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

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.
Authors:
 [1] ;  [2] ; ORCiD logo [3] ;  [4] ;  [2] ; ORCiD logo [5] ;  [6] ;  [2] ; ORCiD logo [7] ;  [2] ;  [2] ;  [2] ;  [8] ;  [2] ;  [2] ;  [2] ;  [2] ;  [2] ;  [2] ;  [9] more »;  [10] ; ORCiD logo [2] ;  [11] ;  [12] ;  [13] ;  [13] ; ORCiD logo [14] ;  [15] ;  [15] ; ORCiD logo [16] ;  [2] ;  [9] ;  [1] « less
  1. Wellcome Trust Genome Campus, Cambridgeshire (United Kingdom); Univ. of Cambridge, Cambridge (United Kingdom)
  2. Wellcome Trust Genome Campus, Cambridgeshire (United Kingdom)
  3. The Francis Crick Institute, London (United Kingdom)
  4. Royal National Orthopaedic Hospital, Middlesex (United Kingdom)
  5. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  6. Wellcome Trust Genome Campus, Cambridgeshire (United Kingdom); UCL Great Ormond Street Institute of Child Health, London (United Kingdom)
  7. Wellcome Trust Center for Human Genetics, Oxford (United Kingdom)
  8. UCL Great Ormond Street Institute of Child Health, London (United Kingdom)
  9. Royal National Orthopaedic Hospital NHS Trust, Middlesex (United Kingdom); Univ. College London Cancer Institute, London (United Kingdom)
  10. The Hospital for Sick Children, Toronto, ON (Canada)
  11. Wellcome Trust Genome Campus, Cambridgeshire (United Kingdom); Univ. of Texas, Houston, TX (United States)
  12. Univ. of Basel, Basel (Switzerland)
  13. Oslo Univ. Hospital, Oslo (Norway)
  14. Oslo Univ. Hospital, Oslo (Norway); Univ. of Bergen, Bergen (Norway)
  15. Royal National Orthopaedic Hospital NHS Trust, Middlesex (United Kingdom)
  16. The Francis Crick Institute, London (United Kingdom); Univ. of Leuven, Leuven (Belgium)
Publication Date:
Report Number(s):
LA-UR-16-27671
Journal ID: ISSN 2041-1723
Grant/Contract Number:
AC52-06NA25396
Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 8; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE Laboratory Directed Research and Development (LDRD) Program
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; Biological Science
OSTI Identifier:
1372794

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., and Campbell, Peter J.. Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma. United States: N. p., Web. doi:10.1038/ncomms15936.
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.. Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma. United States. doi:10.1038/ncomms15936.
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., and Campbell, Peter J.. 2017. "Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma". United States. doi:10.1038/ncomms15936. https://www.osti.gov/servlets/purl/1372794.
@article{osti_1372794,
title = {Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma},
author = {Behjati, Sam and Tarpey, Patrick S. and Haase, Kerstin and Ye, Hongtao and Young, Matthew D. and Alexandrov, Ludmil B. and Farndon, Sarah J. and Collord, Grace and Wedge, David C. and Martincorena, Inigo and Cooke, Susanna L. and Davies, Helen and Mifsud, William and Lidgren, Mathias and Martin, Sancha and Latimer, Calli and Maddison, Mark and Butler, Adam P. and Teague, Jon W. and Pillay, Nischalan and Shlien, Adam and McDermott, Ultan and Futreal, P. Andrew and Baumhoer, Daniel and Zaikova, Olga and Bjerkehagen, Bodil and Myklebost, Ola and Amary, M. Fernanda and Tirabosco, Roberto and Van Loo, Peter and Stratton, Michael R. and Flanagan, Adrienne M. and Campbell, Peter J.},
abstractNote = {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.},
doi = {10.1038/ncomms15936},
journal = {Nature Communications},
number = ,
volume = 8,
place = {United States},
year = {2017},
month = {6}
}