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| Home > Publications database > Molecular characterisation defines clinically-actionable heterogeneity within Group 4 medulloblastoma and improves disease risk-stratification. > print |
| 001 | 275242 | ||
| 005 | 20240229154938.0 | ||
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| 100 | 1 | _ | |a Goddard, Jack |b 0 |
| 245 | _ | _ | |a Molecular characterisation defines clinically-actionable heterogeneity within Group 4 medulloblastoma and improves disease risk-stratification. |
| 260 | _ | _ | |a Heidelberg |c 2023 |b Springer |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1682340755_14651 |2 PUB:(DE-HGF) |
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| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 500 | _ | _ | |a 2023 May;145(5):651-666 |
| 520 | _ | _ | |a 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. |
| 536 | _ | _ | |a 312 - Funktionelle und strukturelle Genomforschung (POF4-312) |0 G:(DE-HGF)POF4-312 |c POF4-312 |f POF IV |x 0 |
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| 650 | _ | 7 | |a Biomarkers |2 Other |
| 650 | _ | 7 | |a Medulloblastoma |2 Other |
| 650 | _ | 7 | |a Paediatric Oncology |2 Other |
| 650 | _ | 7 | |a Risk-stratification |2 Other |
| 700 | 1 | _ | |a Castle, Jemma |b 1 |
| 700 | 1 | _ | |a Southworth, Emily |b 2 |
| 700 | 1 | _ | |a Fletcher, Anya |b 3 |
| 700 | 1 | _ | |a Crosier, Stephen |b 4 |
| 700 | 1 | _ | |a Martin-Guerrero, Idoia |b 5 |
| 700 | 1 | _ | |a García-Ariza, Miguel |b 6 |
| 700 | 1 | _ | |a Navajas, Aurora |b 7 |
| 700 | 1 | _ | |a Masliah-Planchon, Julien |b 8 |
| 700 | 1 | _ | |a Bourdeaut, Franck |b 9 |
| 700 | 1 | _ | |a Dufour, Christelle |b 10 |
| 700 | 1 | _ | |a Ayrault, Olivier |b 11 |
| 700 | 1 | _ | |a Goschzik, Tobias |b 12 |
| 700 | 1 | _ | |a Pietsch, Torsten |b 13 |
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| 700 | 1 | _ | |a Rutkowski, Stefan |b 16 |
| 700 | 1 | _ | |a Richardson, Stacey |b 17 |
| 700 | 1 | _ | |a Hill, Rebecca M |b 18 |
| 700 | 1 | _ | |a Williamson, Daniel |b 19 |
| 700 | 1 | _ | |a Bailey, Simon |b 20 |
| 700 | 1 | _ | |a Schwalbe, Edward C |b 21 |
| 700 | 1 | _ | |a Clifford, Steven C |0 0000-0002-8573-8009 |b 22 |
| 700 | 1 | _ | |a Hicks, Debbie |b 23 |
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