Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma

Patrick S. Tarpey; Sam Behjati; Susanna L. Cooke; Peter Van Loo; David C. Wedge; Nischalan Pillay; John Marshall; Sarah O. Meara; Helen Davies; Serena Nik Zainal; David Beare; Adam Butler; John Gamble; Claire Hardy; Jonathon Hinton; Ming Ming Jia; Alagu Jayakumar; David Jones; Calli Latimer; Mark Maddison; Sancha Martin; Stuart McLaren; Andrew Menzies; Laura Mudie; Keiran Raine; Jon W. Teague; Jose M.C. Tubio; Dina Halai; Roberto Tirabosco; Fernanda Amary; Peter J. Campbell; Michael R. Stratton; Adrienne M. Flanagan; P. Andrew Futreal

doi:10.1038/ng.2668

Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma

Patrick S. Tarpey, Sam Behjati, Susanna L. Cooke, Peter Van Loo, David C. Wedge, Nischalan Pillay, John Marshall, Sarah O. Meara, Helen Davies, Serena Nik Zainal, David Beare, Adam Butler, John Gamble, Claire Hardy, Jonathon Hinton, Ming Ming Jia, Alagu Jayakumar, David Jones, Calli Latimer, Mark MaddisonSancha Martin, Stuart McLaren, Andrew Menzies, Laura Mudie, Keiran Raine, Jon W. Teague, Jose M.C. Tubio, Dina Halai, Roberto Tirabosco, Fernanda Amary, Peter J. Campbell, Michael R. Stratton, Adrienne M. Flanagan, P. Andrew Futreal

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Abstract

Chondrosarcoma is a heterogeneous collection of malignant bone tumors and is the second most common primary malignancy of bone after osteosarcoma. Recent work has identified frequent, recurrent mutations in IDH1 or IDH2 in nearly half of central chondrosarcomas. However, there has been little systematic genomic analysis of this tumor type, and, thus, the contribution of other genes is unclear. Here we report comprehensive genomic analyses of 49 individuals with chondrosarcoma (cases). We identified hypermutability of the major cartilage collagen gene COL2A1, with insertions, deletions and rearrangements identified in 37% of cases. The patterns of mutation were consistent with selection for variants likely to impair normal collagen biosynthesis. In addition, we identified mutations in IDH1 or IDH2 (59%), TP53 (20%), the RB1 pathway (33%) and Hedgehog signaling (18%).

Original language	English (US)
Pages (from-to)	923-926
Number of pages	4
Journal	Nature Genetics
Volume	45
Issue number	8
DOIs	https://doi.org/10.1038/ng.2668
State	Published - Aug 2013
Externally published	Yes

ASJC Scopus subject areas

Genetics

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Tarpey, P. S., Behjati, S., Cooke, S. L., Van Loo, P., Wedge, D. C., Pillay, N., Marshall, J., Meara, S. O., Davies, H., Zainal, S. N., Beare, D., Butler, A., Gamble, J., Hardy, C., Hinton, J., Jia, M. M., Jayakumar, A., Jones, D., Latimer, C., ... Futreal, P. A. (2013). Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma. Nature Genetics, 45(8), 923-926. https://doi.org/10.1038/ng.2668

Tarpey, PS, Behjati, S, Cooke, SL, Van Loo, P, Wedge, DC, Pillay, N, Marshall, J, Meara, SO, Davies, H, Zainal, SN, Beare, D, Butler, A, Gamble, J, Hardy, C, Hinton, J, Jia, MM, Jayakumar, A, Jones, D, Latimer, C, Maddison, M, Martin, S, McLaren, S, Menzies, A, Mudie, L, Raine, K, Teague, JW, Tubio, JMC, Halai, D, Tirabosco, R, Amary, F, Campbell, PJ, Stratton, MR, Flanagan, AM & Futreal, PA 2013, 'Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma', Nature Genetics, vol. 45, no. 8, pp. 923-926. https://doi.org/10.1038/ng.2668

@article{930c87f5f3d54c40ae87045311c3bade,

title = "Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma",

abstract = "Chondrosarcoma is a heterogeneous collection of malignant bone tumors and is the second most common primary malignancy of bone after osteosarcoma. Recent work has identified frequent, recurrent mutations in IDH1 or IDH2 in nearly half of central chondrosarcomas. However, there has been little systematic genomic analysis of this tumor type, and, thus, the contribution of other genes is unclear. Here we report comprehensive genomic analyses of 49 individuals with chondrosarcoma (cases). We identified hypermutability of the major cartilage collagen gene COL2A1, with insertions, deletions and rearrangements identified in 37% of cases. The patterns of mutation were consistent with selection for variants likely to impair normal collagen biosynthesis. In addition, we identified mutations in IDH1 or IDH2 (59%), TP53 (20%), the RB1 pathway (33%) and Hedgehog signaling (18%).",

