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

Group 4 tumours (MB Grp4 ) represent the majority of non-WNT/non-SHH medulloblastomas. Their clinical course is poorly predicted by current risk-factors. MB Grp4 molecular substructures have been identified (e.g. subgroups/cytogenetics/mutations), however their inter-relationships and potential to i...

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Bibliographic Details
Published in:Acta neuropathologica 2023-05, Vol.145 (5), p.651-666
Main Authors: Goddard, Jack, Castle, Jemma, Southworth, Emily, Fletcher, Anya, Crosier, Stephen, Martin-Guerrero, Idoia, García-Ariza, Miguel, Navajas, Aurora, Masliah-Planchon, Julien, Bourdeaut, Franck, Dufour, Christelle, Ayrault, Olivier, Goschzik, Tobias, Pietsch, Torsten, Sill, Martin, Pfister, Stefan M., Rutkowski, Stefan, Richardson, Stacey, Hill, Rebecca M., Williamson, Daniel, Bailey, Simon, Schwalbe, Edward C., Clifford, Steven C., Hicks, Debbie
Format: Article
Language:English
Subjects:
Aneuploidy
Cerebellar Neoplasms - pathology
Child
Chromatin
Chromatin remodeling
Chromosome 7
Chromosome Aberrations
Clinical trials
Cytogenetics
Genomes
Humans
Life Sciences
Medical research
Medicine
Medicine & Public Health
Medicine, Experimental
Medulloblastoma
Medulloblastoma - pathology
Metastases
Metastasis
Methylation
Mutation
Mutation - genetics
Myc protein
Neurosciences
Original Paper
Pathology
Patients
Prognosis
Risk Factors
Risk groups
Survival
Wnt protein
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Summary:Group 4 tumours (MB Grp4 ) represent the majority of non-WNT/non-SHH medulloblastomas. Their clinical course is poorly predicted by current risk-factors. MB Grp4 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 MB Grp4 molecular landscape and determined its utility to improve clinical management. A clinically-annotated discovery cohort (n = 362 MB Grp4 ) 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 
ISSN:0001-6322
1432-0533
DOI:10.1007/s00401-023-02566-0