Letters to Nature

Nature 417, 949-954 (27 June 2002) | doi:10.1038/nature00766; Received 2 February 2002; Accepted 16 May 2002; Published online 9 June 2002

Mutations of the BRAF gene in human cancer

Helen Davies1,2, Graham R. Bignell1,2, Charles Cox1,2, Philip Stephens1,2, Sarah Edkins1, Sheila Clegg1, Jon Teague1, Hayley Woffendin1, Mathew J. Garnett3, William Bottomley1, Neil Davis1, Ed Dicks1, Rebecca Ewing1, Yvonne Floyd1, Kristian Gray1, Sarah Hall1, Rachel Hawes1, Jaime Hughes1, Vivian Kosmidou1, Andrew Menzies1, Catherine Mould1, Adrian Parker1, Claire Stevens1, Stephen Watt1, Steven Hooper3, Rebecca Wilson3, Hiran Jayatilake4, Barry A. Gusterson5, Colin Cooper6, Janet Shipley6, Darren Hargrave7, Katherine Pritchard-Jones7, Norman Maitland8, Georgia Chenevix-Trench9, Gregory J. Riggins10, Darell D. Bigner10, Giuseppe Palmieri11, Antonio Cossu12, Adrienne Flanagan13, Andrew Nicholson14, Judy W. C. Ho15, Suet Y. Leung16, Siu T. Yuen16, Barbara L. Weber17, Hilliard F. Seigler18, Timothy L. Darrow18, Hugh Paterson3, Richard Marais3, Christopher J. Marshall3, Richard Wooster1,6, Michael R. Stratton1,4 & P. Andrew Futreal1

  1. Cancer Genome Project, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK
  2. Cancer Research UK Centre for Cell and Molecular Biology, Chester Beatty Labs, Institute of Cancer Research, London SW3 6JB, UK
  3. Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
  4. Section of Molecular Carcinogenesis, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
  5. Section of Paediatrics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
  6. Department of Pathology, Western Infirmary, University of Glasgow, S11 6NT, UK
  7. Department of Biology, YCR Cancer Research Unit, University of York, York YO10 5YW, UK
  8. Queensland Institute of Medical Research, RBH Post Office Herston, Queensland 4029, Australia
  9. Department of Pathology, Duke University Medical Centre, Durham, North Carolina 27710, USA
  10. Department of Surgery, Duke University Medical Centre, Durham, North Carolina 27710, USA
  11. Institute of Molecular Genetics, C.N.R., Loc. Tramariglio, Alghero 07040, Italy
  12. Department of Pathology, University of Sassari, Azienda USL1, Sassari 07100, Italy
  13. Royal Free & University College Medical School, London WC1E 6JJ, UK
  14. Royal Brompton Hospital, London SW3 6NP, UK
  15. Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong
  16. Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Hong Kong
  17. Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104, USA
  18. These authors contributed equally to this work

Correspondence to: Richard Wooster1,6 Correspondence and requests for materials should be addressed to R.W. (e-mail: Email: rw1@sanger.ac.uk).

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.