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@ARTICLE{Deng:136677,
      author       = {M. Y. Deng$^*$ and M. Sill$^*$ and J. Chiang and J.
                      Schittenhelm and M. Ebinger and M. U. Schuhmann and C.-M.
                      Monoranu and T. Milde$^*$ and A. Wittmann$^*$ and C.
                      Hartmann and C. Sommer and W. Paulus and J. Gärtner and W.
                      Brück and T. Rüdiger and A. Leipold and Z. Jaunmuktane and
                      S. Brandner and F. Giangaspero and P. Nozza and J. Mora and
                      A. Morales la Madrid and O. Cruz Martinez and J. R. Hansford
                      and T. Pietsch and A. Tietze and P. Hernáiz-Driever and I.
                      Stoler and D. Capper and A. Korshunov$^*$ and D. W. Ellison
                      and A. von Deimling$^*$ and S. Pfister$^*$ and F. Sahm$^*$
                      and D. Jones$^*$},
      title        = {{M}olecularly defined diffuse leptomeningeal glioneuronal
                      tumor ({DLGNT}) comprises two subgroups with distinct
                      clinical and genetic features.},
      journal      = {Acta neuropathologica},
      volume       = {136},
      number       = {2},
      issn         = {1432-0533},
      address      = {Berlin},
      publisher    = {Springer},
      reportid     = {DKFZ-2018-01145},
      pages        = {239 - 253},
      year         = {2018},
      abstract     = {Diffuse leptomeningeal glioneuronal tumors (DLGNT)
                      represent rare CNS neoplasms which have been included in the
                      2016 update of the WHO classification. The wide spectrum of
                      histopathological and radiological features can make this
                      enigmatic tumor entity difficult to diagnose. In recent
                      years, large-scale genomic and epigenomic analyses have
                      afforded insight into key genetic alterations occurring in
                      multiple types of brain tumors and provide unbiased,
                      complementary tools to improve diagnostic accuracy. Through
                      genome-wide DNA methylation screening of > 25,000
                      tumors, we discovered a molecularly distinct class
                      comprising 30 tumors, mostly diagnosed histologically as
                      DLGNTs. Copy-number profiles derived from the methylation
                      arrays revealed unifying characteristics, including loss of
                      chromosomal arm 1p in all cases. Furthermore, this molecular
                      DLGNT class can be subdivided into two subgroups [DLGNT
                      methylation class (MC)-1 and DLGNT methylation class
                      (MC)-2], with all DLGNT-MC-2 additionally displaying a gain
                      of chromosomal arm 1q. Co-deletion of 1p/19q, commonly seen
                      in IDH-mutant oligodendroglioma, was frequently observed in
                      DLGNT, especially in DLGNT-MC-1 cases. Both subgroups also
                      had recurrent genetic alterations leading to an aberrant
                      MAPK/ERK pathway, with KIAA1549:BRAF fusion being the most
                      frequent event. Other alterations included fusions of
                      NTRK1/2/3 and TRIM33:RAF1, adding up to an MAPK/ERK pathway
                      activation identified in $80\%$ of cases. In the DLGNT-MC-1
                      group, age at diagnosis was significantly lower (median 5 vs
                      14 years, p < 0.01) and clinical course less aggressive
                      (5-year OS 100, vs $43\%$ in DLGNT-MC-2). Our study proposes
                      an additional molecular layer to the current
                      histopathological classification of DLGNT, of particular use
                      for cases without typical morphological or radiological
                      characteristics, such as diffuse growth and radiologic
                      leptomeningeal dissemination. Recurrent 1p deletion and
                      MAPK/ERK pathway activation represent diagnostic biomarkers
                      and therapeutic targets, respectively-laying the foundation
                      for future clinical trials with, e.g., MEK inhibitors that
                      may improve the clinical outcome of patients with DLGNT.},
      cin          = {B360 / B062 / G340 / L101 / G380},
      ddc          = {610},
      cid          = {I:(DE-He78)B360-20160331 / I:(DE-He78)B062-20160331 /
                      I:(DE-He78)G340-20160331 / I:(DE-He78)L101-20160331 /
                      I:(DE-He78)G380-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29766299},
      doi          = {10.1007/s00401-018-1865-4},
      url          = {https://inrepo02.dkfz.de/record/136677},
}