Development of a gene expression-based prognostic signature for IDH wild-type glioblastoma
Development of a gene expression-based prognostic signature for IDH wild-type glioblastoma
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DOI：
10.1093/neuonc/noaa157
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发表时间：
2020-12-01
期刊：
影响因子：
15.9
通讯作者：
Garcia, Josep
中科院分区：
文献类型：
--
作者：
Johnson, Radia M.;Phillips, Heidi S.;Garcia, Josep
背景。我们的目的是使用代表胶质母细胞瘤临床试验人群的临床试验数据集，为异柠檬酸脱氢酶（IDH）野生型胶质母细胞瘤开发基于基因表达的预后特征。方法。样本采集自 ARTE、TAMIGA、EORTC 26101（称为“ATE”）、AVAglio 和 GLARIUS 试验中或在 UCLA 接受治疗的新诊断 IDH 野生型胶质母细胞瘤患者。转录分析是通过 NanoString 基因表达平台实现的。为了识别对总体生存 (OS) 具有预测作用的基因，我们使用 discovery ATE 数据集构建了弹性净惩罚 Cox 比例风险回归模型。为了在独立数据集（AVAglio、GLARIUS、UCLA）中进行验证，我们将弹性网络选择的基因组合成强大的 z 分数特征（ATE 分数），以克服发现和验证队列之间的基因表达平台差异。结果。 NanoString 数据来自 ATE 数据集中的 512 名患者。 Elastic net 鉴定了 9 个基因（CHEK1、GPR17、IGF2BP3、MGMT、MTHFD1L、PTRH2、SOX11、S100A9 和 TFRC）的预后特征。将加权弹性净得分转化为 ATE 得分保留了基因的预后价值。正如预期的那样，ATE 数据集 (P < 0.0001) 和验证队列 (AVAglio，P < 0.0001；GLARIUS，P = 0.02；UCLA，P = 0.004) 中的 ATE 评分可预测 OS。在调整 O6-甲基鸟嘌呤-DNA 甲基转移酶 (MGMT) 启动子甲基化状态和基线皮质类固醇使用后，ATE 评分仍然具有预后意义。在 MGMT 非甲基化启动子状态的患者中观察到 ATE 评分与原神经/增殖亚型之间呈正相关。结论。 ATE 评分显示出预后价值，并可能使 IDH 野生型胶质母细胞瘤的临床试验分层成为可能。
Background. We aimed to develop a gene expression-based prognostic signature for isocitrate dehydrogenase (IDH) wild-type glioblastoma using clinical trial datasets representative of glioblastoma clinical trial populations.Methods. Samples were collected from newly diagnosed patients with IDH wild-type glioblastoma in the ARTE, TAMIGA, EORTC 26101 (referred to as "ATE"), AVAglio, and GLARIUS trials, or treated at UCLA. Transcriptional profiling was achieved with the NanoString gene expression platform.To identify genes prognostic for overall survival (OS), we built an elastic net penalized Cox proportional hazards regression model using the discovery ATE dataset. For validation in independent datasets (AVAglio, GLARIUS, UCLA), we combined elastic net-selected genes into a robust z-score signature (ATE score) to overcome gene expression platform differences between discovery and validation cohorts.Results. NanoString data were available from 512 patients in the ATE dataset. Elastic net identified a prognostic signature of 9 genes (CHEK1, GPR17, IGF2BP3, MGMT, MTHFD1L, PTRH2, SOX11, S100A9, and TFRC). Translating weighted elastic net scores to the ATE score conserved the prognostic value of the genes. The ATE score was prognostic for OS in the ATE dataset (P < 0.0001), as expected, and in the validation cohorts (AVAglio, P < 0.0001; GLARIUS, P = 0.02; UCLA, P = 0.004). The ATE score remained prognostic following adjustment for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and corticosteroid use at baseline. A positive correlation between ATE score and proneural/proliferative subtypes was observed in patients with MGMT non-methylated promoter status.Conclusions. The ATE score showed prognostic value and may enable clinical trial stratification for IDH wild-type glioblastoma.