Background: High-grade gliomas (HGG) occur in any central nervous system (CNS) location and any age. HGGs in teenagers/young adults (TYA) are understudied. This project aimed to characterise these tumours to support accurate patient stratification.
Methods: 207 histone/IDH-wildtype tumours from patients aged 13-30 years were collected. DNA methylation profiling (Illumina EPIC BeadArrays, brain tumour classifier (MNPv12.6 R package)) classified cases against reference cohorts. Calibrated scores guided characterisation workflows (RNA-based ArcherDx fusion panel (n=92), whole exome sequencing (WES) (n=107), histological review).
Results: 53.4% (n=86) matched paediatric-type subgroups (pedHGG_RTK1A/B/C (31.7%, n=51 PDGFRA, CDKN2A/B, SETD2, NF1 alterations), pedHGG_MYCN (8.1%, n=13, MYCN/ID2 amplifications), and pedHGG_RTK2A/B (7.5%, n=12, TP53, BCOR, ATRX, EGFR alterations)). 18.0% (n=29) classified as adult-type subgroups (GBM_MES (15.5%, n=25, RB1, PTEN, NF1 alterations) and GBM_RTK1/2 (2.5%, n=4, CDK4 amplifications)). 23 cases (14.7%) classified as novel, poorly-characterised 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%), GBM_CBM (n=5 3.1%)) with variable histological morphology. 8 cases (5.1%) showed hypermutator phenotypes, enriched in HGG_E, including siblings with constitutional mismatch repair deficiency (CMMRD). TYA HGGs also develop on a background of childhood cancer treatments. Age-distribution comparisons using publicly available methylation/sequencing data (HGG_B (n=19), GBM_CBM (n=35), GBM_MES_ATYP (n=102)), irrespective of age, show HGG_B is TYA-specific (median 29 years) and GBM_CBM and GBM_MES_ATYP show TYA distribution peaks, with GBM_MES_ATYP showing copy number differences and worse survival compared with adult-specific GBM_MES_TYP.
Conclusion: TYA HGGs comprise novel methylation subgroups with distinct molecular profiles. Accurate stratification will open opportunities to utilise more effective treatments.