Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Neurology, Heidelberg University Hospital, Germany.
Neuro Oncol. 2018 Feb 19;20(3):367-379. doi: 10.1093/neuonc/nox160.
O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status is a predictive biomarker in glioblastoma. We investigated whether this marker furthermore defines a molecularly distinct tumor subtype with clinically different outcome.
We analyzed copy number variation (CNV) and methylation profiles of 1095 primary and 92 progressive isocitrate dehydrogenase wildtype glioblastomas, including paired samples from 49 patients. DNA mutation data from 182 glioblastoma samples of The Cancer Genome Atlas (TCGA) and RNA expression from 107 TCGA and 55 Chinese Glioma Genome Atlas samples were analyzed.
Among untreated glioblastomas, MGMT promoter methylated (mMGMT) and unmethylated (uMGMT) tumors did not show different CNV or specific gene mutations, but a higher mutation count in mMGMT tumors. We identified 3 methylation clusters. Cluster 1 showed the highest average methylation and was enriched for mMGMT tumors. Seventeen genes including gastrulation brain homeobox 2 (GBX2) were found to be hypermethylated and downregulated on the mRNA level in mMGMT tumors. In progressive glioblastomas, platelet derived growth factor receptor alpha (PDGFRA) and GLI2 amplifications were enriched in mMGMT tumors. Methylated MGMT tumors gain PDGFRA amplification of PDGFRA, whereas uMGMT tumors with amplified PDGFRA frequently lose this amplification upon progression. Glioblastoma patients surviving <6 months and with mMGMT harbored less frequent epidermal growth factor receptor (EGFR) amplifications, more frequent TP53 mutations, and a higher tumor necrosis factor-nuclear factor-kappaB (TNF-NFκB) pathway activation compared with patients surviving >12 months.
MGMT promoter methylation status does not define a molecularly distinct glioblastoma subpopulation among untreated tumors. Progressive mMGMT glioblastomas and mMGMT tumors of patients with short survival tend to have more unfavorable molecular profiles.
O6-甲基鸟嘌呤-DNA-甲基转移酶（MGMT）启动子甲基化状态是胶质母细胞瘤的预测性生物标志物。我们研究了该标志物是否还定义了具有临床不同结局的分子上不同的肿瘤亚型。
我们分析了 1095 例原发性和 92 例异柠檬酸脱氢酶野生型胶质母细胞瘤的拷贝数变异（CNV）和甲基化谱，包括 49 例患者的配对样本。分析了来自癌症基因组图谱（TCGA）的 182 例胶质母细胞瘤样本的 DNA 突变数据以及来自 107 例 TCGA 和 55 例中国胶质瘤基因组图谱样本的 RNA 表达数据。
在未经治疗的胶质母细胞瘤中，MGMT 启动子甲基化（mMGMT）和未甲基化（uMGMT）肿瘤没有表现出不同的 CNV 或特定基因突变，但 mMGMT 肿瘤的突变计数更高。我们鉴定了 3 个甲基化簇。簇 1 显示出最高的平均甲基化水平，并富含 mMGMT 肿瘤。在 mMGMT 肿瘤中发现了包括原肠胚形成脑同源框 2（GBX2）在内的 17 个基因被高度甲基化并在 mRNA 水平下调。在进展性胶质母细胞瘤中，血小板衍生生长因子受体 alpha（PDGFRA）和 GLI2 扩增在 mMGMT 肿瘤中富集。甲基化的 MGMT 肿瘤获得 PDGFRA 扩增的 PDGFRA，而 uMGMT 肿瘤中扩增的 PDGFRA 常随着进展而丢失这种扩增。存活时间<6 个月且具有 mMGMT 的胶质母细胞瘤患者中表皮生长因子受体（EGFR）扩增较少，TP53 突变较多，肿瘤坏死因子-核因子-kappaB（TNF-NFκB）通路激活较多存活时间>12 个月的患者。
MGMT 启动子甲基化状态并不能定义未经治疗的肿瘤中分子上不同的胶质母细胞瘤亚群。进展性 mMGMT 胶质母细胞瘤和生存时间较短的 mMGMT 肿瘤倾向于具有更不利的分子谱。
