Development of a gene expression-based prognostic signature for IDH wild-type glioblastoma

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.

Keywords: NanoString; gene expression; glioblastoma; overall survival; prognostic signature.

Fig. 1

Elastic net (EN) penalized Cox proportional hazards regression from ATE datasets. (A) Pearson correlation between z-scored expression of each gene in the signature in the combined ATE dataset; (B, C) Kaplan–Meier plots for overall survival in the biomarker-evaluable population for the EN signature stratified by median, for all ATE cohorts together (B), and per trial (C). P-value corresponds to Cox proportional hazards model.

Fig. 2

Kaplan–Meier plots for overall survival (OS) using the ATE score in the biomarker-evaluable population, stratified by median. (A), ATE score only; (B) adjusted for MGMT promoter methylation status; and (C) adjusted for MGMT promoter methylation status and corticosteroid use at study entry. P-values calculated from log-rank test.

Fig. 3

Kaplan–Meier plots for overall survival (OS) using the ATE score in the biomarker-evaluable population, stratified by median, adjusted for MGMT promoter methylation status when relevant. (A) AVAglio; (B) UCLA; and (C) GLARIUS (which enrolled patients with MGMT promoter non-methylated status only). P-values calculated from log-rank test.

Fig. 4

Forest plots showing multivariate Cox proportional hazard ratios with 95% confidence intervals and P-values for age, sex, surgical status, MGMT promoter methylation status, and ATE score in: (A) ATE, (B) AVAglio, (C) UCLA, and (D) GLARIUS. Corticosteroid use was also included for the ATE and AVAglio cohorts.

Fig. 4

Forest plots showing multivariate Cox proportional hazard ratios with 95% confidence intervals and P-values for age, sex, surgical status, MGMT promoter methylation status, and ATE score in: (A) ATE, (B) AVAglio, (C) UCLA, and (D) GLARIUS. Corticosteroid use was also included for the ATE and AVAglio cohorts.

Fig. 5

(A) ATE score by MGMT promoter methylation status and Phillips subtype in: ATE, AVAglio, UCLA, and GLARIUS; (B) ATE score calculated in individual cells isolated from adult glioblastoma tumors (n = 20) from study GSE131928; (C) hierarchical clustering of average gene expression levels for the 9 ATE signature genes in the 4 cell types identified in study GSE131928. Values indicate fraction of cells with detectable expression.