Molecular analysis of adolescent and young adult high grade gliomas in the SPECTA-AYA study: Poorly characterised tumours with frequent germline alterations
- PMID: 40393126
- DOI: 10.1016/j.ejca.2025.115493
Molecular analysis of adolescent and young adult high grade gliomas in the SPECTA-AYA study: Poorly characterised tumours with frequent germline alterations
Abstract
Background: Adolescent and young adult (AYA) high grade gliomas (HGG) have the worst survival of AYA malignancies yet are poorly represented in large-scale molecular datasets.
Methods: 50 AYAs aged 12-29 with newly diagnosed or recurrent HGG and other high risk central nervous system (CNS) tumours were prospectively recruited to the EORTC SPECTA platform study and underwent whole exome sequencing, RNA sequencing and methylation profiling, with central pathological review. Actionable mutations were reported and patients followed up for therapies and outcome.
Results: From 46 locally diagnosed HGGs and 4 other recurrent CNS tumours, molecular and pathology review resulted in histological grade re-classification (n = 10), diagnostic refinement (n = 9) and revised diagnoses (n = 12) in a substantial proportion. Pathogenic constitutional alterations were present in 14 % overall and were largely limited to cases with IDH-wildtype glioblastoma and paediatric-type diffuse HGGs. 91 % of HGGs had potentially actionable alterations affecting RAS/RAF/MAPK (60 %), PI3K/AKT/mTOR (27 %) and cell cycle genes (11 %). High tumour mutational burden (> 10 somatic non-synonymous mutations per Mb of genome targeted) was present in 12 % at diagnosis and 18 % at recurrence, all in histological grade 4 tumours. Ten patients' treatment was modified on the basis of molecular profile, of whom 5 remained on treatment at last follow-up.
Conclusion: AYA HGGs comprise a diverse group of entities; accurate, molecularly-defined diagnosis is critical to direct primary treatment, determine risk of genetic predisposition and guide molecularly-directed therapy. Current services fail to routinely address diagnosis, personalised molecular profiling or investigation of therapeutic opportunities for this high risk, poor prognosis group of rare cancer patients.
Keywords: AYA; Actionable alterations; Adolescent; Constitutional mutations; High grade glioma; Young adult.
Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.
Conflict of interest statement
Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:The following authors have declarations of interest: MGM: Advisory board (Amgen). Trial funding to another institution (Eisai). FB: a next-of-kin employed by Bristol Myers-Squibb. SMP: Co-founder and shareholder Heidelberg Epignostix GmbH, Advisory Board (Bioskryb). DTWJ: Co-founder and shareholder Heidelberg GmbH, advisory board (Day One Biopharmaceuticals). ER: Advisory board (AstraZeneca, Novartis, Servier). Conference attendance support (MSD, AstraZeneca, Gilead, BMS, Servier, Roche). MP: honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals, Janssen, Servier, Miltenyi, Böhringer-Ingelheim, Telix, Medscape, OncLive. MS: Advisory board (Genenta) and fees (Servier, Novocure). All other authors have no interests to declare.