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@ARTICLE{Bochtler:153234,
      author       = {T. Bochtler$^*$ and A. Reiling$^*$ and V. Endris$^*$ and T.
                      Hielscher$^*$ and A.-L. Volckmar and O. Neumann and M.
                      Kirchner and J. Budczies and L. C. Heukamp and J.
                      Leichsenring and M. Allgäuer and D. Kazdal and H.
                      Löffler$^*$ and W. Weichert$^*$ and P. Schirmacher and A.
                      Stenzinger$^*$ and A. Krämer$^*$},
      title        = {{I}ntegrated clinico-molecular characterization identifies
                      {RAS} activation and {CDKN}2{A} deletion as independent
                      adverse prognostic factors in cancer of unknown primary.},
      journal      = {International journal of cancer},
      volume       = {146},
      number       = {11},
      issn         = {1097-0215},
      address      = {Bognor Regis},
      publisher    = {Wiley-Liss},
      reportid     = {DKFZ-2020-00267},
      pages        = {3053-3064},
      year         = {2020},
      note         = {2020 Jun 1;146(11):3053-3064#EA:A360#LA:A360#},
      abstract     = {Cancer of unknown primary (CUP) denotes a malignancy with
                      histologically confirmed metastatic spread while the primary
                      tumor remains elusive. Here, we address prognostic and
                      therapeutic implications of mutations and copy number
                      variations (CNVs) detected in tumor tissue in the context of
                      a comprehensive clinical risk assessment. Targeted panel
                      sequencing was performed in 252 CUP patients. $71.8\%$ of
                      patients had unfavorable CUP according to ESMO guidelines.
                      $74.7\%$ were adeno- and $13.7\%$ squamous cell carcinomas.
                      DNA was extracted from micro-dissected formalin-fixed,
                      paraffin-embedded tissues. For library preparation, mostly
                      multiplex PCR-based Ion Torrent AmpliSeqTM technology with
                      Oncomine comprehensive assays was used. Most frequent
                      genetic alterations were mutations/deletions of TP53
                      $(49.6\%),$ CDKN2A $(19.0\%)$ and NOTCH1 $(14.1\%)$ as well
                      as oncogenic activation of KRAS $(23.4\%),$ FGFR4 $(14.9\%)$
                      and PIK3CA $(10.7\%).$ KRAS activation was predominantly
                      found in adenocarcinomas (P=0.01), PIK3CA activation in
                      squamous cell carcinomas (P=0.03). Male sex, high ECOG
                      score, unfavorable CUP, higher number of involved organs and
                      RAS activation predicted decreased event-free and overall
                      survival in multivariate analysis. Deletions of CDKN2A were
                      prognostically adverse regarding overall survival. TP53
                      mutations did not significantly influence prognosis in the
                      overall cohort, but worsened prognosis in otherwise
                      favorable CUP subtypes. Although not standard in CUP, for
                      17/198 $(8.6\%)$ patients molecularly targeted treatment was
                      recommended and 10 patients $(5.1\%)$ were treated
                      accordingly. In conclusion, besides the identification of
                      drug targets, panel sequencing in CUP is prognostically
                      relevant, with RAS activation and CDKN2A deletion emerging
                      as novel independent risk factors in a comprehensive
                      assessment with clinico-pathological data. This article is
                      protected by copyright. All rights reserved.},
      cin          = {A360 / HD01 / C060 / MU01},
      ddc          = {610},
      cid          = {I:(DE-He78)A360-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)C060-20160331 / I:(DE-He78)MU01-20160331},
      pnm          = {311 - Signalling pathways, cell and tumor biology
                      (POF3-311)},
      pid          = {G:(DE-HGF)POF3-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31970771},
      doi          = {10.1002/ijc.32882},
      url          = {https://inrepo02.dkfz.de/record/153234},
}