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; Daniel Baumhoer

doi:10.1038/ncomms9940

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, Daniel Baumhoer

University Hospital of Basel
University of Oxford
Olga Hospital
Heidelberg University
Helmholtz Zentrum München German Research Center for Environmental Health
Technical University of Munich
Johann Wolfgang Goethe University
German Cancer Research Center
European Molecular Biology Laboratory Heidelberg
Slovak University of Technology in Bratislava
University Children's Hospital Basel
Klinikum Buch
Universitätsklinikum Münster
University of Munich
Universitätsklinikum Carl Gustav Carus Dresden
Charité – Universitätsmedizin Berlin
University Hospital Basel
Klinikum Kassel GmbH

Research output: Contribution to journal › Article › peer-review

284 Scopus citations

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.

Original language	English
Article number	8940
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9940
State	Published - 3 Dec 2015

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Kovac, M., Blattmann, C., Ribi, S., Smida, J., Mueller, N. S., Engert, F., Castro-Giner, F., Weischenfeldt, J., Kovacova, M., Krieg, A., Andreou, D., Tunn, P. U., Dürr, H. R., Rechl, H., Schaser, K. D., Melcher, I., Burdach, S., Kulozik, A., Specht, K., ... Baumhoer, D. (2015). Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency. Nature Communications, 6, Article 8940. https://doi.org/10.1038/ncomms9940

@article{8059218c7d854b04a3c599673a5fad06,

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.",

author = "Michal Kovac and Claudia Blattmann and Sebastian Ribi and Jan Smida and Mueller, \{Nikola S.\} and Florian Engert and Francesc Castro-Giner and Joachim Weischenfeldt and Monika Kovacova and Andreas Krieg and Dimosthenis Andreou and Tunn, \{Per Ulf\} and D{\"u}rr, \{Hans Roland\} and Hans Rechl and Schaser, \{Klaus Dieter\} and Ingo Melcher and Stefan Burdach and Andreas Kulozik and Katja Specht and Karl Heinimann and Simone Fulda and Stefan Bielack and Gernot Jundt and Ian Tomlinson and Korbel, \{Jan O.\} and Michaela Nathrath and Daniel Baumhoer",

year = "2015",

month = dec,

day = "3",

doi = "10.1038/ncomms9940",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

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Kovac, M, Blattmann, C, Ribi, S, Smida, J, Mueller, NS, Engert, F, Castro-Giner, F, Weischenfeldt, J, Kovacova, M, Krieg, A, Andreou, D, Tunn, PU, Dürr, HR, Rechl, H, Schaser, KD, Melcher, I, Burdach, S, Kulozik, A, Specht, K, Heinimann, K, Fulda, S, Bielack, S, Jundt, G, Tomlinson, I, Korbel, JO, Nathrath, M & Baumhoer, D 2015, 'Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency', Nature Communications, vol. 6, 8940. https://doi.org/10.1038/ncomms9940

TY - JOUR

T1 - Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency

AU - Kovac, Michal

AU - Blattmann, Claudia

AU - Ribi, Sebastian

AU - Smida, Jan

AU - Mueller, Nikola S.

AU - Engert, Florian

AU - Castro-Giner, Francesc

AU - Weischenfeldt, Joachim

AU - Kovacova, Monika

AU - Krieg, Andreas

AU - Andreou, Dimosthenis

AU - Tunn, Per Ulf

AU - Dürr, Hans Roland

AU - Rechl, Hans

AU - Schaser, Klaus Dieter

AU - Melcher, Ingo

AU - Burdach, Stefan

AU - Kulozik, Andreas

AU - Specht, Katja

AU - Heinimann, Karl

AU - Fulda, Simone

AU - Bielack, Stefan

AU - Jundt, Gernot

AU - Tomlinson, Ian

AU - Korbel, Jan O.

AU - Nathrath, Michaela

AU - Baumhoer, Daniel

PY - 2015/12/3

Y1 - 2015/12/3

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84949267302

U2 - 10.1038/ncomms9940

DO - 10.1038/ncomms9940

M3 - Article

C2 - 26632267

AN - SCOPUS:84949267302

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 8940

ER -

Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency

Abstract

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