Mutations of the BRAF gene in human cancer

Helen Davies, Graham R. Bignell, Charles Cox, Philip Stephens, Sarah Edkins, Sheila Clegg, Jon Teague, Hayley Woffendin, Mathew J. Garnett, 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, Steven Hooper, Rebecca Wilson, Hiran Jayatilake, Barry A. Gusterson, Colin Cooper, Janet Shipley, Darren Hargrave, Katherine Pritchard-Jones, Norman Maitland, Georgia Chenevix-Trench, Gregory J. Riggins, Darell D. Bigner, Giuseppe Palmieri, Antonio Cossu, Adrienne Flanagan, Andrew Nicholson, Judy W. C. Ho, Suet Y. Leung, Siu T. Yuen, Barbara L. Weber, Hilliard F. Seigler, Timothy L. Darrow, Hugh Paterson, Richard Marais, Christopher J. Marshall, Richard Wooster (), Michael R. Stratton and P. Andrew Futreal
Additional contact information
Helen Davies: Wellcome Trust Genome Campus
Graham R. Bignell: Wellcome Trust Genome Campus
Charles Cox: Wellcome Trust Genome Campus
Philip Stephens: Wellcome Trust Genome Campus
Sarah Edkins: Wellcome Trust Genome Campus
Sheila Clegg: Wellcome Trust Genome Campus
Jon Teague: Wellcome Trust Genome Campus
Hayley Woffendin: Wellcome Trust Genome Campus
Mathew J. Garnett: Institute of Cancer Research
William Bottomley: Wellcome Trust Genome Campus
Neil Davis: Wellcome Trust Genome Campus
Ed Dicks: Wellcome Trust Genome Campus
Rebecca Ewing: Wellcome Trust Genome Campus
Yvonne Floyd: Wellcome Trust Genome Campus
Kristian Gray: Wellcome Trust Genome Campus
Sarah Hall: Wellcome Trust Genome Campus
Rachel Hawes: Wellcome Trust Genome Campus
Jaime Hughes: Wellcome Trust Genome Campus
Vivian Kosmidou: Wellcome Trust Genome Campus
Andrew Menzies: Wellcome Trust Genome Campus
Catherine Mould: Wellcome Trust Genome Campus
Adrian Parker: Wellcome Trust Genome Campus
Claire Stevens: Wellcome Trust Genome Campus
Stephen Watt: Wellcome Trust Genome Campus
Steven Hooper: Institute of Cancer Research
Rebecca Wilson: Institute of Cancer Research
Hiran Jayatilake: Institute of Cancer Research
Barry A. Gusterson: University of Glasgow
Colin Cooper: Institute of Cancer Research
Janet Shipley: Institute of Cancer Research
Darren Hargrave: Institute of Cancer Research
Katherine Pritchard-Jones: Institute of Cancer Research
Norman Maitland: University of York
Georgia Chenevix-Trench: RBH Post Office Herston
Gregory J. Riggins: Duke University Medical Centre
Darell D. Bigner: Duke University Medical Centre
Giuseppe Palmieri: Institute of Molecular Genetics, C.N.R
Antonio Cossu: University of Sassari
Adrienne Flanagan: Duke University Medical Centre
Andrew Nicholson: Royal Brompton Hospital
Judy W. C. Ho: The University of Hong Kong, Queen Mary Hospital
Suet Y. Leung: The University of Hong Kong, Queen Mary Hospital
Siu T. Yuen: The University of Hong Kong, Queen Mary Hospital
Barbara L. Weber: University of Pennsylvania Cancer Center
Hilliard F. Seigler: Duke University Medical Centre
Timothy L. Darrow: Duke University Medical Centre
Hugh Paterson: Institute of Cancer Research
Richard Marais: Institute of Cancer Research
Christopher J. Marshall: Institute of Cancer Research
Richard Wooster: Wellcome Trust Genome Campus
Michael R. Stratton: Wellcome Trust Genome Campus
P. Andrew Futreal: Wellcome Trust Genome Campus

Nature, 2002, vol. 417, issue 6892, 949-954

Abstract: 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.

Date: 2002
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DOI: 10.1038/nature00766

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