Mutations of the BRAF gene in human cancer

Davies, Helen, Bignell, Graham R, Cox, Charles, Stephens, Philip, Edkins, Sarah, Clegg, Sheila, Teague, Jon, Woffendin, Hayley, Garnett, Mathew J, Bottomley, William, Davis, Neil, Dicks, Ed, Ewing, Rebecca, Floyd, Yvonne, Gray, Kristian, Hawes, Rachel, Hughes, Jaime, Kosmidou, Vivian, Menzies, Andrew, Mould, Catherine, Parker, Adrian, Stevens, Claire, Watt, Stephen, Wilson, Rebecca, Jayatilake, Hiran, Gusterson, Barry A, Cooper, Colin, Shipley, Janet, Hargrave, Darren, Pritchard-Jones, Katherine, Maitland, Norman, Chenevix-Trench, Georgia, Riggins, Gregory J, Bigner, Darell D, Palmieri, Giuseppe, Cossu, Antonio, Flanagan, Adrienne, Nicholson, Andrew, Ho, Judy W C, Leung, Suet Y, Yuen, Siu T, Weber, Barbara L, Seigler, Hilliard F, Darrow, Timothy L, Paterson, Hugh, Marais, Richard, Marshall, Christopher J, Wooster, Richard, Stratton, Michael R and Futreal, P Andrew (2002) Mutations of the BRAF gene in human cancer. Nature, 417 (6892). pp. 949-54. ISSN 0028-0836

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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 signals. 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 RAS. 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.

Item Type: Article
Uncontrolled Keywords: 3t3 cells,amino acid sequence,animals,base sequence,cell division,cell transformation, neoplastic,dna mutational analysis,enzyme activation,humans,map kinase signaling system,melanoma,mice,mitogen-activated protein kinases,molecular sequence data,mutation, missense,neoplasms,protein structure, tertiary,proto-oncogene proteins b-raf,proto-oncogene proteins c-raf,tumor cells, cultured,ras proteins
Faculty \ School: Faculty of Medicine and Health Sciences > School of Rehabilitation Sciences
Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 27 Jan 2014 15:00
Last Modified: 21 Apr 2020 22:32
URI: https://ueaeprints.uea.ac.uk/id/eprint/46170
DOI: 10.1038/nature00766

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