Recurrent PTPRB and PLCG1 mutations in angiosarcoma

Sam Behjati; Patrick S. Tarpey; Helen Sheldon; Inigo Martincorena; Peter Van Loo; Gunes Gundem; David C. Wedge; Manasa Ramakrishna; Susanna L. Cooke; Nischalan Pillay; Hans Kristian M. Vollan; Elli Papaemmanuil; Hans Koss; Tom D. Bunney; Claire Hardy; Olivia R. Joseph; Sancha Martin; Laura Mudie; Adam Butler; Jon W. Teague; Meena Patil; Graham Steers; Yu Cao; Curtis Gumbs; Davis Ingram; Alexander J. Lazar; Latasha Little; Harshad Mahadeshwar; Alexei Protopopov; Ghadah A. Al Sannaa; Sahil Seth; Xingzhi Song; Jiabin Tang; Jianhua Zhang; Vinod Ravi; Keila E. Torres; Bhavisha Khatri; Dina Halai; Ioannis Roxanis; Daniel Baumhoer; Roberto Tirabosco; M. Fernanda Amary; Chris Boshoff; Ultan McDermott; Matilda Katan; Michael R. Stratton; P. Andrew Futreal; Adrienne M. Flanagan; Adrian Harris; Peter J. Campbell

doi:10.1038/ng.2921

Recurrent PTPRB and PLCG1 mutations in angiosarcoma

Sam Behjati, Patrick S. Tarpey, Helen Sheldon, Inigo Martincorena, Peter Van Loo, Gunes Gundem, David C. Wedge, Manasa Ramakrishna, Susanna L. Cooke, Nischalan Pillay, Hans Kristian M. Vollan, Elli Papaemmanuil, Hans Koss, Tom D. Bunney, Claire Hardy, Olivia R. Joseph, Sancha Martin, Laura Mudie, Adam Butler, Jon W. TeagueMeena Patil, Graham Steers, Yu Cao, Curtis Gumbs, Davis Ingram, Alexander J. Lazar, Latasha Little, Harshad Mahadeshwar, Alexei Protopopov, Ghadah A. Al Sannaa, Sahil Seth, Xingzhi Song, Jiabin Tang, Jianhua Zhang, Vinod Ravi, Keila E. Torres, Bhavisha Khatri, Dina Halai, Ioannis Roxanis, Daniel Baumhoer, Roberto Tirabosco, M. Fernanda Amary, Chris Boshoff, Ultan McDermott, Matilda Katan, Michael R. Stratton, P. Andrew Futreal, Adrienne M. Flanagan, Adrian Harris, Peter J. Campbell

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Abstract

Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionizing radiation or chronic lymphoedema. Previous work has identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signaling genes, as a key driver of angiosarcoma. Here we employed whole-genome, whole-exome and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma. We identified recurrent mutations in two genes, PTPRB and PLCG1, which are intimately linked to angiogenesis. The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harbored predominantly truncating mutations in 10 of 39 tumors (26%). PLCG1, a signal transducer of tyrosine kinases, encoded a recurrent, likely activating p.Arg707Gln missense variant in 3 of 34 cases (9%). Overall, 15 of 39 tumors (38%) harbored at least one driver mutation in angiogenesis signaling genes. Our findings inform and reinforce current therapeutic efforts to target angiogenesis signaling in angiosarcoma.

Original language	English (US)
Pages (from-to)	376-379
Number of pages	4
Journal	Nature Genetics
Volume	46
Issue number	4
DOIs	https://doi.org/10.1038/ng.2921
State	Published - Apr 2014

ASJC Scopus subject areas

Genetics

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Behjati, S., Tarpey, P. S., Sheldon, H., Martincorena, I., Van Loo, P., Gundem, G., Wedge, D. C., Ramakrishna, M., Cooke, S. L., Pillay, N., Vollan, H. K. M., Papaemmanuil, E., Koss, H., Bunney, T. D., Hardy, C., Joseph, O. R., Martin, S., Mudie, L., Butler, A., ... Campbell, P. J. (2014). Recurrent PTPRB and PLCG1 mutations in angiosarcoma. Nature Genetics, 46(4), 376-379. https://doi.org/10.1038/ng.2921

