Landscape of Genomic Alterations in <i>IDH</i> Wild-Type Glioblastoma Identifies PI3K as a Favorable Prognostic Factor.

Abstract

<i>IDH</i> wild-type (WT) glioblastoma (GBM) is an aggressive tumor with poor survival despite current therapies. The aim of this study was to characterize its genomic profile and determine whether a particular molecular signature is associated with improved survival outcomes. Tumor samples from 232 patients with <i>IDH</i>-WT GBM were sequenced, and the landscape of genomic alterations was fully delineated. Genomics data from The Cancer Genome Atlas (TCGA) cohort were analyzed for confirmation. Association of alterations with survival was evaluated in both univariable and multivariable approaches. The genomic landscape of <i>IDH</i>-WT GBM revealed a high frequency of <i>CDKN2A/B</i> loss, <i>TERT</i> promoter mutations, <i>PTEN</i> loss, <i>EGFR</i> alteration, and <i>TP53</i> mutations. Novel variants or gene mutations, such as <i>ARID1B</i> and <i>MLL2</i>, were identified. To better understand synergistic effects and facilitate decision making for precision medicine, we identified 11 pairs of gene alterations that tended to co-occur or were mutually exclusive, which were confirmed in the TCGA cohort. Survival analysis showed that genomic alterations in <i>TP53</i> were associated with worse overall survival (OS). However, alterations in PI3K class I genes were associated with significantly better OS (univariable analysis: <i>P</i> = .002; multivariable analysis: hazard ratio [HR], 0.5785; <i>P</i> = .00162) and longer progression-free survival (univariable analysis: <i>P</i> = .0043; multivariable analysis: HR, 0.6228; <i>P</i> = .00913). Genomic alterations in PI3K class I are a favorable prognostic factor in <i>IDH</i>-WT GBM. This new prognostic biomarker may facilitate risk stratification of patients, assist in clinical trial enrollment, and provide potential therapeutic targets.