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@ARTICLE{Goddard:275242,
      author       = {J. Goddard and J. Castle and E. Southworth and A. Fletcher
                      and S. Crosier and I. Martin-Guerrero and M. García-Ariza
                      and A. Navajas and J. Masliah-Planchon and F. Bourdeaut and
                      C. Dufour and O. Ayrault and T. Goschzik and T. Pietsch and
                      M. Sill$^*$ and S. Pfister$^*$ and S. Rutkowski and S.
                      Richardson and R. M. Hill and D. Williamson and S. Bailey
                      and E. C. Schwalbe and S. C. Clifford and D. Hicks},
      title        = {{M}olecular characterisation defines clinically-actionable
                      heterogeneity within {G}roup 4 medulloblastoma and improves
                      disease risk-stratification.},
      journal      = {Acta neuropathologica},
      volume       = {145},
      number       = {5},
      issn         = {0001-6322},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2023-00696},
      pages        = {651-666},
      year         = {2023},
      note         = {2023 May;145(5):651-666},
      abstract     = {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.},
      keywords     = {Biomarkers (Other) / Medulloblastoma (Other) / Paediatric
                      Oncology (Other) / Risk-stratification (Other)},
      cin          = {B062 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)HD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37014508},
      doi          = {10.1007/s00401-023-02566-0},
      url          = {https://inrepo02.dkfz.de/record/275242},
}