author = "Tarpey, {Patrick S.} and Sam Behjati and Cooke, {Susanna L.} and {Van Loo}, Peter and Wedge, {David C.} and Nischalan Pillay and John Marshall and Meara, {Sarah O.} and Helen Davies and Zainal, {Serena Nik} and David Beare and Adam Butler and John Gamble and Claire Hardy and Jonathon Hinton and Jia, {Ming Ming} and Alagu Jayakumar and David Jones and Calli Latimer and Mark Maddison and Sancha Martin and Stuart McLaren and Andrew Menzies and Laura Mudie and Keiran Raine and Teague, {Jon W.} and Tubio, {Jose M.C.} and Dina Halai and Roberto Tirabosco and Fernanda Amary and Campbell, {Peter J.} and Stratton, {Michael R.} and Flanagan, {Adrienne M.} and Futreal, {P. Andrew}",

note = "Funding Information: We are grateful to the patients for participating in the research and to the clinicians and support staff of the London Sarcoma Service involved in their care. This work was supported by funding from the Wellcome Trust (grant 077012/Z/05/Z) and the Skeletal Cancer Action Trust (SCAT), UK. Material was obtained from the Royal National Orthopaedic Hospital Musculoskeletal Research Program and Biobank. Support was provided to A.M.F. by the National Institute for Health Research, the University College London Hospital Biomedical Research Centre and the UCL Experimental Cancer Centre. P.J.C. is personally funded through a Wellcome Trust Senior Clinical Research Fellowship (grant WT088340MA). P.V.L. is a postdoctoral researcher of the Research Foundation–Flanders (FWO). S.B. is funded through the Wellcome Trust PhD Programme for Clinicians.",

year = "2013",

month = aug,

doi = "10.1038/ng.2668",

language = "English (US)",

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T1 - Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma

AU - Tarpey, Patrick S.

AU - Behjati, Sam

AU - Cooke, Susanna L.

AU - Van Loo, Peter

AU - Wedge, David C.

AU - Pillay, Nischalan

AU - Marshall, John

AU - Meara, Sarah O.

AU - Davies, Helen

AU - Zainal, Serena Nik

AU - Beare, David

AU - Butler, Adam

AU - Gamble, John

AU - Hardy, Claire

AU - Hinton, Jonathon

AU - Jia, Ming Ming

AU - Jayakumar, Alagu

AU - Jones, David

AU - Latimer, Calli

AU - Maddison, Mark

AU - Martin, Sancha

AU - McLaren, Stuart

AU - Menzies, Andrew

AU - Mudie, Laura

AU - Raine, Keiran

AU - Teague, Jon W.

AU - Tubio, Jose M.C.

AU - Halai, Dina

AU - Tirabosco, Roberto

AU - Amary, Fernanda

AU - Campbell, Peter J.

AU - Stratton, Michael R.

AU - Flanagan, Adrienne M.

AU - Futreal, P. Andrew

N1 - Funding Information: We are grateful to the patients for participating in the research and to the clinicians and support staff of the London Sarcoma Service involved in their care. This work was supported by funding from the Wellcome Trust (grant 077012/Z/05/Z) and the Skeletal Cancer Action Trust (SCAT), UK. Material was obtained from the Royal National Orthopaedic Hospital Musculoskeletal Research Program and Biobank. Support was provided to A.M.F. by the National Institute for Health Research, the University College London Hospital Biomedical Research Centre and the UCL Experimental Cancer Centre. P.J.C. is personally funded through a Wellcome Trust Senior Clinical Research Fellowship (grant WT088340MA). P.V.L. is a postdoctoral researcher of the Research Foundation–Flanders (FWO). S.B. is funded through the Wellcome Trust PhD Programme for Clinicians.

PY - 2013/8

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N2 - Chondrosarcoma is a heterogeneous collection of malignant bone tumors and is the second most common primary malignancy of bone after osteosarcoma. Recent work has identified frequent, recurrent mutations in IDH1 or IDH2 in nearly half of central chondrosarcomas. However, there has been little systematic genomic analysis of this tumor type, and, thus, the contribution of other genes is unclear. Here we report comprehensive genomic analyses of 49 individuals with chondrosarcoma (cases). We identified hypermutability of the major cartilage collagen gene COL2A1, with insertions, deletions and rearrangements identified in 37% of cases. The patterns of mutation were consistent with selection for variants likely to impair normal collagen biosynthesis. In addition, we identified mutations in IDH1 or IDH2 (59%), TP53 (20%), the RB1 pathway (33%) and Hedgehog signaling (18%).

AB - Chondrosarcoma is a heterogeneous collection of malignant bone tumors and is the second most common primary malignancy of bone after osteosarcoma. Recent work has identified frequent, recurrent mutations in IDH1 or IDH2 in nearly half of central chondrosarcomas. However, there has been little systematic genomic analysis of this tumor type, and, thus, the contribution of other genes is unclear. Here we report comprehensive genomic analyses of 49 individuals with chondrosarcoma (cases). We identified hypermutability of the major cartilage collagen gene COL2A1, with insertions, deletions and rearrangements identified in 37% of cases. The patterns of mutation were consistent with selection for variants likely to impair normal collagen biosynthesis. In addition, we identified mutations in IDH1 or IDH2 (59%), TP53 (20%), the RB1 pathway (33%) and Hedgehog signaling (18%).

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Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma

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