Abstract

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.

中文翻译：

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开发基于基因表达的 IDH 野生型胶质母细胞瘤预后特征。

摘要

背景

我们旨在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

样本是从ARTE、TAMIGA、EORTC 26101（简称“ATE”）、AVAglio 和 GLARIUS 试验中新诊断的IDH野生型胶质母细胞瘤患者中收集的，或在加州大学洛杉矶分校接受治疗。NanoString 基因表达平台实现了转录分析。为了确定总体生存 (OS) 预后的基因，我们使用发现 ATE 数据集构建了弹性网络惩罚 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一个强大的z分数签名（ATE 分数），以克服发现和验证群组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 确定了 9 个基因（CHEK1、GPR17、IGF2BP3、MGMT、MTHFD1L、PTRH2、SOX11、S100A9和TFRC）的预后特征。将加权弹性净分数转换为 ATE 分数保留了基因的预后价值。 正如预期的那样，ATE 评分在 ATE 数据集（P < 0.0001）和验证队列（AVAglio，P  < 0.0001；GLARIUS，P =  0.02；UCLA，P =  0.004）中是 OS 的预后指标。在调整 O ^{6 -}甲基鸟嘌呤 - DNA 甲基转移酶 ( MGMT) 后，ATE 评分仍然具有预后意义) 启动子甲基化状态和基线皮质类固醇使用。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 评分显示了预后价值，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。