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@ARTICLE{Gdicke:287281,
      author       = {S. Gödicke and C. Kresbach and M. Ehlert and D. Obrecht
                      and L. Altendorf and K. Hack and K. von Hoff and H. Carén
                      and V. Melcher and K. Kerl and B. Englinger and M. Filbin
                      and K. W. Pajtler$^*$ and J. Gojo and T. Pietsch and S.
                      Rutkowski and U. Schüller},
      title        = {{C}linically relevant molecular hallmarks of {PFA}
                      ependymomas display intratumoral heterogeneity and correlate
                      with tumor morphology.},
      journal      = {Acta neuropathologica},
      volume       = {147},
      number       = {1},
      issn         = {0001-6322},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2024-00206},
      pages        = {23},
      year         = {2024},
      abstract     = {Posterior fossa type A (PF-EPN-A, PFA) ependymoma are
                      aggressive tumors that mainly affect children and have a
                      poor prognosis. Histopathology shows significant
                      intratumoral heterogeneity, ranging from loose tissue to
                      often sharply demarcated, extremely cell-dense tumor areas.
                      To determine molecular differences in morphologically
                      different areas and to understand their clinical
                      significance, we analyzed 113 PF-EPN-A samples, including 40
                      corresponding relapse samples. Cell-dense areas ranged from
                      0 to $100\%$ of the tumor area and displayed a higher
                      proportion of proliferating tumor cells (p < 0.01).
                      Clinically, cell density was associated with poor
                      progression-free and overall survival (pPFS = 0.0026, pOS <
                      0.01). Molecularly, tumor areas with low and high cell
                      density showed diverging DNA methylation profiles regarding
                      their similarity to distinct previously discovered PF-EPN-A
                      subtypes in 9/21 cases. Prognostically relevant chromosomal
                      changes at 1q and 6q showed spatial heterogeneity within
                      single tumors and were significantly enriched in cell-dense
                      tumor areas as shown by single-cell RNA (scRNA)-sequencing
                      as well as copy number profiling and fluorescence in situ
                      hybridization (FISH) analyses of different tumor areas.
                      Finally, spatial transcriptomics revealed cell-dense areas
                      of different tumors to be more similar than various
                      different areas of the same tumor. High-density areas
                      distinctly overexpressed genes encoding histone proteins,
                      WNT5A, TGFB1, or IGF2. Relapsing tumors displayed a higher
                      proportion of cell-dense areas (p = 0.036), a change in
                      PF-EPN-A methylation subtypes (13/32 patients), and novel
                      chromosome 1q gains and 6q losses (12/32 cases) compared to
                      corresponding primary tumors. Our data suggest that PF-EPN-A
                      ependymomas habor a previously unrecognized intratumoral
                      heterogeneity with clinical implications, which has to be
                      accounted for when selecting diagnostic material, inter
                      alia, by histological evaluation of the proportion of
                      cell-dense areas.},
      keywords     = {Child / Humans / In Situ Hybridization, Fluorescence /
                      Neoplasm Recurrence, Local / Ependymoma / Histones / Gene
                      Expression Profiling / 1q gain (Other) / 6q loss (Other) /
                      DNA methylation (Other) / Ependymoma (Other) / Intratumoral
                      heterogeneity (Other) / Morphology (Other) / Histones (NLM
                      Chemicals)},
      cin          = {B062 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)HD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38265527},
      doi          = {10.1007/s00401-023-02682-x},
      url          = {https://inrepo02.dkfz.de/record/287281},
}