glioblastoma [A systematic review of MGMT methylation in GBM].
机构信息
Department of Neuro-Oncology, University of California, San Francisco, 400 Parnassus Ave, San Francisco, CA, USA.
Department of Bioinformatics, University of California, Los Angeles, Los Angeles, CA, USA.
出版信息
BMC Neurol. 2024 Mar 23;24(1):103. doi: 10.1186/s12883-024-03605-3.
BACKGROUND
MGMT (O 6 -methylguanine-DNA methyltransferase) promoter methylation is a commonly assessed prognostic marker in glioblastoma (GBM). Epigenetic silencing of the MGMT gene by promoter methylation is associated with greater overall and progression free survival with alkylating agent regimens. To date, there is marked heterogeneity in how MGMT promoter methylation is tested and which CpG sites are interrogated.
METHODS
To further elucidate which MGMT promoter CpG sites are of greatest interest, we performed comprehensive searches in PubMed, Web of Science, and Embase and reviewed 2,925 article abstracts. We followed the GRADE scoring system to assess risk of bias and the quality of the studies we included.
RESULTS
We included articles on adult glioblastoma that examined significant sites or regions within MGMT promoter for the outcomes: overall survival, progression free survival, and/or MGMT expression. We excluded systemic reviews and articles on lower grade glioma. fifteen articles met inclusion criteria with variable overlap in laboratory and statistical methods employed, as well as CpG sites interrogated. Pyrosequencing or BeadChip arrays were the most popular methods utilized, and CpG sites between CpG's 70-90 were most frequently investigated. Overall, there was moderate concordance between the CpG sites that the studies reported to be highly predictive of prognosis. Combinations or means of sites between CpG's 73-89 were associated with improved OS and PFS. Six studies identified CpG sites associated with prognosis that were closer to the transcription start site: CpG's 8, 19, 22, 25, 27, 32,38, and CpG sites 21-37, as well as low methylation level of the enhancer regions.
CONCLUSION
The following systematic review details a comprehensive investigation of the current literature and highlights several potential key CpG sites that demonstrate significant association with OS, PFS, and MGMT expression. However, the relationship between extent of MGMT promoter methylation and survival may be non-linear and could be influenced by potential CpG hotspots, the extent of methylation at each CpG site, and MGMT enhancer methylation status. There were several limitations within the studies such as smaller sample sizes, variance between methylation testing methods, and differences in the various statistical methods to test for association to outcome. Further studies of high impact CpG sites in MGMT methylation is warranted.
背景
MGMT（O 6 -甲基鸟嘌呤-DNA 甲基转移酶）启动子甲基化是胶质母细胞瘤（GBM）中常用的预后标志物。MGMT 基因启动子甲基化导致基因沉默，与烷化剂治疗方案的总生存期和无进展生存期延长相关。迄今为止，MGMT 启动子甲基化的检测方法以及检测的 CpG 位点存在明显的异质性。
方法
为了进一步阐明哪些 MGMT 启动子 CpG 位点最具意义，我们在 PubMed、Web of Science 和 Embase 中进行了全面检索，并对 2925 篇文章摘要进行了综述。我们采用 GRADE 评分系统评估偏倚风险和纳入研究的质量。
结果
我们纳入了研究成人胶质母细胞瘤的文章，这些文章检查了 MGMT 启动子中与总生存期、无进展生存期和/或 MGMT 表达相关的重要位点或区域。我们排除了系统评价和低级别胶质瘤的文章。15 篇文章符合纳入标准，其使用的实验室和统计方法以及检测的 CpG 位点存在差异。焦磷酸测序或 BeadChip 芯片是最常用的方法，最常研究的 CpG 位点在 CpG 70-90 之间。总体而言，研究报告的与预后高度相关的 CpG 位点之间存在中度一致性。CpG 73-89 之间的位点组合或平均值与 OS 和 PFS 改善相关。六项研究确定了与预后相关的 CpG 位点，这些位点更接近转录起始位点：CpG 8、19、22、25、27、32、38 以及增强子区域的低甲基化水平。
结论
本系统综述详细描述了对当前文献的全面调查，并强调了几个潜在的关键 CpG 位点，这些位点与 OS、PFS 和 MGMT 表达显著相关。然而，MGMT 启动子甲基化程度与生存之间的关系可能是非线性的，并且可能受到潜在 CpG 热点、每个 CpG 位点的甲基化程度以及 MGMT 增强子甲基化状态的影响。研究中存在一些局限性，例如样本量较小、甲基化检测方法的差异以及用于检测与结果关联的各种统计方法的差异。有必要对 MGMT 甲基化中的高影响 CpG 位点进行进一步研究。
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