Behjati, S, Tarpey, PS, Sheldon, H, Martincorena, I, Van Loo, P, Gundem, G, Wedge, DC, Ramakrishna, M, Cooke, SL, Pillay, N, Vollan, HKM, Papaemmanuil, E, Koss, H, Bunney, TD, Hardy, C, Joseph, OR, Martin, S, Mudie, L, Butler, A, Teague, JW, Patil, M, Steers, G, Cao, Y, Gumbs, C, Ingram, D, Lazar, AJ, Little, L, Mahadeshwar, H, Protopopov, A, Al Sannaa, GA, Seth, S, Song, X, Tang, J, Zhang, J, Ravi, V , Torres, KE, Khatri, B, Halai, D, Roxanis, I, Baumhoer, D, Tirabosco, R, Amary, MF, Boshoff, C, McDermott, U, Katan, M, Stratton, MR, Futreal, PA, Flanagan, AM, Harris, A & Campbell, PJ 2014, 'Recurrent PTPRB and PLCG1 mutations in angiosarcoma', Nature Genetics, vol. 46, no. 4, pp. 376-379. https://doi.org/10.1038/ng.2921

@article{2d8bf90275b740758d419f367a03fb2d,

title = "Recurrent PTPRB and PLCG1 mutations in angiosarcoma",

abstract = "Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionizing radiation or chronic lymphoedema. Previous work has identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signaling genes, as a key driver of angiosarcoma. Here we employed whole-genome, whole-exome and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma. We identified recurrent mutations in two genes, PTPRB and PLCG1, which are intimately linked to angiogenesis. The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harbored predominantly truncating mutations in 10 of 39 tumors (26%). PLCG1, a signal transducer of tyrosine kinases, encoded a recurrent, likely activating p.Arg707Gln missense variant in 3 of 34 cases (9%). Overall, 15 of 39 tumors (38%) harbored at least one driver mutation in angiogenesis signaling genes. Our findings inform and reinforce current therapeutic efforts to target angiogenesis signaling in angiosarcoma.",

author = "Sam Behjati and Tarpey, {Patrick S.} and Helen Sheldon and Inigo Martincorena and {Van Loo}, Peter and Gunes Gundem and Wedge, {David C.} and Manasa Ramakrishna and Cooke, {Susanna L.} and Nischalan Pillay and Vollan, {Hans Kristian M.} and Elli Papaemmanuil and Hans Koss and Bunney, {Tom D.} and Claire Hardy and Joseph, {Olivia R.} and Sancha Martin and Laura Mudie and Adam Butler and Teague, {Jon W.} and Meena Patil and Graham Steers and Yu Cao and Curtis Gumbs and Davis Ingram and Lazar, {Alexander J.} and Latasha Little and Harshad Mahadeshwar and Alexei Protopopov and {Al Sannaa}, {Ghadah A.} and Sahil Seth and Xingzhi Song and Jiabin Tang and Jianhua Zhang and Vinod Ravi and Torres, {Keila E.} and Bhavisha Khatri and Dina Halai and Ioannis Roxanis and Daniel Baumhoer and Roberto Tirabosco and Amary, {M. Fernanda} and Chris Boshoff and Ultan McDermott and Matilda Katan and Stratton, {Michael R.} and Futreal, {P. Andrew} and Flanagan, {Adrienne M.} and Adrian Harris and Campbell, {Peter J.}",

note = "Funding Information: We thank M. Taylor and R. Leek for sample preparation. We are grateful to the patients for participating in the research and to the clinicians and support staff involved in their care from the Oxford University Hospitals NHS Trust, the University of Texas MD Anderson Cancer Center Sarcoma Program and the London Sarcoma Service. This work was supported by funding from the Wellcome Trust (grant reference 077012/Z/05/Z). The material was obtained from the Royal National Orthopaedic Hospital Musculoskeletal Research Program and Biobank and from the Oxford Radcliffe 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 Cancer Research UK University College London Experimental Cancer Medicine Centre. Support was provided to A.H. by Cancer Research UK, the Oxford Biomedical Research Centre and the Breast Cancer Research Foundation. P.J.C. is personally funded through a Wellcome Trust Senior Clinical Research Fellowship (grant reference WT088340MA). P.V.L. is a postdoctoral researcher of the Research Foundation–Flanders (FWO). H.K.M.V. is supported by the Norwegian Radium Hospital{\textquoteright}s Foundation. S.B. is funded through the Wellcome Trust PhD Programme for Clinicians. P.A.F. is supported by the Cancer Prevention Research Institute of Texas and the Welch Foundation.",

year = "2014",

month = apr,

doi = "10.1038/ng.2921",

language = "English (US)",

volume = "46",

pages = "376--379",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "4",

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TY - JOUR

T1 - Recurrent PTPRB and PLCG1 mutations in angiosarcoma

AU - Behjati, Sam

AU - Tarpey, Patrick S.

