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@ARTICLE{Paramasivam:143626,
      author       = {N. Paramasivam$^*$ and D. Hübschmann$^*$ and U. H.
                      Toprak$^*$ and N. Ishaque$^*$ and M. Neidert and D.
                      Schrimpf$^*$ and D. Stichel$^*$ and D. Reuss$^*$ and P.
                      Sievers$^*$ and A. Reinhardt$^*$ and A. K. Wefers$^*$ and D.
                      T. W. Jones$^*$ and Z. Gu$^*$ and J. Werner$^*$ and S.
                      Uhrig$^*$ and H.-G. Wirsching and M. Schick$^*$ and M.
                      Bewerunge-Hudler$^*$ and K. Beck$^*$ and S. Brehmer and S.
                      Urbschat and M. Seiz-Rosenhagen and D. Hänggi and C.
                      Herold-Mende and R. Ketter and R. Eils$^*$ and Z. Ram and S.
                      M. Pfister$^*$ and W. Wick$^*$ and M. Weller and R.
                      Grossmann and A. von Deimling$^*$ and M. Schlesner$^*$ and
                      F. Sahm$^*$},
      title        = {{M}utational patterns and regulatory networks in epigenetic
                      subgroups of meningioma.},
      journal      = {Acta neuropathologica},
      volume       = {138},
      number       = {2},
      issn         = {1432-0533},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2019-01203},
      pages        = {295-308},
      year         = {2019},
      abstract     = {DNA methylation patterns delineate clinically relevant
                      subgroups of meningioma. We previously established the six
                      meningioma methylation classes (MC) benign 1-3, intermediate
                      A and B, and malignant. Here, we set out to identify
                      subgroup-specific mutational patterns and gene regulation.
                      Whole genome sequencing was performed on 62 samples across
                      all MCs and WHO grades from 62 patients with matched blood
                      control, including 40 sporadic meningiomas and 22
                      meningiomas arising after radiation (Mrad). RNA sequencing
                      was added for 18 of these cases and
                      chromatin-immunoprecipitation for histone H3 lysine 27
                      acetylation (H3K27ac) followed by sequencing (ChIP-seq) for
                      16 samples. Besides the known mutations in meningioma,
                      structural variants were found as the mechanism of NF2
                      inactivation in a small subset $(5\%)$ of sporadic
                      meningiomas, similar to previous reports for Mrad.
                      Aberrations of DMD were found to be enriched in MCs with NF2
                      mutations, and DMD was among the most differentially
                      upregulated genes in NF2 mutant compared to NF2 wild-type
                      cases. The mutational signature AC3, which has been
                      associated with defects in homologous recombination repair
                      (HRR), was detected in both sporadic meningioma and Mrad,
                      but widely distributed across the genome in sporadic cases
                      and enriched near genomic breakpoints in Mrad. Compared to
                      the other MCs, the number of single nucleotide variants
                      matching the AC3 pattern was significantly higher in the
                      malignant MC, which also exhibited higher genomic
                      instability, determined by the numbers of both large
                      segments affected by copy number alterations and breakpoints
                      between large segments. ChIP-seq analysis for H3K27ac
                      revealed a specific activation of genes regulated by the
                      transcription factor FOXM1 in the malignant MC. This
                      analysis also revealed a super enhancer near the HOXD gene
                      cluster in this MC, which, together with general
                      upregulation of HOX genes in the malignant MC, indicates a
                      role of HOX genes in meningioma aggressiveness. This data
                      elucidates the biological mechanisms rendering different
                      epigenetic subgroups of meningiomas, and suggests leveraging
                      HRR as a novel therapeutic target.},
      cin          = {B080 / A010 / B300 / B360 / B330 / W110 / B062 / B320 /
                      B240 / B087},
      ddc          = {610},
      cid          = {I:(DE-He78)B080-20160331 / I:(DE-He78)A010-20160331 /
                      I:(DE-He78)B300-20160331 / I:(DE-He78)B360-20160331 /
                      I:(DE-He78)B330-20160331 / I:(DE-He78)W110-20160331 /
                      I:(DE-He78)B062-20160331 / I:(DE-He78)B320-20160331 /
                      I:(DE-He78)B240-20160331 / I:(DE-He78)B087-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31069492},
      doi          = {10.1007/s00401-019-02008-w},
      url          = {https://inrepo02.dkfz.de/record/143626},
}