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@ARTICLE{Misove:181956,
      author       = {A. Misove and A. Vicha and P. Broz and K. Vanova and D.
                      Sumerauer and L. Stolova and L. Sramkova and M. Koblizek and
                      J. Zamecnik and M. Kyncl and Z. Holubova and P. Liby and J.
                      Taborsky and V. Benes and I. Pernikova and D. Jones$^*$ and
                      M. Sill$^*$ and T. Stancokova and L. Krskova and M.
                      Zapotocky},
      title        = {{I}ntegrated genomic analysis reveals actionable targets in
                      pediatric spinal cord low-grade gliomas.},
      journal      = {Acta Neuropathologica Communications},
      volume       = {10},
      number       = {1},
      issn         = {2051-5960},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DKFZ-2022-02326},
      pages        = {143},
      year         = {2022},
      abstract     = {Gliomas are the most common central nervous tumors in
                      children and adolescents. However, spinal cord low-grade
                      gliomas (sLGGs) are rare, with scarce information on tumor
                      genomics and epigenomics. To define the molecular landscape
                      of sLGGs, we integrated clinical data, histology, and
                      multi-level genetic and epigenetic analyses on a consecutive
                      cohort of 26 pediatric patients. Driver molecular alteration
                      was found in $92\%$ of patients (24/26). A novel variant of
                      KIAA1549:BRAF fusion (ex10:ex9) was identified using RNA-seq
                      in four cases. Importantly, only one-third of oncogenic
                      drivers could be revealed using standard diagnostic methods,
                      and two-thirds of pediatric patients with sLGGs required
                      extensive molecular examination. The majority (23/24) of
                      detected alterations were potentially druggable targets.
                      Four patients in our cohort received targeted therapy with
                      MEK or NTRK inhibitors. Three of those exhibited clinical
                      improvement (two with trametinib, one with larotrectinib),
                      and two patients achieved partial response. Methylation
                      profiling was implemented to further refine the diagnosis
                      and revealed intertumoral heterogeneity in sLGGs. Although
                      $55\%$ of tumors clustered with pilocytic astrocytoma, other
                      rare entities were identified in this patient population. In
                      particular, diffuse leptomeningeal glioneuronal tumors (n =
                      3) and high-grade astrocytoma with piloid features (n = 1)
                      and pleomorphic xanthoastrocytoma (n = 1) were present. A
                      proportion of tumors $(14\%)$ had no match with the current
                      version of the classifier. Complex molecular genetic sLGGs
                      characterization was invaluable to refine diagnosis, which
                      has proven to be essential in such a rare tumor entity.
                      Moreover, identifying a high proportion of drugable targets
                      in sLGGs opened an opportunity for new treatment
                      modalities.},
      keywords     = {Adolescent / Astrocytoma: genetics / Brain Neoplasms:
                      genetics / Child / Genomics / Glioma: genetics / Glioma:
                      pathology / Humans / Mitogen-Activated Protein Kinase
                      Kinases / Proto-Oncogene Proteins B-raf: genetics / Spinal
                      Cord Neoplasms: genetics / KIAA1549:BRAF fusion (Other) /
                      Low-grade glioma (Other) / Methylation profiling (Other) /
                      NTRK fusion (Other) / Spinal cord (Other) / Proto-Oncogene
                      Proteins B-raf (NLM Chemicals) / Mitogen-Activated Protein
                      Kinase Kinases (NLM Chemicals)},
      cin          = {B360 / C060},
      ddc          = {610},
      cid          = {I:(DE-He78)B360-20160331 / I:(DE-He78)C060-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36163281},
      pmc          = {pmc:PMC9513869},
      doi          = {10.1186/s40478-022-01446-0},
      url          = {https://inrepo02.dkfz.de/record/181956},
}