Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma

Sam Behjati, Patrick S. Tarpey, Kerstin Haase, Hongtao Ye, Matthew D. Young, Ludmil B. Alexandrov, Sarah J. Farndon, Grace Collord, David C. Wedge, Inigo Martincorena, Susanna L. Cooke, Helen Davies, William Mifsud, Mathias Lidgren, Sancha Martin, Calli Latimer, Mark Maddison, Adam P. Butler, Jon W. Teague, Nischalan Pillay, Adam Shlien, Ultan McDermott, P. Andrew Futreal, Daniel Baumhoer, Olga Zaikova, Bodil Bjerkehagen, Ola Myklebost, M. Fernanda Amary, Roberto Tirabosco, Peter Van Loo, Michael R. Stratton, Adrienne M. Flanagan and Peter J. Campbell ()
Additional contact information
Sam Behjati: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Patrick S. Tarpey: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Kerstin Haase: The Francis Crick Institute
Hongtao Ye: Royal National Orthopaedic Hospital NHS Trust
Matthew D. Young: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Ludmil B. Alexandrov: Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory
Sarah J. Farndon: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Grace Collord: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
David C. Wedge: Oxford Big Data Institute and Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, Roosevelt Drive
Inigo Martincorena: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Susanna L. Cooke: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Helen Davies: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
William Mifsud: UCL Great Ormond Street Institute of Child Health
Mathias Lidgren: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Sancha Martin: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Calli Latimer: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Mark Maddison: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Adam P. Butler: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Jon W. Teague: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Nischalan Pillay: Royal National Orthopaedic Hospital NHS Trust
Adam Shlien: The Hospital for Sick Children
Ultan McDermott: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
P. Andrew Futreal: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Daniel Baumhoer: Bone Tumour Reference Centre, Institute of Pathology, University Hospital Basel, University of Basel
Olga Zaikova: Oslo University Hospital
Bodil Bjerkehagen: Oslo University Hospital
Ola Myklebost: Oslo University Hospital
M. Fernanda Amary: Royal National Orthopaedic Hospital NHS Trust
Roberto Tirabosco: Royal National Orthopaedic Hospital NHS Trust
Peter Van Loo: The Francis Crick Institute
Michael R. Stratton: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Adrienne M. Flanagan: Royal National Orthopaedic Hospital NHS Trust
Peter J. Campbell: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus

Nature Communications, 2017, vol. 8, issue 1, 1-8

Abstract: Abstract Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation, we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. It may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike.

Date: 2017
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DOI: 10.1038/ncomms15936

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