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

IF 10 1区医学 Q1 ONCOLOGY

Clinical Cancer Research Pub Date : 2025-03-10 DOI:10.1158/1078-0432.ccr-24-1256

Rita Pereira, Alan Mackay, Yura Grabovska, Amelia Bradley, Tabitha Bloom, James Nicoll, Delphine Boche, John Procter, Mellissa Maybury, Johanna Schagen, Liam Walker, Federico Roncaroli, Konstantina Karabatsou, Olumide Ogunbiyi, Thijs van Dalen, Jai Sidpra, Sabrina Rossi, Evelina Miele, David S. Ziegler, Zhifeng Shi, Thomas S. Jacques, Darren Hargrave, Bassel Zebian, Cristina Bleil, Joseph Yates, Emma Norton, Henry Mandeville, Antonia Creak, Liam Welsh, Lynley Marshall, Fernando Carceller, Sucheta J. Vaidya, Zita Reisz, Safa Al-Sarraj, Angela Mastronuzzi, Andrea Carai, Maria Vinci, Kathreena M. Kurian, Ho-keung Ng, Sebastian Brandner, Chris Jones, Matthew Clarke

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引用次数: 0

Abstract

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.

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来源期刊

Clinical Cancer Research 医学-肿瘤学

CiteScore

20.10

自引率

1.70%

发文量

1207

审稿时长

2.1 months

期刊介绍： Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.