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Mutations of theBRAF gene in human cancer

Naturevolume 417, pages949–954 (2002)Cite this article

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 threeRAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS1,2,3. Here we reportBRAF 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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Figure 1: Mutations in theBRAF gene.
Figure 2: Sequence conservation and mutations in theBRAF activation segment and G loop.
Figure 3: BRAF and ERK activation.

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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.

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Author notes

  1. Helen Davies, Graham R. Bignell, Charles Cox and Philip Stephens: These authors contributed equally to this work

Authors and Affiliations

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

    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

    Adrienne Flanagan, 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

Authors
  1. Helen Davies

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  2. Graham R. Bignell

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  3. Charles Cox

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  4. Philip Stephens

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  7. Jon Teague

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  8. Hayley Woffendin

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  9. Mathew J. Garnett

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  10. William Bottomley

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  11. Neil Davis

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  33. Norman Maitland

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  35. Gregory J. Riggins

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  36. Darell D. Bigner

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  37. Giuseppe Palmieri

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  38. Antonio Cossu

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  39. Adrienne Flanagan

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  40. Andrew Nicholson

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  41. Judy W. C. Ho

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  42. Suet Y. Leung

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  43. Siu T. Yuen

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  44. Barbara L. Weber

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  45. Hilliard F. Seigler

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  46. Timothy L. Darrow

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  47. Hugh Paterson

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  48. Richard Marais

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  49. Christopher J. Marshall

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  50. Richard Wooster

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  51. Michael R. Stratton

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  52. P. Andrew Futreal

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Corresponding author

Correspondence toRichard Wooster.

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Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

41586_2002_BFnature00766_MOESM1_ESM.xls

Supplementary Table 1: Primer sequences used to amplify BRAF, HRAS, KRAS and NRAS; BRAF mutations; BRAF polymorphisms; RAS mutations; Full list of cell lines screened (XLS 69 kb)

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Davies, H., Bignell, G., Cox, C.et al. Mutations of theBRAF gene in human cancer.Nature417, 949–954 (2002). https://doi.org/10.1038/nature00766

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