TY - JOUR A1 - Gröschel, Stefan A1 - Hübschmann, Daniel A1 - Raimondi, Francesco A1 - Horak, Peter A1 - Warsow, Gregor A1 - Fröhlich, Martina A1 - Klink, Barbara A1 - Gieldon, Laura A1 - Hutter, Barbara A1 - Kleinheinz, Kortine A1 - Bonekamp, David A1 - Marschal, Oliver A1 - Chudasama, Priya A1 - Mika, Jagoda A1 - Groth, Marie A1 - Uhrig, Sebastian A1 - Krämer, Stephen A1 - Heining, Christoph A1 - Heilig, Christoph E. A1 - Richter, Daniela A1 - Reisinger, Eva A1 - Pfütze, Katrin A1 - Eils, Roland A1 - Wolf, Stephan A1 - Kalle, Christof von A1 - Brandts, Christian Hubertus A1 - Scholl, Claudia A1 - Weichert, Wilko A1 - Richter, Stephan A1 - Bauer, Sebastian A1 - Penzel, Roland A1 - Schröck, Evelin A1 - Stenzinger, Albrecht A1 - Schlenk, Richard Friedrich A1 - Brors, Benedikt A1 - Russell, Robert B. A1 - Glimm, Hanno A1 - Schlesner, Matthias A1 - Fröhling, Stefan T1 - Defective homologous recombination DNA repair as therapeutic target in advanced chordoma T2 - Nature Communications N2 - 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. KW - Cancer KW - Cancer genetics KW - Cancer genomics KW - Genomic instability KW - Molecular medicine Y1 - 2019 UR - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/50067 UR - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-500678 SN - 2041-1723 N1 - Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. VL - 10 IS - 1, Art. 1635 SP - 1 EP - 9 PB - Nature Publishing Group UK CY - [London] ER -