%0 Journal Article
%A Goddard, Jack
%A Castle, Jemma
%A Southworth, Emily
%A Fletcher, Anya
%A Crosier, Stephen
%A Martin-Guerrero, Idoia
%A García-Ariza, Miguel
%A Navajas, Aurora
%A Masliah-Planchon, Julien
%A Bourdeaut, Franck
%A Dufour, Christelle
%A Ayrault, Olivier
%A Goschzik, Tobias
%A Pietsch, Torsten
%A Sill, Martin
%A Pfister, Stefan
%A Rutkowski, Stefan
%A Richardson, Stacey
%A Hill, Rebecca M
%A Williamson, Daniel
%A Bailey, Simon
%A Schwalbe, Edward C
%A Clifford, Steven C
%A Hicks, Debbie
%T Molecular characterisation defines clinically-actionable heterogeneity within Group 4 medulloblastoma and improves disease risk-stratification.
%J Acta neuropathologica
%V 145
%N 5
%@ 0001-6322
%C Heidelberg
%I Springer
%M DKFZ-2023-00696
%P 651-666
%D 2023
%Z 2023 May;145(5):651-666
%X 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
%K Biomarkers (Other)
%K Medulloblastoma (Other)
%K Paediatric Oncology (Other)
%K Risk-stratification (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:37014508
%R 10.1007/s00401-023-02566-0
%U https://inrepo02.dkfz.de/record/275242