Precision Prognostication in Adult-Type Diffuse Gliomas through Multi-Cohort Validation of Key Genomic Alterations

Background Despite advances in molecular classification of adult-type diffuse gliomas, limited data exist on the prognostic implications of specific genetic alterations. We integrated molecular profiles of adult-type diffuse glioma subtypes in a multicenter cohort and examined the prognostic significance, especially in glioblastoma, IDH -wildtype. Methods After analyzing 470 primary adult-type diffuse gliomas using next-generation sequencing, multivariable Cox regression and Kaplan–Meier survival analyses were performed. Associations between molecular profiles and overall survival were independently validated using 840 cases of primary glioblastoma, IDH -wildtype, from four external cohorts: CPTAC, GLASS, MSKCC, and TCGA. Results Distinct genetic landscapes were identified in oligodendroglioma, IDH-mutant, 1p/19q co-deleted, astrocytoma, IDH -mutant, and glioblastoma, IDH -wildtype. In glioblastoma, PIK3R1 mutation (hazard ratio [HR] = 1.53, 95% confidence interval [CI] 1.06–2.20; P  = 0.022), CDKN2A/B deletion (1.41 [1.09–1.83]; P  = 0.009), and MET amplification (2.78 [1.40–5.51]; P  = 0.003) were significant prognostic markers, along with negative O6-methylguanine-DNA methyltransferase promoter methylation status (1.51 [1.14–2.00]; P  = 0.004). External validation confirmed the prognostic impact of PIK3R1 in CPTAC (HR [95% CI] = 3.72 [1.44–9.58]; P  = 0.007) and MET amplification in MSKCC (2.74 [1.12–6.68]; P  = 0.027); CDKN2A/B showed cohort-specific effects. Tumor mutational burden lacked prognostic significance across all cohorts. Although 45.4% of glioblastomas exhibited MTAP deletion, no significant association with overall survival was detected. Conclusions CDKN2A/B deletion, MET amplification, and PIK3R1 mutation were identified as independent markers of poor prognosis in glioblastoma, potentially enabling molecular-based risk stratification.