The spectrum of IDH- and H3-wildtype high-grade glioma subgroups occurring across teenage and young adult patient populations

Abstract

Background: high-grade gliomas (HGG) occur in any central nervous system (CNS) location and at any age. HGGs in teenagers/young adults (TYA) are understudied. This project aimed to characterise these tumours to support accurate stratification of patients.

Methods: 207 histone/IDH-wildtype tumours from patients aged 13–30 years were collected. DNA methylation profiling (Illumina EPIC BeadArrays, brain tumour classifier (MNPv12.8 R package)) classified cases against reference cohorts of HGG. 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 as 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, enriched for 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, one of which was associated with constitutional mismatch repair deficiency (CMMRD), and their sibling who was diagnosed with the same syndrome, was diagnosed with a tumour which classified as a pedHGG_RTK1B. HGGs which have developed on a background of previous treatment for a childhood cancer are detected in the TYA population, classifying most frequently as pedHGG_RTK1B, 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 GBM_MES_ATYP (n=102), irrespective of age, show that HGG_B is a TYA-specific subgroup (median age 29 years) and that GBM_CBM and GBM_MES_ATYP show a peak of distribution in the TYA population, but also have a wider age distribution (median age 35.7 and 50.5 years respectively) with the latter showing distinct differences in copy number profiles compared to older adults in the same subgroup, and containing fewer chr7 gains, chr10 losses, more CDKN2A/B deletions and MET amplifications, and a worse survival compared with adult-specific GBM_MES_TYP.

Conclusion: 158 TYA HGGs comprise novel methylation subgroups with distinct methylation and molecular profiles. Accurate stratification of these patients will open opportunities to more effective treatments including immune check point, MAPK-pathway and PDGFRA inhibitors.

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Identifiers

ORCID for J. Nicoll: orcid.org/0000-0002-9444-7246

ORCID for D. Boche: orcid.org/0000-0002-5884-130X

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