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Molecular characterisation defines clinically-actionable heterogeneity within Group 4 medulloblastoma and improves disease risk-stratification

Lookup NU author(s): Dr Jack GoddardORCiD, Jemma Castle, Emily Southworth, Anya Fletcher, Dr Stephen Crosier, Dr Stacey Richardson, Dr Rebecca Hill, Dr Daniel Williamson, Professor Simon BaileyORCiD, Dr Ed Schwalbe, Professor Steven CliffordORCiD, Dr Debbie Hicks



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2023, The Author(s).Group 4 tumours (MBGrp4) represent the majority of non-WNT/non-SHH medulloblastomas. Their clinical course is poorly predicted by current risk-factors. MBGrp4 molecular substructures have been identified (e.g. subgroups/cytogenetics/mutations), however their inter-relationships and potential to improve clinical sub-classification and risk-stratification remain undefined. We comprehensively characterised the paediatric MBGrp4 molecular landscape and determined its utility to improve clinical management. A clinically-annotated discovery cohort (n = 362 MBGrp4) was assembled from UK-CCLG institutions and SIOP-UKCCSG-PNET3, HIT-SIOP-PNET4 and PNET HR + 5 clinical trials. Molecular profiling was undertaken, integrating driver mutations, second-generation non-WNT/non-SHH subgroups (1–8) and whole-chromosome aberrations (WCAs). Survival models were derived for patients ≥ 3 years of age who received contemporary multi-modal therapies (n = 323). We first independently derived and validated a favourable-risk WCA group (WCA-FR) characterised by ≥ 2 features from chromosome 7 gain, 8 loss, and 11 loss. Remaining patients were high-risk (WCA-HR). Subgroups 6 and 7 were enriched for WCA-FR (p < 0·0001) and aneuploidy. Subgroup 8 was defined by predominantly balanced genomes with isolated isochromosome 17q (p < 0·0001). While no mutations were associated with outcome and overall mutational burden was low, WCA-HR harboured recurrent chromatin remodelling mutations (p = 0·007). Integration of methylation and WCA groups improved risk-stratification models and outperformed established prognostication schemes. Our MBGrp4 risk-stratification scheme defines: favourable-risk (non-metastatic disease and (i) subgroup 7 or (ii) WCA-FR (21% of patients, 5-year PFS 97%)), very-high-risk (metastatic disease with WCA-HR (36%, 5-year PFS 49%)) and high-risk (remaining patients; 43%, 5-year PFS 67%). These findings validated in an independent MBGrp4 cohort (n = 668). Importantly, our findings demonstrate that previously established disease-wide risk-features (i.e. LCA histology and MYC(N) amplification) have little prognostic relevance in MBGrp4 disease. Novel validated survival models, integrating clinical features, methylation and WCA groups, improve outcome prediction and re-define risk-status for ~ 80% of MBGrp4. Our MBGrp4 favourable-risk group has MBWNT-like excellent outcomes, thereby doubling the proportion of medulloblastoma patients who could benefit from therapy de-escalation approaches, aimed at reducing treatment induced late-effects while sustaining survival outcomes. Novel approaches are urgently required for the very-high-risk patients.

Publication metadata

Author(s): Goddard J, Castle J, Southworth E, Fletcher A, Crosier S, Martin-Guerrero I, Garcia-Ariza M, Navajas A, Masliah-Planchon J, Bourdeaut F, Dufour C, Ayrault O, Goschzik T, Pietsch T, Sill M, Pfister SM, Rutkowski S, Richardson S, Hill RM, Williamson D, Bailey S, Schwalbe EC, Clifford SC, Hicks D

Publication type: Article

Publication status: Published

Journal: Acta Neuropathologica

Year: 2023

Volume: 145

Pages: 651–666

Print publication date: 01/05/2023

Online publication date: 04/04/2023

Acceptance date: 17/03/2023

Date deposited: 27/04/2023

ISSN (print): 0001-6322

ISSN (electronic): 1432-0533

Publisher: Springer Science and Business Media Deutschland GmbH


DOI: 10.1007/s00401-023-02566-0


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