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Abstract

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS–RAF–MEK–ERK–MAP kinase pathway mediates cellular responses to growth signals1. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS1,2,3. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.

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Acknowledgements

We would like to thank all the patients who donated samples for these studies, the UK Children's Cancer Study Group for provision of paediatric primary tumour samples, the NCCGP for provision of cord blood control DNA samples, and W. Haynes for assistance with preparation of the manuscript. We would also like to acknowledge the Wellcome Trust, Institute of Cancer Research and Cancer Research UK for support. C.J.M. is a Gibb life fellow of the Cancer Research UK. G.P. and A.C. are funded in part by Regione Autonoma della Sardegna. B.A.G. is supported by Breakthrough Breast Cancer.

Author information

Author notes

    • Helen Davies
    • , Graham R. Bignell
    • , Charles Cox
    •  & Philip Stephens

    These authors contributed equally to this work

Affiliations

  1. Cancer Genome Project, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK

    • Helen Davies
    • , Graham R. Bignell
    • , Charles Cox
    • , Philip Stephens
    • , Sarah Edkins
    • , Sheila Clegg
    • , Jon Teague
    • , Hayley Woffendin
    • , William Bottomley
    • , Neil Davis
    • , Ed Dicks
    • , Rebecca Ewing
    • , Yvonne Floyd
    • , Kristian Gray
    • , Sarah Hall
    • , Rachel Hawes
    • , Jaime Hughes
    • , Vivian Kosmidou
    • , Andrew Menzies
    • , Catherine Mould
    • , Adrian Parker
    • , Claire Stevens
    • , Stephen Watt
    • , Richard Wooster
    • , Michael R. Stratton
    •  & P. Andrew Futreal
  2. Cancer Research UK Centre for Cell and Molecular Biology, Chester Beatty Labs, Institute of Cancer Research, London SW3 6JB, UK

    • Mathew J. Garnett
    • , Steven Hooper
    • , Rebecca Wilson
    • , Hugh Paterson
    • , Richard Marais
    •  & Christopher J. Marshall
  3. Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK

    • Hiran Jayatilake
    •  & Michael R. Stratton
  4. Section of Molecular Carcinogenesis, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK

    • Colin Cooper
    • , Janet Shipley
    •  & Richard Wooster
  5. Section of Paediatrics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK

    • Darren Hargrave
    •  & Katherine Pritchard-Jones
  6. Department of Pathology, Western Infirmary, University of Glasgow, S11 6NT, UK

    • Barry A. Gusterson
  7. Department of Biology, YCR Cancer Research Unit, University of York, York YO10 5YW, UK

    • Norman Maitland
  8. Queensland Institute of Medical Research, RBH Post Office Herston, Queensland 4029, Australia

    • Georgia Chenevix-Trench
  9. Department of Pathology, Duke University Medical Centre, Durham, North Carolina 27710, USA

    • Gregory J. Riggins
    •  & Darell D. Bigner
  10. Department of Surgery, Duke University Medical Centre, Durham, North Carolina 27710, USA

    • Hilliard F. Seigler
    •  & Timothy L. Darrow
  11. Institute of Molecular Genetics, C.N.R., Loc. Tramariglio, Alghero 07040, Italy

    • Giuseppe Palmieri
  12. Department of Pathology, University of Sassari, Azienda USL1, Sassari 07100, Italy

    • Antonio Cossu
  13. Royal Free & University College Medical School, London WC1E 6JJ, UK

    • Adrienne Flanagan
  14. Royal Brompton Hospital, London SW3 6NP, UK

    • Andrew Nicholson
  15. Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong

    • Judy W. C. Ho
  16. Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Hong Kong

    • Suet Y. Leung
    •  & Siu T. Yuen
  17. Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104, USA

    • Barbara L. Weber

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Competing interests

The authors declare that they have no competing financial interests.

Corresponding author

Correspondence to Richard Wooster.

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DOI

https://doi.org/10.1038/nature00766

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