The Spectrum of IDH- and H3-Wildtype High-Grade Glioma Subgroups Occurring across Teenage and Young Adult Patient Populations.

PURPOSE: High-grade gliomas (HGG) occur in any central nervous system location and at any age. HGGs in teenagers/young adults (TYA) are understudied. This project aimed to characterize these tumors to support accurate stratification of patients. EXPERIMENTAL DESIGN: 207 histone/IDH wild-type tumors from patients aged 13 to 30 years were collected. DNA methylation profiling [Illumina EPIC BeadArrays, brain tumor classifier (MNPv12.8 R package)] classified cases against reference cohorts of HGG. Calibrated scores guided characterization workflows [RNA-based ArcherDx fusion panel (n = 92), whole-exome sequencing (n = 107), and histology review). RESULTS: 53.4% (n = 86) matched as pediatric-type subgroups [pedHGG_RTK1A/B/C (31.7%, n = 51, PDGFRA, CDKN2A/B, SETD2, and NF1 alterations), pedHGG_MYCN (8.1%, n = 13, MYCN/ID2 amplifications), and pedHGG_RTK2A/B (7.5%, n = 12, TP53, BCOR, ATRX, and EGFR alterations)]. Eighteen percent (n = 29) classified as adult-type subgroups [GBM_MES (15.5%, n = 25, enriched for RB1, PTEN, and NF1 alterations) and GBM_RTK1/2 (2.5%, n = 4, CDK4 amplifications)]. Twenty-three cases (14.7%) classified as novel, poorly characterized subgroups with distinct methylation profiles and molecular features [pedHGG_A/B (n = 10 6.2%), HGG_E (n = 6 3.7%), HGG_B (n = 2 1.0%), and GBM_CBM (n = 5 3.1%)] with variable histologic morphology. Eight cases (5.1%) showed hypermutator phenotypes, enriched in HGG_E, one of which was associated with constitutional mismatch repair deficiency, and their sibling, who was diagnosed with the same syndrome, was diagnosed with a tumor that classified as a pedHGG_RTK1B. HGGs that have developed on a background of previous treatment for a childhood cancer are detected in the TYA population, classifying most frequently as pedHGG_RTK1 and contributing to the poor prognosis of this subgroup. Age distribution/molecular profile comparisons using publicly available methylation/sequencing data (and from local diagnostic cohorts) for HGG_B (n = 19), GBM_CBM (n = 35), and ...