The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone
The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone
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DOI：
10.1093/neuonc/nou005
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发表时间：
2014-09-01
期刊：
影响因子：
15.9
通讯作者：
Bleeker, Fonnet E.
中科院分区：
文献类型：
--
作者：
Molenaar, Remco J.;Verbaan, Dagmar;Bleeker, Fonnet E.
背景胶质母细胞瘤的遗传和表观遗传分析提供了一个改变的癌症基因的全面列表，其中只有0 -6-甲基鸟嘌呤-甲基转移酶（MGMT）甲基化迄今为止被用作临床环境中的预测标志物。我们研究了胶质母细胞瘤患者的遗传学和表观遗传学改变的预后意义。我们通过PCR和多重连接依赖探针扩增（MLPA）筛选了98例人胶质母细胞瘤样本中10个基因和染色体位点的遗传和表观遗传学改变。我们测试了这些遗传和表观遗传改变与胶质母细胞瘤患者生存率之间的关联。随后，我们开发了一个2基因生存预测。多因素分析显示，异柠檬酸脱氢酶1（IDH 1）突变，MGMT启动子甲基化，照射剂量和Karnofsky体力状态（KFS）是独立的预后因素。生成胶质母细胞瘤存活的2基因预测因子。根据IDH 1和MGMT的遗传和表观遗传状态，胶质母细胞瘤患者分为3种临床不同的基因型：IDH 1 mt/MGMTmet的胶质母细胞瘤患者生存期最长，其次是IDH 1 mt/MGMTunmet或IDH 1 wt/MGMTmet患者，IDH 1 wt/MGMTunmet患者生存期最短。这种2基因预测因子是一个独立的预后因素，在预测生存率方面比单独的IDH 1突变或MGMT甲基化明显更好。该预测模型在3个外部样本中进行了验证。IDH 1突变和MGMT甲基化的组合在预测胶质母细胞瘤患者的存活率方面优于单独的IDH 1突变或MGMT甲基化。这些信息将有助于增加我们对胶质母细胞瘤生物学的理解，并且可能有助于未来临床试验中的基线比较。
Background. Genetic and epigenetic profiling of glioblastomas has provided a comprehensive list of altered cancer genes of which only O-6-methylguanine-methyltransferase (MGMT) methylation is used thus far as a predictive marker in a clinical setting. We investigated the prognostic significance of genetic and epigenetic alterations in glioblastoma patients.Methods. We screened 98 human glioblastoma samples for genetic and epigenetic alterations in 10 genes and chromosomal loci by PCR and multiplex ligation-dependent probe amplification (MLPA). We tested the association between these genetic and epigenetic alterations and glioblastoma patient survival. Subsequently, we developed a 2-gene survival predictor.Results. Multivariate analyses revealed that mutations in isocitrate dehydrogenase 1 (IDH1), promoter methylation of MGMT, irradiation dosage, and Karnofsky Performance Status (KFS) were independent prognostic factors. A 2-gene predictor for glioblastoma survival was generated. Based on the genetic and epigenetic status of IDH1 and MGMT, glioblastoma patients were stratified into 3 clinically different genotypes: glioblastoma patients with IDH1mt/MGMTmet had the longest survival, followed by patients with IDH1mt/MGMTunmet or IDH1wt/MGMTmet, and patients with IDH1wt/MGMTunmet had the shortest survival. This 2-gene predictor was an independent prognostic factor and performed significantly better in predicting survival than either IDH1 mutations or MGMT methylation alone. The predictor was validated in 3 external datasets.Discussion. The combination of IDH1 mutations and MGMT methylation outperforms either IDH1 mutations or MGMT methylation alone in predicting survival of glioblastoma patients. This information will help to increase our understanding of glioblastoma biology, and it may be helpful for baseline comparisons in future clinical trials.