% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Rivera:130418,
      author       = {B. Rivera and T. Gayden and J. Carrot-Zhang and J. Nadaf
                      and T. Boshari and D. Faury and M. Zeinieh and R. Blanc and
                      D. L. Burk and S. Fahiminiya and E. Bareke and U. Schüller
                      and C. M. Monoranu and R. Sträter and K. Kerl and T.
                      Niederstadt and G. Kurlemann and B. Ellezam and Z. Michalak
                      and M. Thom and P. J. Lockhart and R. J. Leventer and M. Ohm
                      and D. MacGregor and D. Jones$^*$ and J. Karamchandani and
                      C. M. T. Greenwood and A. M. Berghuis and S. Bens and R.
                      Siebert and M. Zakrzewska and P. P. Liberski and K.
                      Zakrzewski and S. M. Sisodiya and W. Paulus and S. Albrecht
                      and M. Hasselblatt and N. Jabado and W. D. Foulkes and J.
                      Majewski},
      title        = {{G}ermline and somatic {FGFR}1 abnormalities in
                      dysembryoplastic neuroepithelial tumors.},
      journal      = {Acta neuropathologica},
      volume       = {131},
      number       = {6},
      issn         = {1432-0533},
      address      = {Berlin},
      publisher    = {Springer},
      reportid     = {DKFZ-2017-05497},
      pages        = {847 - 863},
      year         = {2016},
      abstract     = {Dysembryoplastic neuroepithelial tumor (DNET) is a benign
                      brain tumor associated with intractable drug-resistant
                      epilepsy. In order to identify underlying genetic
                      alterations and molecular mechanisms, we examined three
                      family members affected by multinodular DNETs as well as 100
                      sporadic tumors from 96 patients, which had been referred to
                      us as DNETs. We performed whole-exome sequencing on 46
                      tumors and targeted sequencing for hotspot FGFR1 mutations
                      and BRAF p.V600E was used on the remaining samples. FISH,
                      copy number variation assays and Sanger sequencing were used
                      to validate the findings. By whole-exome sequencing of the
                      familial cases, we identified a novel germline FGFR1
                      mutation, p.R661P. Somatic activating FGFR1 mutations
                      (p.N546K or p.K656E) were observed in the tumor samples and
                      further evidence for functional relevance was obtained by in
                      silico modeling. The FGFR1 p.K656E mutation was confirmed to
                      be in cis with the germline p.R661P variant. In 43 sporadic
                      cases, in which the diagnosis of DNET could be confirmed on
                      central blinded neuropathology review, FGFR1 alterations
                      were also frequent and mainly comprised intragenic tyrosine
                      kinase FGFR1 duplication and multiple mutants in cis (25/43;
                      $58.1 \%)$ while BRAF p.V600E alterations were absent
                      (0/43). In contrast, in 53 cases, in which the diagnosis of
                      DNET was not confirmed, FGFR1 alterations were less common
                      (10/53; $19 \%;$ p < 0.0001) and hotspot BRAF p.V600E
                      (12/53; $22.6 \%)$ (p < 0.001) prevailed. We observed
                      overexpression of phospho-ERK in FGFR1 p.R661P and p.N546K
                      mutant expressing HEK293 cells as well as FGFR1 mutated
                      tumor samples, supporting enhanced MAP kinase pathway
                      activation under these conditions. In conclusion,
                      constitutional and somatic FGFR1 alterations and MAP kinase
                      pathway activation are key events in the pathogenesis of
                      DNET. These findings point the way towards existing targeted
                      therapies.},
      keywords     = {FGFR1 protein, human (NLM Chemicals) / Receptor, Fibroblast
                      Growth Factor, Type 1 (NLM Chemicals) / Proto-Oncogene
                      Proteins B-raf (NLM Chemicals)},
      cin          = {B062 / L101},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)L101-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:26920151},
      pmc          = {pmc:PMC5039033},
      doi          = {10.1007/s00401-016-1549-x},
      url          = {https://inrepo02.dkfz.de/record/130418},
}