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@ARTICLE{Korshunov:126906,
      author       = {A. Korshunov$^*$ and M. Ryzhova and V. Hovestadt$^*$ and S.
                      Bender$^*$ and D. Sturm$^*$ and D. Capper$^*$ and J.
                      Meyer$^*$ and D. Schrimpf$^*$ and M. Kool$^*$ and P. A.
                      Northcott$^*$ and O. Zheludkova and T. Milde$^*$ and O.
                      Witt$^*$ and A. E. Kulozik$^*$ and G. Reifenberger$^*$ and
                      N. Jabado and A. Perry and P. Lichter$^*$ and A. von
                      Deimling$^*$ and S. Pfister$^*$ and D. Jones$^*$},
      title        = {{I}ntegrated analysis of pediatric glioblastoma reveals a
                      subset of biologically favorable tumors with associated
                      molecular prognostic markers.},
      journal      = {Acta neuropathologica},
      volume       = {129},
      number       = {5},
      issn         = {1432-0533},
      address      = {Berlin},
      publisher    = {Springer},
      reportid     = {DKFZ-2017-02934},
      pages        = {669 - 678},
      year         = {2015},
      abstract     = {Pediatric glioblastoma (pedGBM) is amongst the most common
                      malignant brain tumors of childhood and carries a dismal
                      prognosis. In contrast to adult GBM, few molecular
                      prognostic markers for the pediatric counterpart have been
                      established. We, therefore, investigated the prognostic
                      significance of genomic and epigenetic alterations through
                      molecular analysis of 202 pedGBM (1-18 years) with
                      comprehensive clinical annotation. Routinely prepared
                      formalin-fixed paraffin-embedded tumor samples were assessed
                      for genome-wide DNA methylation profiles, with known
                      candidate genes screened for alterations via direct
                      sequencing or FISH. Unexpectedly, a subset of histologically
                      diagnosed GBM (n = 40, 20 $\%)$ displayed methylation
                      profiles similar to those of either low-grade gliomas or
                      pleomorphic xanthoastrocytomas (PXA). These tumors showed a
                      markedly better prognosis, with molecularly PXA-like tumors
                      frequently harboring BRAF V600E mutations and 9p21 (CDKN2A)
                      homozygous deletion. The remaining 162 tumors with pedGBM
                      molecular signatures comprised four subgroups: H3.3
                      G34-mutant (15 $\%),$ H3.3/H3.1 K27-mutant (43 $\%),$
                      IDH1-mutant (6 $\%),$ and H3/IDH wild-type (wt) GBM (36
                      $\%).$ These subgroups were associated with specific
                      cytogenetic aberrations, MGMT methylation patterns and
                      clinical outcomes. Analysis of follow-up data identified a
                      set of biomarkers feasible for use in risk stratification:
                      pedGBM with any oncogene amplification and/or K27M mutation
                      (n = 124) represents a particularly unfavorable group, with
                      3-year overall survival (OS) of 5 $\%,$ whereas tumors
                      without these markers (n = 38) define a more favorable group
                      (3-year OS ~70 $\%).Combined$ with the lower grade-like
                      lesions, almost 40 $\%$ of pedGBM cases had distinct
                      molecular features associated with a more favorable outcome.
                      This refined prognostication method for pedGBM using a
                      molecular risk algorithm may allow for improved therapeutic
                      choices and better planning of clinical trial stratification
                      for this otherwise devastating disease.},
      keywords     = {Biomarkers, Tumor (NLM Chemicals) / Proto-Oncogene Proteins
                      B-raf (NLM Chemicals)},
      cin          = {G380 / B060 / B062 / G340 / L101 / L401},
      ddc          = {610},
      cid          = {I:(DE-He78)G380-20160331 / I:(DE-He78)B060-20160331 /
                      I:(DE-He78)B062-20160331 / I:(DE-He78)G340-20160331 /
                      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:25752754},
      doi          = {10.1007/s00401-015-1405-4},
      url          = {https://inrepo02.dkfz.de/record/126906},
}