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@ARTICLE{Pietsch:120134,
      author       = {T. Pietsch and R. Schmidt and M. Remke and A. Korshunov$^*$
                      and V. Hovestadt$^*$ and D. Jones$^*$ and J. Felsberg$^*$
                      and K. Kaulich$^*$ and T. Goschzik and M. Kool$^*$ and P. A.
                      Northcott$^*$ and K. von Hoff and A. O. von Bueren and C.
                      Friedrich and M. Mynarek and H. Skladny and G. Fleischhack
                      and M. D. Taylor and F. Cremer and P. Lichter$^*$ and A.
                      Faldum and G. Reifenberger$^*$ and S. Rutkowski and S.
                      Pfister$^*$},
      title        = {{P}rognostic significance of clinical, histopathological,
                      and molecular characteristics of medulloblastomas in the
                      prospective {HIT}2000 multicenter clinical trial cohort.},
      journal      = {Acta neuropathologica},
      volume       = {128},
      number       = {1},
      issn         = {1432-0533},
      address      = {Berlin},
      publisher    = {Springer},
      reportid     = {DKFZ-2017-00717},
      pages        = {137 - 149},
      year         = {2014},
      abstract     = {This study aimed to prospectively evaluate clinical,
                      histopathological and molecular variables for outcome
                      prediction in medulloblastoma patients. Patients from the
                      HIT2000 cooperative clinical trial were prospectively
                      enrolled based on the availability of sufficient tumor
                      material and complete clinical information. This revealed a
                      cohort of 184 patients (median age 7.6 years), which was
                      randomly split at a 2:1 ratio into a training (n = 127), and
                      a test (n = 57) dataset in order to build and test a risk
                      score for this population. Independent validation was
                      performed in a non-overlapping cohort (n = 83). All samples
                      were subjected to thorough histopathological investigation,
                      CTNNB1 mutation analysis, quantitative PCR, MLPA and FISH
                      analyses for cytogenetic variables, and methylome analysis.
                      By univariable analysis, clinical factors (M-stage),
                      histopathological variables (large cell component,
                      endothelial proliferation, synaptophysin pattern), and
                      molecular features (chromosome 6q status, MYC amplification,
                      subgrouping) were found to be prognostic. Molecular
                      consensus subgrouping (WNT, SHH, Group 3, Group 4) was
                      validated as an independent feature to stratify patients
                      into different risk groups. When comparing methods for the
                      identification of WNT-driven medulloblastoma, this study
                      identified CTNNB1 sequencing and methylation profiling to
                      most reliably identify these patients. After removing
                      patients with particularly favorable (CTNNB1 mutation,
                      extensive nodularity) or unfavorable (MYC amplification)
                      markers, a risk score for the remaining 'intermediate
                      molecular risk' population dependent on age, M-stage,
                      pattern of synaptophysin expression, and MYCN copy-number
                      status was identified, with speckled synaptophysin
                      expression indicating worse outcome. Test and independent
                      validation of the score confirmed significant discrimination
                      of patients by risk profile. Methylation subgrouping and
                      CTNNB1 mutation status represent robust tools for the risk
                      stratification of medulloblastoma. A simple
                      clinico-pathological risk score was identified, which was
                      confirmed in a test set and by independent clinical
                      validation.},
      keywords     = {Biomarkers (NLM Chemicals) / CTNNB1 protein, human (NLM
                      Chemicals) / MYCN protein, human (NLM Chemicals) / N-Myc
                      Proto-Oncogene Protein (NLM Chemicals) / Nuclear Proteins
                      (NLM Chemicals) / Oncogene Proteins (NLM Chemicals) / SYP
                      protein, human (NLM Chemicals) / Synaptophysin (NLM
                      Chemicals) / beta Catenin (NLM Chemicals)},
      cin          = {G380 / B060 / B062 / L101 / L401},
      ddc          = {610},
      cid          = {I:(DE-He78)G380-20160331 / I:(DE-He78)B060-20160331 /
                      I:(DE-He78)B062-20160331 / I:(DE-He78)L101-20160331 /
                      I:(DE-He78)L401-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:24791927},
      pmc          = {pmc:PMC4059991},
      doi          = {10.1007/s00401-014-1276-0},
      url          = {https://inrepo02.dkfz.de/record/120134},
}