AU - Sheldon, Helen

AU - Martincorena, Inigo

AU - Van Loo, Peter

AU - Gundem, Gunes

AU - Wedge, David C.

AU - Ramakrishna, Manasa

AU - Cooke, Susanna L.

AU - Pillay, Nischalan

AU - Vollan, Hans Kristian M.

AU - Papaemmanuil, Elli

AU - Koss, Hans

AU - Bunney, Tom D.

AU - Hardy, Claire

AU - Joseph, Olivia R.

AU - Martin, Sancha

AU - Mudie, Laura

AU - Butler, Adam

AU - Teague, Jon W.

AU - Patil, Meena

AU - Steers, Graham

AU - Cao, Yu

AU - Gumbs, Curtis

AU - Ingram, Davis

AU - Lazar, Alexander J.

AU - Little, Latasha

AU - Mahadeshwar, Harshad

AU - Protopopov, Alexei

AU - Al Sannaa, Ghadah A.

AU - Seth, Sahil

AU - Song, Xingzhi

AU - Tang, Jiabin

AU - Zhang, Jianhua

AU - Ravi, Vinod

AU - Torres, Keila E.

AU - Khatri, Bhavisha

AU - Halai, Dina

AU - Roxanis, Ioannis

AU - Baumhoer, Daniel

AU - Tirabosco, Roberto

AU - Amary, M. Fernanda

AU - Boshoff, Chris

AU - McDermott, Ultan

AU - Katan, Matilda

AU - Stratton, Michael R.

AU - Futreal, P. Andrew

AU - Flanagan, Adrienne M.

AU - Harris, Adrian

AU - Campbell, Peter J.

N1 - Funding Information: We thank M. Taylor and R. Leek for sample preparation. We are grateful to the patients for participating in the research and to the clinicians and support staff involved in their care from the Oxford University Hospitals NHS Trust, the University of Texas MD Anderson Cancer Center Sarcoma Program and the London Sarcoma Service. This work was supported by funding from the Wellcome Trust (grant reference 077012/Z/05/Z). The material was obtained from the Royal National Orthopaedic Hospital Musculoskeletal Research Program and Biobank and from the Oxford Radcliffe 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 Cancer Research UK University College London Experimental Cancer Medicine Centre. Support was provided to A.H. by Cancer Research UK, the Oxford Biomedical Research Centre and the Breast Cancer Research Foundation. P.J.C. is personally funded through a Wellcome Trust Senior Clinical Research Fellowship (grant reference WT088340MA). P.V.L. is a postdoctoral researcher of the Research Foundation–Flanders (FWO). H.K.M.V. is supported by the Norwegian Radium Hospital’s Foundation. S.B. is funded through the Wellcome Trust PhD Programme for Clinicians. P.A.F. is supported by the Cancer Prevention Research Institute of Texas and the Welch Foundation.

PY - 2014/4

Y1 - 2014/4

N2 - Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionizing radiation or chronic lymphoedema. Previous work has identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signaling genes, as a key driver of angiosarcoma. Here we employed whole-genome, whole-exome and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma. We identified recurrent mutations in two genes, PTPRB and PLCG1, which are intimately linked to angiogenesis. The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harbored predominantly truncating mutations in 10 of 39 tumors (26%). PLCG1, a signal transducer of tyrosine kinases, encoded a recurrent, likely activating p.Arg707Gln missense variant in 3 of 34 cases (9%). Overall, 15 of 39 tumors (38%) harbored at least one driver mutation in angiogenesis signaling genes. Our findings inform and reinforce current therapeutic efforts to target angiogenesis signaling in angiosarcoma.

AB - Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionizing radiation or chronic lymphoedema. Previous work has identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signaling genes, as a key driver of angiosarcoma. Here we employed whole-genome, whole-exome and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma. We identified recurrent mutations in two genes, PTPRB and PLCG1, which are intimately linked to angiogenesis. The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harbored predominantly truncating mutations in 10 of 39 tumors (26%). PLCG1, a signal transducer of tyrosine kinases, encoded a recurrent, likely activating p.Arg707Gln missense variant in 3 of 34 cases (9%). Overall, 15 of 39 tumors (38%) harbored at least one driver mutation in angiogenesis signaling genes. Our findings inform and reinforce current therapeutic efforts to target angiogenesis signaling in angiosarcoma.

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ER -

Recurrent PTPRB and PLCG1 mutations in angiosarcoma

Abstract

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