TY  - JOUR
AU  - Goddard, Jack
AU  - Castle, Jemma
AU  - Southworth, Emily
AU  - Fletcher, Anya
AU  - Crosier, Stephen
AU  - Martin-Guerrero, Idoia
AU  - García-Ariza, Miguel
AU  - Navajas, Aurora
AU  - Masliah-Planchon, Julien
AU  - Bourdeaut, Franck
AU  - Dufour, Christelle
AU  - Ayrault, Olivier
AU  - Goschzik, Tobias
AU  - Pietsch, Torsten
AU  - Sill, Martin
AU  - Pfister, Stefan
AU  - Rutkowski, Stefan
AU  - Richardson, Stacey
AU  - Hill, Rebecca M
AU  - Williamson, Daniel
AU  - Bailey, Simon
AU  - Schwalbe, Edward C
AU  - Clifford, Steven C
AU  - Hicks, Debbie
TI  - Molecular characterisation defines clinically-actionable heterogeneity within Group 4 medulloblastoma and improves disease risk-stratification.
JO  - Acta neuropathologica
VL  - 145
IS  - 5
SN  - 0001-6322
CY  - Heidelberg
PB  - Springer
M1  - DKFZ-2023-00696
SP  - 651-666
PY  - 2023
N1  - 2023 May;145(5):651-666
AB  - 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
KW  - Biomarkers (Other)
KW  - Medulloblastoma (Other)
KW  - Paediatric Oncology (Other)
KW  - Risk-stratification (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37014508
DO  - DOI:10.1007/s00401-023-02566-0
UR  - https://inrepo02.dkfz.de/record/275242
ER  -