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@ARTICLE{Thomas:168126,
      author       = {C. Thomas and F. Thierfelder$^*$ and M. Träger and P.
                      Soschinski and M. Müther and D. Edelmann$^*$ and A.
                      Förster and C. Geiler and H.-Y. Kim$^*$ and K. Filipski$^*$
                      and P. Harter$^*$ and J. Schittenhelm and F. Eckert and G.
                      Ntoulias and S.-A. May and W. Stummer and J. Onken and P.
                      Vajkoczy and U. Schüller and F. L. Heppner$^*$ and D.
                      Capper$^*$ and A. Koch$^*$ and D. Kaul and W. Paulus and M.
                      Hasselblatt and L. Schweizer$^*$},
      title        = {{TERT} promoter mutation and chromosome 6 loss define a
                      high-risk subtype of ependymoma evolving from posterior
                      fossa subependymoma.},
      journal      = {Acta neuropathologica},
      volume       = {141},
      number       = {6},
      issn         = {1432-0533},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2021-00694},
      pages        = {959-970},
      year         = {2021},
      note         = {141(6):959-970},
      abstract     = {Subependymomas are benign tumors characteristically
                      encountered in the posterior fossa of adults that show
                      distinct epigenetic profiles assigned to the molecular group
                      'subependymoma, posterior fossa' (PFSE) of the recently
                      established DNA methylation-based classification of central
                      nervous system tumors. In contrast, most posterior fossa
                      ependymomas exhibit a more aggressive biological behavior
                      and are allocated to the molecular subgroups PFA or PFB. A
                      subset of ependymomas shows epigenetic similarities with
                      subependymomas, but the precise biology of these tumors and
                      their potential relationships remain unknown. We therefore
                      set out to characterize epigenetic traits, mutational
                      profiles, and clinical outcomes of 50 posterior fossa
                      ependymal tumors of the PFSE group. On histo-morphology,
                      these tumors comprised 12 ependymomas, 14 subependymomas and
                      24 tumors with mixed ependymoma-subependymoma morphology.
                      Mixed ependymoma-subependymoma tumors varied in their extent
                      of ependymoma differentiation $(2-95\%)$ but consistently
                      exhibited global epigenetic profiles of the PFSE group.
                      Selective methylome analysis of microdissected tumor
                      components revealed CpG signatures in mixed tumors that
                      coalesce with their pure counterparts. Loss of chr6 (20/50
                      cases), as well as TERT mutations (21/50 cases), were
                      frequent events enriched in tumors with pure ependymoma
                      morphology (p < 0.001) and confined to areas with ependymoma
                      differentiation in mixed tumors. Clinically, pure ependymoma
                      phenotype, chr6 loss, and TERT mutations were associated
                      with shorter progression-free survival (each p < 0.001). In
                      conclusion, our results suggest that subependymomas may
                      acquire genetic and epigenetic changes throughout tumor
                      evolution giving rise to subclones with ependymoma
                      morphology (resulting in mixed tumors) that eventually
                      overpopulate the subependymoma component (pure PFSE
                      ependymomas).},
      keywords     = {Chromosome 6 (Other) / DNA methylation (Other) / Mixed
                      ependymoma–subependymoma (Other) / Subependymoma (Other) /
                      TERT (Other)},
      cin          = {BE01 / FM01 / C060},
      ddc          = {610},
      cid          = {I:(DE-He78)BE01-20160331 / I:(DE-He78)FM01-20160331 /
                      I:(DE-He78)C060-20160331},
      pnm          = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
      pid          = {G:(DE-HGF)POF4-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33755803},
      doi          = {10.1007/s00401-021-02300-8},
      url          = {https://inrepo02.dkfz.de/record/168126},
}