Defective homologous recombination DNA repair as therapeutic target in advanced chordoma.

Gröschel, Stefan; Hübschmann, Daniel; Raimondi, Francesco; Horak, Peter; Warsow, Gregor; Fröhlich, Martina; Klink, Barbara; Gieldon, Laura; Hutter, Barbara; Kleinheinz, Kortine; Bonekamp, David; Marschal, Oliver; Chudasama, Priya; Mika, Jagoda; Groth, Marie; Uhrig, Sebastian; Krämer, Stephen; Heining, Christoph; Heilig, Christoph E; Richter, Daniela; Reisinger, Eva; Pfütze, Katrin; Eils, Roland; Wolf, Stephan; von Kalle, Christof; Brandts, Christian; Scholl, Claudia; Weichert, Wilko; Richter, Stephan; Bauer, Sebastian; Penzel, Roland; Schröck, Evelin; Stenzinger, Albrecht; Schlenk, Richard F; Brors, Benedikt; Russell, Robert B; Glimm, Hanno; Schlesner, Matthias; Fröhling, Stefan     «

Gröschel, Stefan; Hübschmann, Daniel; Raimondi, Francesco; Horak, Peter; Warsow, Gregor; Fröhlich, Martina; Klink, Barbara; Gieldon, Laura; Hutter, Barbara; Kleinheinz, Kortine; Bonekamp, David; Marschal, Oliver; Chudasama, Priya; Mika, Jagoda; Groth, Marie; Uhrig, Sebastian; Krämer, Stephen; Heining, Christoph; Heilig, Christoph E; Richter, Daniela; Reisinger, Eva; Pfütze, Katrin; Eils, Roland; Wolf, Stephan; von Kalle, Christof; Brandts, Christian; Scholl, Claudia; Weichert, Wilko; Richter, St...     »

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.      «

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 e...     »