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@ARTICLE{Dieter:124344,
      author       = {S. Dieter$^*$ and C. Heining$^*$ and A. Agaimy and D.
                      Huebschmann$^*$ and D. Bonekamp$^*$ and B. Hutter$^*$ and K.
                      R. Ehrenberg$^*$ and M. Fröhlich$^*$ and M. Schlesner$^*$
                      and C. Scholl$^*$ and H.-P. Schlemmer$^*$ and S. Wolf$^*$
                      and A. Mavratzas and C. S. Jung and S. Gröschel$^*$ and C.
                      von Kalle$^*$ and R. Eils$^*$ and B. Brors$^*$ and R. Penzel
                      and M. Kriegsmann and D. E. Reuss and P. Schirmacher$^*$ and
                      A. Stenzinger and P. A. Federspil and W. Weichert$^*$ and H.
                      Glimm$^*$ and S. Fröhling$^*$},
      title        = {{M}utant {KIT} as imatinib-sensitive target in metastatic
                      sinonasal carcinoma.},
      journal      = {Annals of oncology},
      volume       = {28},
      number       = {1},
      issn         = {1569-8041},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DKFZ-2017-01223},
      pages        = {142-148},
      year         = {2017},
      abstract     = {Sinonasal carcinomas (SNCs) comprise various rare tumor
                      types that are characterized by marked histologic diversity
                      and largely unknown molecular profiles, yet share an overall
                      poor prognosis owing to an aggressive clinical course and
                      frequent late-stage diagnosis. The lack of effective
                      systemic therapies for locally advanced or metastatic SNC
                      poses a major challenge to therapeutic decision making for
                      individual patients. We here aimed to identify actionable
                      genetic alterations in a patient with metastatic SNC whose
                      tumor, despite all diagnostic efforts, could not be assigned
                      to any known SNC category and was refractory to multimodal
                      therapy.We used whole-exome and transcriptome sequencing to
                      identify a KIT exon 11 mutation $(c.1733_1735del,$
                      p.D579del) as potentially druggable target in this patient
                      and carried out cancer hotspot panel sequencing to detect
                      secondary resistance-conferring mutations in KIT.
                      Furthermore, as a step towards clinical exploitation of the
                      recently described signatures of mutational processes in
                      cancer genomes, we established and applied a novel
                      bioinformatics algorithm that enables supervised analysis of
                      the mutational catalogs of individual tumors.Molecularly
                      guided treatment with imatinib in analogy to the management
                      of gastrointestinal stromal tumor (GIST) resulted in a
                      dramatic and durable response with remission of nearly all
                      tumor manifestations, indicating a dominant driver function
                      of mutant KIT in this tumor. KIT dependency was further
                      validated by a secondary KIT exon 17 mutation
                      $(c.2459_2462delATTCinsG,$ $p.D820_S821delinsG)$ that was
                      detected upon tumor progression after 10 months of imatinib
                      treatment and provided a rationale for salvage therapy with
                      regorafenib, which has activity against KIT exon 11/17
                      mutant GIST.These observations highlight the potential of
                      unbiased genomic profiling for uncovering the
                      vulnerabilities of individual malignancies, particularly in
                      rare and unclassifiable tumors, and underscore that KIT exon
                      11 mutations represent tractable therapeutic targets across
                      different histologies.},
      keywords     = {Antineoplastic Agents (NLM Chemicals) / Biomarkers, Tumor
                      (NLM Chemicals) / Imatinib Mesylate (NLM Chemicals) /
                      Proto-Oncogene Proteins c-kit (NLM Chemicals)},
      cin          = {G100 / B080 / E010 / G200 / W190 / G102 / G240 / L101 /
                      L701},
      ddc          = {610},
      cid          = {I:(DE-He78)G100-20160331 / I:(DE-He78)B080-20160331 /
                      I:(DE-He78)E010-20160331 / I:(DE-He78)G200-20160331 /
                      I:(DE-He78)W190-20160331 / I:(DE-He78)G102-20160331 /
                      I:(DE-He78)G240-20160331 / I:(DE-He78)L101-20160331 /
                      I:(DE-He78)L701-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:27687311},
      doi          = {10.1093/annonc/mdw446},
      url          = {https://inrepo02.dkfz.de/record/124344},
}