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Title: The driver landscape of sporadic chordoma

Abstract

Chordoma is a malignant, often incurable bone tumour showing notochordal differentiation. Here, we defined the somatic driver landscape of 104 cases of sporadic chordoma. We reveal somatic duplications of the notochordal transcription factor brachyury (T) in up to 27% of cases. These variants recapitulate the rearrangement architecture of the pathogenic germline duplications of T that underlie familial chordoma. In addition, we find potentially clinically actionable PI3K signalling mutations in 16% of cases. Intriguingly, one of the most frequently altered genes, mutated exclusively by inactivating mutation, was LYST (10%), which may represent a novel cancer gene in chordoma.

Authors:
 [1];  [2];  [1];  [1]; ORCiD logo [3];  [4];  [1];  [1];  [1];  [1];  [1];  [5];  [6]; ORCiD logo [7];  [7];  [7];  [7];  [7];  [8]; ORCiD logo [9] more »;  [10];  [10];  [11];  [11];  [12];  [13];  [13];  [14];  [7];  [1];  [14];  [15] « less
  1. Wellcome Trust Genome Campus, Hinxton (United Kingdom). Cancer Genome Project. Wellcome Trust Sanger Inst.
  2. Wellcome Trust Genome Campus, Hinxton (United Kingdom). Cancer Genome Project. Wellcome Trust Sanger Inst.; Univ. of Cambridge (United Kingdom). Dept. of Paediatrics; Corpus Christi College, Cambridge (United Kingdom)
  3. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  4. Wellcome Trust Genome Campus, Hinxton (United Kingdom). Cancer Genome Project. Wellcome Trust Sanger Inst.; UCL Great Ormond Street Inst. of Child Health, London (United Kingdom)
  5. The Hospital for Sick Children, Toronto, ON (Canada). Dept. of Paediatric Laboratory Medicine
  6. Univ. of Texas, Houston, TX (United States). Dept. of Genomic Medicine. MD Anderson Cancer Center
  7. Univ. of British Columbia, Vancouver, BC (Canada)
  8. Univ. of Basel (Switzerland). Bone Tumour Reference Centre. Inst. of Pathology. University Hospital Basel
  9. Univ. College Hospital NHS Foundation Trust and UCL Inst. of Neurology, London (United Kingdom). Division of Neuropathology. Dept. of Neurodegenerative Disease. The National Hospital for Neurology and Neurosurgery
  10. Mount Sinai Hospital, Toronto, ON (Canada). Dept. of Pathology and Lab. Medicine
  11. Chordoma Foundation, Durham, NC (United States)
  12. Univ. of California, San Francisco, CA (United States). Dept. of Neurosurgery
  13. Royal National Orthopaedic Hospital NHS Trust, Stanmore (United Kingdom). Dept. of Histopathology
  14. Royal National Orthopaedic Hospital NHS Trust, Stanmore (United Kingdom). Dept. of Histopathology; Univ. College London Cancer Inst., London (United Kingdom)
  15. Wellcome Trust Genome Campus, Hinxton (United Kingdom). Cancer Genome Project. Wellcome Trust Sanger Inst.; Univ. of Cambridge (United Kingdom). Dept. of Haematology
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE; Wellcome Trust (United Kingdom); Skeletal Cancer Action Trust UK (United Kingdom); Royal National Orthopaedic Hospital NHS Trust (United Kingdom); Rosetrees Trust (United Kingdom); Chordoma Foundation USA (United States); Chordoma UK (United Kingdom) Terry Fox Research Inst. (Canada); National Inst. for Health Research (NIHR) (United Kingdom); UCLH Biomedical Research Centre (United Kingdom); UCL Experimental Cancer Centre (United Kingdom)
OSTI Identifier:
1402623
Report Number(s):
LA-UR-17-20423
Journal ID: ISSN 2041-1723
Grant/Contract Number:
AC52-06NA25396
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 8; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Biological Science

