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@ARTICLE{Korshunov:167482,
      author       = {A. Korshunov$^*$ and K. Okonechnikov$^*$ and D. Stichel$^*$
                      and M. Ryzhova and D. Schrimpf$^*$ and F. Sahm$^*$ and P.
                      Sievers$^*$ and O. Absalyamova and O. Zheludkova and A.
                      Golanov and D. T. W. Jones$^*$ and S. M. Pfister$^*$ and A.
                      von Deimling$^*$ and M. Kool$^*$},
      title        = {{I}ntegrated molecular analysis of adult {S}onic {H}edgehog
                      ({SHH})-activated medulloblastomas reveals two clinically
                      relevant tumor subsets with {VEGFA} as potent prognostic
                      indicator.},
      journal      = {Neuro-Oncology},
      volume       = {23},
      number       = {9},
      issn         = {1523-5866},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DKFZ-2021-00383},
      pages        = {1576-1585},
      year         = {2021},
      note         = {#EA:B300#B062#LA:B062# / 2021 Sep 1;23(9):1576-1585},
      abstract     = {Up to now, adult medulloblastoma (MB) patients are treated
                      according to the protocols elaborated for pediatric MB
                      although these tumors are different in terms of clinical
                      outcomes and biology. Approximately $70\%$ of adult MB
                      disclose a Sonic Hedgehog (SHH) molecular signature in
                      contrast to about $30\%$ in pediatric cohorts. In addition,
                      adult SHH-MB (aSHH-MB) are clinically heterogeneous but
                      there is consensus neither on their optimal treatment nor on
                      risk stratification. Thus, the identification of clinically
                      relevant molecular subsets of aSHH-MB and identification of
                      potential treatment targets remains inconclusive.We analyzed
                      96 samples of institutionally diagnosed aSHH-MB through
                      genome-wide DNA methylation profiling, targeted DNA
                      sequencing and RNA sequencing to identify molecular
                      subcategories of these tumors and assess their prognostic
                      significance.We defined two aSHH-MB numerically comparable
                      epigenetic subsets with clinical and molecular variability.
                      The subset 'aSHH-MBI' $(46/48\%)$ was associated with
                      PTCH1/SMO $(54\%/46\%)$ mutations, 'neuronal'
                      transcriptional signatures, and favorable outcomes after
                      combined radio-chemotherapy (5-year PFS = $80\%$ and OS =
                      $92\%).$ The clinically unfavorable 'aSHH-MBII' subset
                      $(50/52\%;$ 5-year PFS = $24\%$ and OS = $45\%)$ disclosed
                      GLI2 amplifications $(8\%),$ loss of 10q $(22\%),$ and gene
                      expression signatures associated with angiogenesis and
                      embryonal development. aSHH-MBII tumors revealed strong and
                      ubiquitous expression of VEGFA both at transcript and
                      protein levels that was correlated with unfavorable
                      outcome.1. The histologically uniform aSHH-MB cohort
                      exhibits clear molecular heterogeneity separating these
                      tumors into two molecular subsets (aSHH-MBI and aSHH-MBII),
                      which are associated with different cytogenetics, mutational
                      landscapes, gene expression signatures, and clinical course.
                      2. VEGFA appears to be a promising biomarker to predict
                      clinical course, which needs further prospective validation
                      as its potential role in the pathogenesis of this subset.},
      keywords     = {Adult (Other) / Medulloblastoma (Other) / SHH (Other) /
                      VEGFA (Other) / prognosis (Other) / transcriptome (Other)},
      cin          = {B300 / B062 / HD01 / B360},
      ddc          = {610},
      cid          = {I:(DE-He78)B300-20160331 / I:(DE-He78)B062-20160331 /
                      I:(DE-He78)HD01-20160331 / I:(DE-He78)B360-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33589929},
      doi          = {10.1093/neuonc/noab031},
      url          = {https://inrepo02.dkfz.de/record/167482},
}