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@ARTICLE{Sharma:143580,
      author       = {T. Sharma$^*$ and E. C. Schwalbe and D. Williamson and M.
                      Sill$^*$ and V. Hovestadt and M. Mynarek and S. Rutkowski
                      and G. W. Robinson and A. Gajjar and F. Cavalli and V.
                      Ramaswamy and M. D. Taylor and J. C. Lindsey and R. M. Hill
                      and N. Jäger$^*$ and A. Korshunov$^*$ and D. Hicks and S.
                      Bailey and M. Kool$^*$ and L. Chavez and P. A. Northcott and
                      S. Pfister$^*$ and S. C. Clifford},
      title        = {{S}econd-generation molecular subgrouping of
                      medulloblastoma: an international meta-analysis of {G}roup 3
                      and {G}roup 4 subtypes.},
      journal      = {Acta neuropathologica},
      volume       = {138},
      number       = {2},
      issn         = {1432-0533},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2019-01160},
      pages        = {309-326},
      year         = {2019},
      abstract     = {In 2012, an international consensus paper reported that
                      medulloblastoma comprises four molecular subgroups (WNT,
                      SHH, Group 3, and Group 4), each associated with distinct
                      genomic features and clinical behavior. Independently,
                      multiple recent reports have defined further intra-subgroup
                      heterogeneity in the form of biologically and clinically
                      relevant subtypes. However, owing to differences in patient
                      cohorts and analytical methods, estimates of subtype number
                      and definition have been inconsistent, especially within
                      Group 3 and Group 4. Herein, we aimed to reconcile the
                      definition of Group 3/Group 4 MB subtypes through the
                      analysis of a series of 1501 medulloblastomas with
                      DNA-methylation profiling data, including 852 with matched
                      transcriptome data. Using multiple complementary
                      bioinformatic approaches, we compared the concordance of
                      subtype calls between published cohorts and analytical
                      methods, including assessments of class-definition
                      confidence and reproducibility. While the lowest complexity
                      solutions continued to support the original consensus
                      subgroups of Group 3 and Group 4, our analysis most strongly
                      supported a definition comprising eight robust Group 3/Group
                      4 subtypes (types I-VIII). Subtype II was consistently
                      identified across all component studies, while all others
                      were supported by multiple class-definition methods.
                      Regardless of analytical technique, increasing cohort size
                      did not further increase the number of identified Group
                      3/Group 4 subtypes. Summarizing the molecular and
                      clinico-pathological features of these eight subtypes
                      indicated enrichment of specific driver gene alterations and
                      cytogenetic events amongst subtypes, and identified highly
                      disparate survival outcomes, further supporting their
                      biological and clinical relevance. Collectively, this study
                      provides continued support for consensus Groups 3 and 4
                      while enabling robust derivation of, and categorical
                      accounting for, the extensive intertumoral heterogeneity
                      within Groups 3 and 4, revealed by recent high-resolution
                      subclassification approaches. Furthermore, these findings
                      provide a basis for application of emerging methods (e.g.,
                      proteomics/single-cell approaches) which may additionally
                      inform medulloblastoma subclassification. Outputs from this
                      study will help shape definition of the next generation of
                      medulloblastoma clinical protocols and facilitate the
                      application of enhanced molecularly guided risk
                      stratification to improve outcomes and quality of life for
                      patients and their families.},
      cin          = {B062 / B300},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)B300-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31076851},
      doi          = {10.1007/s00401-019-02020-0},
      url          = {https://inrepo02.dkfz.de/record/143580},
}