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

Behjati, Sam; Tarpey, Patrick S.; Haase, Kerstin; Ye, Hongtao; Young, Matthew D.; Alexandrov, Ludmil B.; Farndon, Sarah J.; Collord, Grace; Wedge, David C.; Martincorena, Inigo; Cooke, Susanna L.; Davies, Helen; Mifsud, William; Lidgren, Mathias; Martin, Sancha; Latimer, Calli; Maddison, Mark; Butler, Adam P.; Teague, Jon W.; Pillay, Nischalan; Shlien, Adam; McDermott, Ultan; Futreal, P. Andrew; Baumhoer, Daniel; Zaikova, Olga; Bjerkehagen, Bodil; Myklebost, Ola; Amary, M. Fernanda; Tirabosco, Roberto; Van Loo, Peter; Stratton, Michael R.; Flanagan, Adrienne M.; Campbell, Peter J.

doi:10.1038/ncomms15936

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

Journal Article · Fri Jun 23 00:00:00 EDT 2017 · Nature Communications

DOI:https://doi.org/10.1038/ncomms15936· OSTI ID:1372794

Behjati, Sam ^[1]; Tarpey, Patrick S. ^[2];

^[3]; Ye, Hongtao ^[4]; Young, Matthew D. ^[2];

^[5]; Farndon, Sarah J. ^[6]; Collord, Grace ^[2];

^[7]; Martincorena, Inigo ^[2]; Cooke, Susanna L. ^[2]; Davies, Helen ^[2]; Mifsud, William ^[8]; Lidgren, Mathias ^[2]; Martin, Sancha ^[2]; Latimer, Calli ^[2]; Maddison, Mark ^[2]; Butler, Adam P. ^[2]; Teague, Jon W. ^[2]; Pillay, Nischalan ^[9] more »

Wellcome Trust Genome Campus, Cambridgeshire (United Kingdom); Univ. of Cambridge, Cambridge (United Kingdom)
Wellcome Trust Genome Campus, Cambridgeshire (United Kingdom)
The Francis Crick Institute, London (United Kingdom)
Royal National Orthopaedic Hospital, Middlesex (United Kingdom)
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Wellcome Trust Genome Campus, Cambridgeshire (United Kingdom); UCL Great Ormond Street Institute of Child Health, London (United Kingdom)
Wellcome Trust Center for Human Genetics, Oxford (United Kingdom)
UCL Great Ormond Street Institute of Child Health, London (United Kingdom)
Royal National Orthopaedic Hospital NHS Trust, Middlesex (United Kingdom); Univ. College London Cancer Institute, London (United Kingdom)
The Hospital for Sick Children, Toronto, ON (Canada)
Wellcome Trust Genome Campus, Cambridgeshire (United Kingdom); Univ. of Texas, Houston, TX (United States)
Univ. of Basel, Basel (Switzerland)
Oslo Univ. Hospital, Oslo (Norway)
Oslo Univ. Hospital, Oslo (Norway); Univ. of Bergen, Bergen (Norway)
Royal National Orthopaedic Hospital NHS Trust, Middlesex (United Kingdom)
The Francis Crick Institute, London (United Kingdom); Univ. of Leuven, Leuven (Belgium)

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. Lastly, it may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike.

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Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE Laboratory Directed Research and Development (LDRD) Program

Grant/Contract Number:: AC52-06NA25396

OSTI ID:: 1372794

Report Number(s):: LA-UR-16-27671

Journal Information:: Nature Communications, Vol. 8; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

Citation Metrics:

Cited by: 134 works

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