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Background  Recent studies have identified that glioblastoma IDH-wildtype (GBM IDH-WT) might be comprised of molecular subgroups with distinct prognoses. Therefore, we investigated the correlation between genetic alterations and survival in 282 GBM IDH-WT patients, to identify subgroups with distinct outcomes.    Methods  We reviewed characteristics of GBM IDH-WT (2009–2019) patients analyzed by next-generation sequencing interrogating 205 genes and 26 rearrangements. Progression-free survival (PFS) and overall survival (OS) were evaluated with the log-rank test and Cox regression models. We validated our results utilizing data from cBioPortal (MSK-IMPACT dataset).    Results  Multivariable analysis of GBM IDH-WT revealed that treatment with chemoradiation and  RB1- mutant status correlated with improved PFS (hazard ratio [HR] 0.25,  P  < .001 and HR 0.47,  P  = .002) and OS (HR 0.24,  P  < .001 and HR 0.49,  P  = .016). In addition, younger age (<55 years) was associated with improved OS. Karnofsky performance status less than 80 (HR 1.44,  P  = .024) and  KDR  amplification (HR 2.51,  P  = .008) were predictors of worse OS.  KDR- amplified patients harbored coexisting  PDGFRA  and  KIT  amplification ( P  < .001) and  TP53  mutations ( P  = .04).  RB1- mutant patients had less frequent  CDKN2A/B  and  EGFR  alterations ( P  < .001). Conversely,  RB1- mutant patients had more frequent  TP53  ( P  < .001) and  SETD2  ( P  = .006) mutations. Analysis of the MSK-IMPACT dataset ( n  = 551) validated the association between  RB1  mutations and improved PFS (11.0 vs 8.7 months,  P =  .009) and OS (34.7 vs 21.7 months,  P =  .016).    Conclusions    RB1 -mutant GBM IDH-WT is a molecular subgroup with improved PFS and OS. Meanwhile, 4q12 amplification ( KDR/PDGFRA/KIT)  denoted patients with worse OS. Identifying subgroups of GBM IDH-WT with distinct survival is important for optimal clinical trial design, incorporation of targeted therapies, and personalized neuro-oncological care.

The role of RB1 alteration and 4q12 amplification in IDH-WT glioblastoma