Pediatric H3 K27-altered diffuse midline gliomas may consist of two clinically relevant subsets based on patient age and molecular genetic profile.

Background: Diffuse midline gliomas, H3 K27-altered (DMG), are rare CNS WHO grade 4 tumors characterized by the global loss of K27me3 on histone H3. DMGs cannot be safely resected and are associated with poor outcomes in children, though relatively few DMGs have undergone extensive molecular and clinical profiling. Herein, we describe the clinical and molecular profiles of 36 pediatric DMGs as they relate to patient outcomes. Methods: Pediatric patients (<18 y/o) between 2015 and 2024 with biopsy-proven DMGs and next-generation sequencing (NGS) panels of 86 hotspot genes were reviewed for clinicopathologic characteristics and survival outcomes. Gene Ontology (GO) enrichment analysis was performed. Progression-free survival (PFS) and overall survival (OS) were calculated according to the Kaplan-Meier method. Multivariate Cox regression analysis was performed. Results: Thirty-six patients were included (median age = 9 y/o). Patients <10 y/o at diagnosis (n = 24) progressed significantly earlier and experienced significantly greater mortality than patients ≥10 y/o at diagnosis (n = 11); PFS and OS at 12 months were 9.0% and 26% for <10 y/o and 36% and 64% for ≥10 y/o (PFS: P ≤ .03, OS: P < .03). NGS findings revealed PIK3CA mutations occurred only in patients <10 y/o (10/25), and GO analysis revealed patients <10 y/o were significantly more enriched for PI3K/AKT signaling pathway alterations than patients ≥10 y/o (P ≤ .03). Conclusion: We present findings that suggest "adolescent" DMGs carry more favorable prognosis and are molecularly distinct from earlier onset pediatric DMGs. These findings have implications in the design and interpretation of clinical trials, in addition to informing clinical practice.