Mutations of the BRAF gene in human cancer

H Davies, G R Bignell, C Cox, P Stephens, S Edkins, S Clegg, J Teague, H Woffendin, M J Garnett, W Bottomley, N Davis, N Dicks, R Ewing, Y Floyd, K Gray, S Hall, R Hawes, J Hughes, V Kosmidou, A MenziesC Mould, A Parker, C Stevens, S Watt, S Hooper, R Wilson, H Jayatilake, B A Gusterson, C Cooper, J Shipley, D Hargrave, K Pritchard-Jones, N Maitland, G Chenevix-Trench, G J Riggins, D D Bigner, G Palmieri, A Cossu, A Flanagan, A Nicholson, J W C Ho, S Y Leung, S T Yuen, B L Weber, H F Siegler, T L Darrow, H Paterson, R Marais, C J Marshall, R Wooster, M R Stratton, P A Futreal

Research output: Contribution to journalArticlepeer-review

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(1). RAS is mutated to an oncogenic formin about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS(1-3). 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.

Original languageEnglish
Pages (from-to)949-954
Number of pages6
JournalNature
Volume417
Issue number6892
Publication statusPublished - 27 Jun 2002

Keywords

  • DEPENDENT PROTEIN-KINASE
  • TYROSINE KINASE
  • B-RAF
  • ACTIVATION
  • PATHWAY
  • PROLIFERATION
  • INHIBITOR

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