Mutations of the BRAF gene in human cancer.

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.

• Authors: 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, P Andrew Futreal
• Journal: Nature (Nature) Vol. 417 Issue 6892 Pg. 949-54 (Jun 27 2002) ISSN: 0028-0836 [Print] England
• PMID: 12068308 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BRAF protein, human
• Braf protein, mouse
• Proto-Oncogene Proteins B-raf
• Proto-Oncogene Proteins c-raf
• Mitogen-Activated Protein Kinases
• ras Proteins

Topics

• 3T3 Cells
• Amino Acid Sequence
• Animals
• Base Sequence
• Cell Division
• Cell Transformation, Neoplastic (genetics)
• DNA Mutational Analysis
• Enzyme Activation
• Humans
• MAP Kinase Signaling System
• Melanoma (enzymology, genetics, metabolism, pathology)
• Mice
• Mitogen-Activated Protein Kinases (metabolism)
• Molecular Sequence Data
• Mutation, Missense (genetics)
• Neoplasms (enzymology, genetics, metabolism, pathology)
• Protein Structure, Tertiary
• Proto-Oncogene Proteins B-raf
• Proto-Oncogene Proteins c-raf (chemistry, genetics, metabolism)
• Tumor Cells, Cultured
• ras Proteins (immunology, metabolism)