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@ARTICLE{Peifer:127281,
      author       = {M. Peifer and F. Hertwig$^*$ and F. Roels$^*$ and D.
                      Dreidax$^*$ and M. Gartlgruber$^*$ and R. Menon and A.
                      Krämer and J. L. Roncaioli and F. Sand and J. M. Heuckmann
                      and F. Ikram and R. Schmidt and S. Ackermann and A. Engesser
                      and Y. Kahlert and W. Vogel and J. Altmüller and P.
                      Nürnberg and J. Thierry-Mieg and D. Thierry-Mieg and A.
                      Mariappan and S. Heynck and E. Mariotti and K.-O.
                      Henrich$^*$ and C. Gloeckner and G. Bosco and I. Leuschner
                      and M. R. Schweiger and L. Savelyeva$^*$ and S. C. Watkins
                      and C. Shao and E. Bell and T. Höfer and V. Achter and U.
                      Lang and J. Theissen and R. Volland and M. Saadati$^*$ and
                      A. Eggert and B. de Wilde and F. Berthold and Z. Peng and C.
                      Zhao and L. Shi and M. Ortmann and R. Büttner and S. Perner
                      and B. Hero and A. Schramm and J. Schulte$^*$ and C.
                      Herrmann$^*$ and R. J. O'Sullivan and F. Westermann$^*$ and
                      R. K. Thomas and M. Fischer$^*$},
      title        = {{T}elomerase activation by genomic rearrangements in
                      high-risk neuroblastoma.},
      journal      = {Nature},
      volume       = {526},
      number       = {7575},
      issn         = {1476-4687},
      address      = {London [u.a.]},
      publisher    = {Nature Publ. Group},
      reportid     = {DKFZ-2017-03306},
      pages        = {700 - 704},
      year         = {2015},
      abstract     = {Neuroblastoma is a malignant paediatric tumour of the
                      sympathetic nervous system. Roughly half of these tumours
                      regress spontaneously or are cured by limited therapy. By
                      contrast, high-risk neuroblastomas have an unfavourable
                      clinical course despite intensive multimodal treatment, and
                      their molecular basis has remained largely elusive. Here we
                      have performed whole-genome sequencing of 56 neuroblastomas
                      (high-risk, n = 39; low-risk, n = 17) and discovered
                      recurrent genomic rearrangements affecting a chromosomal
                      region at 5p15.33 proximal of the telomerase reverse
                      transcriptase gene (TERT). These rearrangements occurred
                      only in high-risk neuroblastomas (12/39, $31\%)$ in a
                      mutually exclusive fashion with MYCN amplifications and ATRX
                      mutations, which are known genetic events in this tumour
                      type. In an extended case series (n = 217), TERT
                      rearrangements defined a subgroup of high-risk tumours with
                      particularly poor outcome. Despite a large structural
                      diversity of these rearrangements, they all induced massive
                      transcriptional upregulation of TERT. In the remaining
                      high-risk tumours, TERT expression was also elevated in
                      MYCN-amplified tumours, whereas alternative lengthening of
                      telomeres was present in neuroblastomas without TERT or MYCN
                      alterations, suggesting that telomere lengthening represents
                      a central mechanism defining this subtype. The 5p15.33
                      rearrangements juxtapose the TERT coding sequence to strong
                      enhancer elements, resulting in massive chromatin
                      remodelling and DNA methylation of the affected region.
                      Supporting a functional role of TERT, neuroblastoma cell
                      lines bearing rearrangements or amplified MYCN exhibited
                      both upregulated TERT expression and enzymatic telomerase
                      activity. In summary, our findings show that remodelling of
                      the genomic context abrogates transcriptional silencing of
                      TERT in high-risk neuroblastoma and places telomerase
                      activation in the centre of transformation in a large
                      fraction of these tumours.},
      keywords     = {Chromatin (NLM Chemicals) / MYCN protein, human (NLM
                      Chemicals) / N-Myc Proto-Oncogene Protein (NLM Chemicals) /
                      Nuclear Proteins (NLM Chemicals) / Oncogene Proteins (NLM
                      Chemicals) / RNA, Messenger (NLM Chemicals) / TERT protein,
                      human (NLM Chemicals) / Telomerase (NLM Chemicals) / DNA
                      Helicases (NLM Chemicals) / ATRX protein, human (NLM
                      Chemicals)},
      cin          = {B087 / B086 / C060 / B080 / L101 / L201},
      ddc          = {070},
      cid          = {I:(DE-He78)B087-20160331 / I:(DE-He78)B086-20160331 /
                      I:(DE-He78)C060-20160331 / I:(DE-He78)B080-20160331 /
                      I:(DE-He78)L101-20160331 / I:(DE-He78)L201-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:26466568},
      pmc          = {pmc:PMC4881306},
      doi          = {10.1038/nature14980},
      url          = {https://inrepo02.dkfz.de/record/127281},
}