Abstract

Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionizing radiation or chronic lymphoedema1. Previous work has identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signaling genes, as a key driver of angiosarcoma1. 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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Acknowledgements

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.

Author information

Author notes

    • Sam Behjati
    • , Patrick S Tarpey
    •  & Helen Sheldon

    These authors contributed equally to this work.

Affiliations

  1. Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Sam Behjati
    • , Patrick S Tarpey
    • , Inigo Martincorena
    • , Peter Van Loo
    • , Gunes Gundem
    • , David C Wedge
    • , Manasa Ramakrishna
    • , Susanna L Cooke
    • , Hans Kristian M Vollan
    • , Elli Papaemmanuil
    • , Claire Hardy
    • , Olivia R Joseph
    • , Sancha Martin
    • , Laura Mudie
    • , Adam Butler
    • , Jon W Teague
    • , Ultan McDermott
    • , Michael R Stratton
    • , P Andrew Futreal
    •  & Peter J Campbell
  2. Department of Paediatrics, University of Cambridge, Cambridge, UK.

    • Sam Behjati
  3. Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

    • Helen Sheldon
    •  & Adrian Harris
  4. Human Genome Laboratory, Department of Human Genetics, VIB and KU Leuven, Leuven, Belgium.

    • Peter Van Loo
  5. Histopathology, Royal National Orthopaedic Hospital National Health Service (NHS) Trust, Stanmore, UK.

    • Nischalan Pillay
    • , Bhavisha Khatri
    • , Dina Halai
    • , Roberto Tirabosco
    • , M Fernanda Amary
    •  & Adrienne M Flanagan
  6. University College London Cancer Institute, London, UK.

    • Nischalan Pillay
    • , Chris Boshoff
    •  & Adrienne M Flanagan
  7. Department of Oncology, Oslo University Hospital, Oslo, Norway.

    • Hans Kristian M Vollan
  8. KG Jebsen Center for Breast Cancer Research, University of Oslo, Oslo, Norway.

    • Hans Kristian M Vollan
  9. Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London, UK.

    • Hans Koss
    • , Tom D Bunney
    •  & Matilda Katan
  10. Division of Molecular Structure, Medical Research Council (MRC) National Institute for Medical Research, London, UK.

    • Hans Koss
  11. Department of Pathology, John Radcliffe Hospital, Oxford, UK.

    • Meena Patil
    • , Graham Steers
    • , Ioannis Roxanis
    •  & Adrian Harris
  12. Department of Genomic Medicine, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.

    • 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
    •  & P Andrew Futreal
  13. Bone Tumour Reference Centre, Institute of Pathology, University Hospital Basel, Institute for Applied Cancer Science, Basel, Switzerland.

    • Daniel Baumhoer
  14. Pfizer Oncology, La Jolla, California, USA.

    • Chris Boshoff
  15. Department of Haematology, Addenbrooke's Hospital, Cambridge, UK.

    • Peter J Campbell
  16. Department of Haematology, University of Cambridge, Cambridge, UK.

    • Peter J Campbell

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Contributions

S.B. and P.S.T. performed analyses of sequencing data. H.S. performed in vitro experiments. P.V.L. performed copy number analysis. D.C.W. and I.M. performed statistical analyses. S.L.C. performed rearrangement analysis. G.G., N.P., M.R., H.K.M.V. and E.P. contributed to data analysis. H.K., T.D.B. and M.K. contributed structural analyses. C.H., O.R.J., L.M., H.M., A.P., J.T., L.L., Y.C. and C.G. coordinated sample processing and technical investigations. S.M. coordinated sample acquisition. A.B., J.W.T., S.S., X.S. and J.Z. coordinated informatics analyses. B.K., D.H., D.B., M.P., G.S., I.R., R.T., M.F.A., A.M.F., C.B., V.R., K.E.T., D.I., A.J.L., G.A.A.S. and A.H. provided samples and clinical data. P.J.C., M.R.S., A.H., P.A.F., U.M. and A.M.F. directed the research. M.R.S., P.J.C., S.B. and P.S.T. wrote the manuscript, with contributions from A.H., A.M.F. and P.A.F.

Competing interests

C.B. is an employee of Pfizer.

Corresponding author

Correspondence to Peter J Campbell.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–4 and Supplementary Table 6

Excel files

  1. 1.

    Supplementary Table 1

    Clinical features of cases included in this study with likely driver mutations.

  2. 2.

    Supplementary Table 2

    Coding mutations in 11 angiosarcomas subjected to whole-genome or whole-exome sequencing.

  3. 3.

    Supplementary Table 3

    Substitutions and indels identified in three angiosarcoma genomes.

  4. 4.

    Supplementary Table 4

    Rearrangements identified in three angiosarcoma genomes.

  5. 5.

    Supplementary Table 5

    Amplification and homozygous deletions identified in three angiosarcoma genomes.

  6. 6.

    Supplementary Table 7

    Cancer genes screened by targeted sequencing.

About this article

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DOI

https://doi.org/10.1038/ng.2921

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