Redefining Treatment Paradigms for Glioma in Adolescents and Young Adults: Population-Based Evidence for Molecular Classification.

Abstract

Gliomas represent the second most common malignancy and leading cause of cancer death in adolescents and young adults (AYA; ages 15-39 years), yet their molecular landscape remains incompletely characterized. This study aims to characterize the molecular landscape of primary gliomas in AYAs by integrating multi-omics data. We recruited a cohort of patients with histopathologically diagnosed primary gliomas. The data encompassed clinical, imaging, histopathologic, genomic testing, and survival outcome data. The correlations of clinicopathologic features, molecular characteristics, and anatomic heterogeneity with prognosis were evaluated. Adult-type gliomas (66.2%) predominated, but pediatric-type gliomas constituted 23.6%, exhibiting distinct clinicopathologic profiles: pediatric-type tumors harbored frequent H3.3 (51.9%), TP53 (35.1%), and BRAF mutations (22.8%), whereas adult-type showed isocitrate dehydrogenase (IDH, 72.5%) and TP53 alterations (48.6%). IDH and H3.3/BRAF mutations were mutually exclusive. Anatomically, midline involvement (18.3%) correlated with younger age (≤25 years, P = 0.019), frontal gliomas were predominantly IDH mutations (58.3%), and midline tumors were enriched H3.3 K27M mutations (52.5%). Survival analysis revealed that H3.3 K27M-mutant high-grade gliomas had the poorest prognosis (median survival: 16 months), whereas BRAF-driven low-grade gliomas showed favorable outcomes. Pediatric-type molecular alterations are enriched in AYA gliomas. IDH wild-type tumors require sequencing to detect pediatric-type drivers (e.g., H3.3/BRAF mutations). The treatment strategies for AYA gliomas should be determined by molecular classification rather than age-based stratification. Adult-type and pediatric-type gliomas exhibit distinct biological and driver profiles. AYA gliomas exhibit significant molecular-anatomic heterogeneity, with specific anatomic regions demonstrating enrichment of molecular signatures.