Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency

Michal Kovac, Claudia Blattmann, Sebastian Ribi, Jan Smida, Nikola S. Mueller, Florian Engert, Francesc Castro-Giner, Joachim Weischenfeldt, Monika Kovacova, Andreas Krieg, Dimosthenis Andreou, Per-Ulf Tunn, Hans Roland Dürr, Hans Rechl, Klaus-Dieter Schaser, Ingo Melcher, Stefan Burdach, Andreas Kulozik, Katja Specht, Karl Heinimann, Simone Fulda, Stefan Bielack, Gernot Jundt, Ian Tomlinson, Jan O. Korbel, Michaela Nathrath and Daniel Baumhoer ()
Additional contact information
Michal Kovac: Bone Tumour Reference Center at the Institute of Pathology, University Hospital Basel
Claudia Blattmann: Pediatrics 5 (Oncology, Hematology, Immunology), Klinikum Stuttgart Olgahospital
Sebastian Ribi: Bone Tumour Reference Center at the Institute of Pathology, University Hospital Basel
Jan Smida: Institute of Radiation Biology, Clinical Cooperation Group Osteosarcoma, Helmholtz Zentrum München
Nikola S. Mueller: Institute of Computational Biology, Helmholtz Zentrum München
Florian Engert: Institute for Experimental Cancer Research in Pediatrics, Goethe-University
Francesc Castro-Giner: The Wellcome Trust Centre for Human Genetics, University of Oxford
Joachim Weischenfeldt: European Molecular Biology Laboratory (EMBL), Genome Biology Unit
Monika Kovacova: The Institute of Mathematics and Physics, Faculty of Mechanical Engineering, Slovak University of Technology
Andreas Krieg: Basel University Childrens Hospital (UKBB)
Dimosthenis Andreou: Sarcoma Center Berlin-Brandenburg, HELIOS Klinikum Berlin-Buch
Per-Ulf Tunn: Sarcoma Center Berlin-Brandenburg, HELIOS Klinikum Berlin-Buch
Hans Roland Dürr: Ludwig-Maximilians-University Munich, Campus Grosshadern
Hans Rechl: Clinic and Policlinic of Orthopedics and Sports Orthopedics, Technische Universität München
Klaus-Dieter Schaser: University Hospital Dresden
Ingo Melcher: Center for Musculoskeletal Surgery, Charité—University Medicine Berlin, Campus Virchow Klinikum
Stefan Burdach: Pediatric Oncology Center, Technische Universität München and Comprehensive Cancer Center
Andreas Kulozik: Oncology, Immunology and Pulmology, University of Heidelberg
Katja Specht: Institute of Pathology, Technische Universität München
Karl Heinimann: Medical Genetics, University Hospital Basel
Simone Fulda: Institute for Experimental Cancer Research in Pediatrics, Goethe-University
Stefan Bielack: Pediatrics 5 (Oncology, Hematology, Immunology), Klinikum Stuttgart Olgahospital
Gernot Jundt: Bone Tumour Reference Center at the Institute of Pathology, University Hospital Basel
Ian Tomlinson: The Wellcome Trust Centre for Human Genetics, University of Oxford
Jan O. Korbel: European Molecular Biology Laboratory (EMBL), Genome Biology Unit
Michaela Nathrath: Institute of Radiation Biology, Clinical Cooperation Group Osteosarcoma, Helmholtz Zentrum München
Daniel Baumhoer: Bone Tumour Reference Center at the Institute of Pathology, University Hospital Basel

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: Abstract Osteosarcomas are aggressive bone tumours with a high degree of genetic heterogeneity, which has historically complicated driver gene discovery. Here we sequence exomes of 31 tumours and decipher their evolutionary landscape by inferring clonality of the individual mutation events. Exome findings are interpreted in the context of mutation and SNP array data from a replication set of 92 tumours. We identify 14 genes as the main drivers, of which some were formerly unknown in the context of osteosarcoma. None of the drivers is clearly responsible for the majority of tumours and even TP53 mutations are frequently mapped into subclones. However, >80% of osteosarcomas exhibit a specific combination of single-base substitutions, LOH, or large-scale genome instability signatures characteristic of BRCA1/2-deficient tumours. Our findings imply that multiple oncogenic pathways drive chromosomal instability during osteosarcoma evolution and result in the acquisition of BRCA-like traits, which could be therapeutically exploited.

Date: 2015
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DOI: 10.1038/ncomms9940

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