Abstract INTRODUCTION 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 was 9.0% and 26% for 10 y/o and 36% and 64% for ≥10 y/o (PFS: p ≤ 0.03, OS: p 0.03). 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 ≤ 0.03). 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.
Yang et al. (Tue,) studied this question.