title: Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency.
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.
authors.affiliation: Bone Tumour Reference Center at the Institute of Pathology, University Hospital Basel, Schönbeinstrasse 40, 4031 Basel, Switzerland.|The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Michal
authors.initials: M
authors.lastname: Kovac
authors.affiliation: Pediatrics 5 (Oncology, Hematology, Immunology), Klinikum Stuttgart Olgahospital, Kriegsbergstrasse 62, 70174 Stuttgart, Germany.|Department of Pediatric Hematology, Oncology, Immunology and Pulmology, University of Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Blattmann
authors.affiliation: Bone Tumour Reference Center at the Institute of Pathology, University Hospital Basel, Schönbeinstrasse 40, 4031 Basel, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ribi
authors.affiliation: Institute of Radiation Biology, Clinical Cooperation Group Osteosarcoma, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.|Pediatric Oncology Center, Department of Pediatrics, Technische Universität München and Comprehensive Cancer Center, Kölner Platz 1, 80804 Munich, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Smida
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors.forename: Nikola S
authors.initials: NS
authors.lastname: Mueller
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstrasse 3a, 60528 Frankfurt, Germany.|German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.|German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Engert
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Francesc
authors.identifier: http://orcid.org/0000-0001-6111-0754
authors.initials: F
authors.lastname: Castro-Giner
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Weischenfeldt
authors.affiliation: The Institute of Mathematics and Physics, Faculty of Mechanical Engineering, Slovak University of Technology, 84248 Bratislava, Slovak Republic.
authors.forename: Monika
authors.initials: M
authors.lastname: Kovacova
authors.affiliation: Orthopaedic Department, Basel University Childrens Hospital (UKBB), Spitalstrasse 33, 4056 Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Krieg
authors.affiliation: Department of Orthopedic Oncology, Sarcoma Center Berlin-Brandenburg, HELIOS Klinikum Berlin-Buch, Schwanebecker Chaussee 50, 13125 Berlin, Germany.
authors.forename: Dimosthenis
authors.identifier: http://orcid.org/0000-0002-5083-9678
authors.initials: D
authors.lastname: Andreou
authors.affiliation: Department of Orthopedic Oncology, Sarcoma Center Berlin-Brandenburg, HELIOS Klinikum Berlin-Buch, Schwanebecker Chaussee 50, 13125 Berlin, Germany.
authors.forename: Per-Ulf
authors.initials: PU
authors.lastname: Tunn
authors.affiliation: Department of Orthopedic Surgery, Ludwig-Maximilians-University Munich, Campus Grosshadern, Marchionistrasse 15, 81377 Munich, Germany.
authors.forename: Hans Roland
authors.initials: HR
authors.lastname: Dürr
authors.affiliation: Clinic and Policlinic of Orthopedics and Sports Orthopedics, Technische Universität München, Ismaninger Strasse 22, 81675 Munich, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Rechl
authors.affiliation: Department of Orthopaedics and Trauma Surgery, University Hospital Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Schaser
authors.affiliation: Center for Musculoskeletal Surgery, Charité-University Medicine Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Melcher
authors.affiliation: Pediatric Oncology Center, Department of Pediatrics, Technische Universität München and Comprehensive Cancer Center, Kölner Platz 1, 80804 Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Burdach
authors.affiliation: Department of Pediatric Hematology, Oncology, Immunology and Pulmology, University of Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kulozik
authors.affiliation: Institute of Pathology, Technische Universität München, Trogerstrasse 18, 81675 Munich, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Specht
authors.affiliation: Medical Genetics, University Hospital Basel, Burgfelderstrasse 101, 4055 Basel, Switzerland.
authors.forename: Karl
authors.initials: K
authors.lastname: Heinimann
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstrasse 3a, 60528 Frankfurt, Germany.|German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.|German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
authors.affiliation: Pediatrics 5 (Oncology, Hematology, Immunology), Klinikum Stuttgart Olgahospital, Kriegsbergstrasse 62, 70174 Stuttgart, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bielack
authors.affiliation: Bone Tumour Reference Center at the Institute of Pathology, University Hospital Basel, Schönbeinstrasse 40, 4031 Basel, Switzerland.
authors.forename: Gernot
authors.initials: G
authors.lastname: Jundt
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Jan O
authors.identifier: http://orcid.org/0000-0002-2798-3794
authors.initials: JO
authors.lastname: Korbel
authors.affiliation: Institute of Radiation Biology, Clinical Cooperation Group Osteosarcoma, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.|Pediatric Oncology Center, Department of Pediatrics, Technische Universität München and Comprehensive Cancer Center, Kölner Platz 1, 80804 Munich, Germany.|Department of Pediatric Oncology, Klinikum Kassel, Mönchebergstrasse 41-43, 34125 Kassel, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Nathrath
authors.affiliation: Bone Tumour Reference Center at the Institute of Pathology, University Hospital Basel, Schönbeinstrasse 40, 4031 Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Baumhoer
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D059472:Exome / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D009154:Mutation; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D010793:Phthalazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology
chemical_list: D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C586365:talazoparib