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@ARTICLE{Castel:141666,
      author       = {D. Castel and C. Philippe and T. Kergrohen and M. Sill$^*$
                      and J. Merlevede and E. Barret and S. Puget and C.
                      Sainte-Rose and C. M. Kramm and C. Jones and P. Varlet and
                      S. Pfister$^*$ and J. Grill and D. Jones$^*$ and M.-A.
                      Debily},
      title        = {{T}ranscriptomic and epigenetic profiling of diffuse
                      midline gliomas, {H}3 {K}27{M}-mutant discriminate two
                      subgroups based on the type of histone {H}3 mutated and not
                      supratentorial or infratentorial location.},
      journal      = {Acta Neuropathologica Communications},
      volume       = {6},
      number       = {1},
      issn         = {2051-5960},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DKFZ-2018-01937},
      pages        = {117},
      year         = {2018},
      abstract     = {Diffuse midline glioma (DMG), H3 K27M-mutant, is a new
                      entity in the updated WHO classification grouping together
                      diffuse intrinsic pontine gliomas and infiltrating glial
                      neoplasms of the midline harboring the same canonical
                      mutation at the Lysine 27 of the histones H3 tail.Two
                      hundred and fifteen patients younger than 18 years old with
                      centrally-reviewed pediatric high-grade gliomas (pHGG) were
                      included in this study. Comprehensive transcriptomic
                      (n = 140) and methylation (n = 80) profiling was
                      performed depending on the material available, in order to
                      assess the biological uniqueness of this new entity compared
                      to other midline and hemispheric pHGG.Tumor classification
                      based on gene expression (GE) data highlighted the
                      similarity of K27M DMG independently of their location along
                      the midline. T-distributed Stochastic Neighbor Embedding
                      (tSNE) analysis of methylation profiling confirms the
                      discrimination of DMG from other well defined supratentorial
                      tumor subgroups. Patients with diffuse intrinsic pontine
                      gliomas (DIPG) and thalamic DMG exhibited a similarly poor
                      prognosis (11.1 and 10.8 months median overall survival,
                      respectively). Interestingly, H3.1-K27M and H3.3-K27M
                      primary tumor samples could be distinguished based both on
                      their GE and DNA methylation profiles, suggesting that they
                      might arise from a different precursor or from a different
                      epigenetic reorganization.These differences in DNA
                      methylation profiles were conserved in glioma stem-like cell
                      culture models of DIPG which mimicked their corresponding
                      primary tumor. ChIP-seq profiling of H3K27me3 in these
                      models indicate that H3.3-K27M mutated DIPG stem cells
                      exhibit higher levels of H3K27 trimethylation which are
                      correlated with fewer genes expressed by RNAseq. When
                      considering the global distribution of the H3K27me3 mark, we
                      observed that intergenic regions were more trimethylated in
                      the H3.3-K27M mutated cells compared to the H3.1-K27M
                      mutated ones.H3 K27M-mutant DMG represent a homogenous group
                      of neoplasms compared to other pediatric gliomas that could
                      be further separated based on the type of histone H3 variant
                      mutated and their respective epigenetic landscapes. As these
                      characteristics drive different phenotypes, these findings
                      may have important implication for the design of future
                      trials in these specific types of neoplasms.},
      cin          = {B062 / L101 / B360},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)L101-20160331 /
                      I:(DE-He78)B360-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30396367},
      pmc          = {pmc:PMC6219253},
      doi          = {10.1186/s40478-018-0614-1},
      url          = {https://inrepo02.dkfz.de/record/141666},
}