Citation Formats

Tarpey, Patrick S., Behjati, Sam, Young, Matthew D., Martincorena, Inigo, Alexandrov, Ludmil B., Farndon, Sarah J., Guzzo, Charlotte, Hardy, Claire, Latimer, Calli, Butler, Adam P., Teague, Jon W., Shlien, Adam, Futreal, P. Andrew, Shah, Sohrab, Bashashati, Ali, Jamshidi, Farzad, Nielsen, Torsten O., Huntsman, David, Baumhoer, Daniel, Brandner, Sebastian, Wunder, Jay, Dickson, Brendan, Cogswell, Patricia, Sommer, Josh, Phillips, Joanna J., Amary, M. Fernanda, Tirabosco, Roberto, Pillay, Nischalan, Yip, Stephen, Stratton, Michael R., Flanagan, Adrienne M., and Campbell, Peter J. The driver landscape of sporadic chordoma. United States: N. p., 2017. Web. doi:10.1038/s41467-017-01026-0.
Tarpey, Patrick S., Behjati, Sam, Young, Matthew D., Martincorena, Inigo, Alexandrov, Ludmil B., Farndon, Sarah J., Guzzo, Charlotte, Hardy, Claire, Latimer, Calli, Butler, Adam P., Teague, Jon W., Shlien, Adam, Futreal, P. Andrew, Shah, Sohrab, Bashashati, Ali, Jamshidi, Farzad, Nielsen, Torsten O., Huntsman, David, Baumhoer, Daniel, Brandner, Sebastian, Wunder, Jay, Dickson, Brendan, Cogswell, Patricia, Sommer, Josh, Phillips, Joanna J., Amary, M. Fernanda, Tirabosco, Roberto, Pillay, Nischalan, Yip, Stephen, Stratton, Michael R., Flanagan, Adrienne M., & Campbell, Peter J. The driver landscape of sporadic chordoma. United States. doi:10.1038/s41467-017-01026-0.
Tarpey, Patrick S., Behjati, Sam, Young, Matthew D., Martincorena, Inigo, Alexandrov, Ludmil B., Farndon, Sarah J., Guzzo, Charlotte, Hardy, Claire, Latimer, Calli, Butler, Adam P., Teague, Jon W., Shlien, Adam, Futreal, P. Andrew, Shah, Sohrab, Bashashati, Ali, Jamshidi, Farzad, Nielsen, Torsten O., Huntsman, David, Baumhoer, Daniel, Brandner, Sebastian, Wunder, Jay, Dickson, Brendan, Cogswell, Patricia, Sommer, Josh, Phillips, Joanna J., Amary, M. Fernanda, Tirabosco, Roberto, Pillay, Nischalan, Yip, Stephen, Stratton, Michael R., Flanagan, Adrienne M., and Campbell, Peter J. Thu . "The driver landscape of sporadic chordoma". United States. doi:10.1038/s41467-017-01026-0. https://www.osti.gov/servlets/purl/1402623.
@article{osti_1402623,
title = {The driver landscape of sporadic chordoma},
author = {Tarpey, Patrick S. and Behjati, Sam and Young, Matthew D. and Martincorena, Inigo and Alexandrov, Ludmil B. and Farndon, Sarah J. and Guzzo, Charlotte and Hardy, Claire and Latimer, Calli and Butler, Adam P. and Teague, Jon W. and Shlien, Adam and Futreal, P. Andrew and Shah, Sohrab and Bashashati, Ali and Jamshidi, Farzad and Nielsen, Torsten O. and Huntsman, David and Baumhoer, Daniel and Brandner, Sebastian and Wunder, Jay and Dickson, Brendan and Cogswell, Patricia and Sommer, Josh and Phillips, Joanna J. and Amary, M. Fernanda and Tirabosco, Roberto and Pillay, Nischalan and Yip, Stephen and Stratton, Michael R. and Flanagan, Adrienne M. and Campbell, Peter J.},
abstractNote = {Chordoma is a malignant, often incurable bone tumour showing notochordal differentiation. Here, we defined the somatic driver landscape of 104 cases of sporadic chordoma. We reveal somatic duplications of the notochordal transcription factor brachyury (T) in up to 27% of cases. These variants recapitulate the rearrangement architecture of the pathogenic germline duplications of T that underlie familial chordoma. In addition, we find potentially clinically actionable PI3K signalling mutations in 16% of cases. Intriguingly, one of the most frequently altered genes, mutated exclusively by inactivating mutation, was LYST (10%), which may represent a novel cancer gene in chordoma.},
doi = {10.1038/s41467-017-01026-0},
journal = {Nature Communications},
number = ,
volume = 8,
place = {United States},
year = {Thu Oct 12 00:00:00 EDT 2017},
month = {Thu Oct 12 00:00:00 EDT 2017}
}

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