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@ARTICLE{Grschel:143513,
      author       = {S. Gröschel$^*$ and D. Hübschmann$^*$ and F. Raimondi and
                      P. Horak$^*$ and G. Warsow$^*$ and M. Fröhlich$^*$ and B.
                      Klink and L. Gieldon$^*$ and B. Hutter$^*$ and K.
                      Kleinheinz$^*$ and D. Bonekamp$^*$ and O. Marschal and P.
                      Chudasama$^*$ and J. Mika$^*$ and M. Groth and S. Uhrig$^*$
                      and S. Krämer$^*$ and C. Heining and C. Heilig$^*$ and D.
                      Richter$^*$ and E. Reisinger$^*$ and K. Pfütze$^*$ and R.
                      Eils$^*$ and S. Wolf$^*$ and C. von Kalle$^*$ and C.
                      Brandts$^*$ and C. Scholl$^*$ and W. Weichert$^*$ and S.
                      Richter and S. Bauer$^*$ and R. Penzel$^*$ and E.
                      Schröck$^*$ and A. Stenzinger$^*$ and R. Schlenk$^*$ and B.
                      Brors$^*$ and R. B. Russell and H. Glimm$^*$ and M.
                      Schlesner$^*$ and S. Fröhling$^*$},
      title        = {{D}efective homologous recombination {DNA} repair as
                      therapeutic target in advanced chordoma.},
      journal      = {Nature Communications},
      volume       = {10},
      number       = {1},
      issn         = {2041-1723},
      address      = {[London]},
      publisher    = {Nature Publishing Group UK},
      reportid     = {DKFZ-2019-01097},
      pages        = {1635},
      year         = {2019},
      abstract     = {Chordomas are rare bone tumors with few therapeutic
                      options. Here we show, using whole-exome and genome
                      sequencing within a precision oncology program, that
                      advanced chordomas (n = 11) may be characterized by
                      genomic patterns indicative of defective homologous
                      recombination (HR) DNA repair and alterations affecting
                      HR-related genes, including, for example, deletions and
                      pathogenic germline variants of BRCA2, NBN, and CHEK2. A
                      mutational signature associated with HR deficiency was
                      significantly enriched in $72.7\%$ of samples and
                      co-occurred with genomic instability. The poly(ADP-ribose)
                      polymerase (PARP) inhibitor olaparib, which is
                      preferentially toxic to HR-incompetent cells, led to
                      prolonged clinical benefit in a patient with refractory
                      chordoma, and whole-genome analysis at progression revealed
                      a PARP1 p.T910A mutation predicted to disrupt the
                      autoinhibitory PARP1 helical domain. These findings uncover
                      a therapeutic opportunity in chordoma that warrants further
                      exploration, and provide insight into the mechanisms
                      underlying PARP inhibitor resistance.},
      cin          = {A380 / L101 / B080 / A010 / B340 / B240 / B330 / E010 /
                      A360 / W190 / B290 / L301 / L501 / L701 / L401},
      ddc          = {500},
      cid          = {I:(DE-He78)A380-20160331 / I:(DE-He78)L101-20160331 /
                      I:(DE-He78)B080-20160331 / I:(DE-He78)A010-20160331 /
                      I:(DE-He78)B340-20160331 / I:(DE-He78)B240-20160331 /
                      I:(DE-He78)B330-20160331 / I:(DE-He78)E010-20160331 /
                      I:(DE-He78)A360-20160331 / I:(DE-He78)W190-20160331 /
                      I:(DE-He78)B290-20160331 / I:(DE-He78)L301-20160331 /
                      I:(DE-He78)L501-20160331 / I:(DE-He78)L701-20160331 /
                      I:(DE-He78)L401-20160331},
      pnm          = {311 - Signalling pathways, cell and tumor biology
                      (POF3-311)},
      pid          = {G:(DE-HGF)POF3-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30967556},
      pmc          = {pmc:PMC6456501},
      doi          = {10.1038/s41467-019-09633-9},
      url          = {https://inrepo02.dkfz.de/record/143513},
}