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; Peter J. Campbell

doi:10.1038/ncomms15936

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 PillayAdam 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, Peter J. Campbell

Division of Cancer Sciences (L5)

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	Nature Communications
DOIs	https://doi.org/10.1038/ncomms15936
Publication status	Published - 23 Jun 2017

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

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10.1038/ncomms15936Licence: CC BY

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Behjati, S., Tarpey, P. S., Haase, K., Ye, H., Young, M. D., Alexandrov, L. B., Farndon, S. J., Collord, G., Wedge, D. C., Martincorena, I., Cooke, S. L., Davies, H., Mifsud, W., Lidgren, M., Martin, S., Latimer, C., Maddison, M., Butler, A. P., Teague, J. W., ... Campbell, P. J. (2017). Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma. Nature Communications. https://doi.org/10.1038/ncomms15936

@article{66952ada08ed456e8464b01387791a90,

title = "Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma",

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.",

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

year = "2017",

month = jun,

day = "23",

doi = "10.1038/ncomms15936",

language = "English",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Springer Nature",

}

Behjati, S, Tarpey, PS, Haase, K, Ye, H, Young, MD, Alexandrov, LB, Farndon, SJ, Collord, G, Wedge, DC, Martincorena, I, Cooke, SL, Davies, H, Mifsud, W, Lidgren, M, Martin, S, Latimer, C, Maddison, M, Butler, AP, Teague, JW, Pillay, N, Shlien, A, McDermott, U, Futreal, PA, Baumhoer, D, Zaikova, O, Bjerkehagen, B, Myklebost, O, Amary, MF, Tirabosco, R, Loo, PV, Stratton, MR, Flanagan, AM & Campbell, PJ 2017, 'Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma', Nature Communications. https://doi.org/10.1038/ncomms15936

TY - JOUR

T1 - Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma

AU - Behjati, Sam

AU - Tarpey, Patrick S.

AU - Haase, Kerstin

AU - Ye, Hongtao

AU - Young, Matthew D.

AU - Alexandrov, Ludmil B.

AU - Farndon, Sarah J.

AU - Collord, Grace

AU - Wedge, David C.

AU - Martincorena, Inigo

AU - Cooke, Susanna L.

AU - Davies, Helen

AU - Mifsud, William

AU - Lidgren, Mathias

AU - Martin, Sancha

AU - Latimer, Calli

AU - Maddison, Mark

AU - Butler, Adam P.

AU - Teague, Jon W.

AU - Pillay, Nischalan

AU - Shlien, Adam

AU - McDermott, Ultan

AU - Futreal, P. Andrew

AU - Baumhoer, Daniel

AU - Zaikova, Olga

AU - Bjerkehagen, Bodil

AU - Myklebost, Ola

AU - Amary, M. Fernanda

AU - Tirabosco, Roberto

AU - Loo, Peter Van

AU - Stratton, Michael R.

AU - Flanagan, Adrienne M.

AU - Campbell, Peter J.

PY - 2017/6/23

Y1 - 2017/6/23

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms15936

DO - 10.1038/ncomms15936

M3 - Article

SN - 2041-1723

JO - Nature Communications

JF - Nature Communications

ER -

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

Abstract

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