PTHP-13. Clinical and molecular features of IDH- and H3-wildtype high-grade glioma groups in adolescent and young adult (AYA) patients

Abstract High-grade gliomas (HGG) present a molecularly diverse group of aggressive tumors occurring in patients of any age, and are particularly understudied in adolescents and young adult patients (AYAs) aged 15-39 years. Previous studies have indicated that the more recently DNA methylation-defined subgroup of pediatric-type HGG, H3-/IDH-wildtype (pedHGG, H3-/IDH-wildtype), is more prevalent in AYAs than in children, whereas glioblastoma, IDH-wildtype (GBM), is relatively rare in AYAs. However, the molecular-pathological landscapes of pedHGG, H3-/IDH-wildtype, and in particular whether these are linked to distinct clinical features and outcomes, remain poorly understood. In this monocentric study, we retrospectively analyzed a cohort of n=165 AYA patients with a suspected diagnosis of HGG, treated at our institution between 2000 and 2025. Molecular classification into pedHGG, H3-/IDH-wildtype, and GBM, was confirmed in n=30 and n=43 cases, respectively, by genome-wide DNA methylation profiling. Furthermore, we identified an additional n=20 pedHGG, H3-/IDH-wildtype, in younger pediatric and older adult patients, and contrasted these with their AYA counterparts as well as n=20 age-matched GBM. Targeted exome-sequencing was performed for n=50 tumors. A comprehensive clinical assessment was performed for n=100 patients where clinical data was available. Our preliminary analyses of n=14 pedHGG, H3-/IDH-wildtype, and n=25 GBM in the AYA population show comparable clinical outcomes between the two molecular subgroups. Median progression-free survivals were 14.3 and 9.2 months in pedHGG H3-/IDH-wildtype, and GBM, respectively. Ongoing analyses include assessment of genetic alterations, as well as clinical endpoints including overall survival, radiological features, symptom burden, seizure frequency, tumor therapy and associated adverse events. Our work provides deeper insights into the potentially distinct clinical consequences of different molecular glioma groups in AYA patients.