title: 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.affiliation: Cancer Genome Project, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Davies
authors.forename: Graham R
authors.initials: GR
authors.lastname: Bignell
authors.forename: Charles
authors.initials: C
authors.lastname: Cox
authors.forename: Philip
authors.initials: P
authors.lastname: Stephens
authors.forename: Sarah
authors.initials: S
authors.lastname: Edkins
authors.forename: Sheila
authors.initials: S
authors.lastname: Clegg
authors.forename: Jon
authors.initials: J
authors.lastname: Teague
authors.forename: Hayley
authors.initials: H
authors.lastname: Woffendin
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Garnett
authors.forename: William
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authors.lastname: Bottomley
authors.forename: Neil
authors.initials: N
authors.lastname: Davis
authors.forename: Ed
authors.initials: E
authors.lastname: Dicks
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ewing
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Floyd
authors.forename: Kristian
authors.initials: K
authors.lastname: Gray
authors.forename: Sarah
authors.initials: S
authors.lastname: Hall
authors.forename: Rachel
authors.initials: R
authors.lastname: Hawes
authors.forename: Jaime
authors.initials: J
authors.lastname: Hughes
authors.forename: Vivian
authors.initials: V
authors.lastname: Kosmidou
authors.forename: Andrew
authors.initials: A
authors.lastname: Menzies
authors.forename: Catherine
authors.initials: C
authors.lastname: Mould
authors.forename: Adrian
authors.initials: A
authors.lastname: Parker
authors.forename: Claire
authors.initials: C
authors.lastname: Stevens
authors.forename: Stephen
authors.initials: S
authors.lastname: Watt
authors.forename: Steven
authors.initials: S
authors.lastname: Hooper
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wilson
authors.forename: Hiran
authors.initials: H
authors.lastname: Jayatilake
authors.forename: Barry A
authors.initials: BA
authors.lastname: Gusterson
authors.forename: Colin
authors.initials: C
authors.lastname: Cooper
authors.forename: Janet
authors.initials: J
authors.lastname: Shipley
authors.forename: Darren
authors.initials: D
authors.lastname: Hargrave
authors.forename: Katherine
authors.initials: K
authors.lastname: Pritchard-Jones
authors.forename: Norman
authors.initials: N
authors.lastname: Maitland
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riggins
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palmieri
authors.forename: Antonio
authors.initials: A
authors.lastname: Cossu
authors.forename: Adrienne
authors.initials: A
authors.lastname: Flanagan
authors.forename: Andrew
authors.initials: A
authors.lastname: Nicholson
authors.forename: Judy W C
authors.initials: JW
authors.lastname: Ho
authors.forename: Suet Y
authors.initials: SY
authors.lastname: Leung
authors.forename: Siu T
authors.initials: ST
authors.lastname: Yuen
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Weber
authors.forename: Hilliard F
authors.initials: HF
authors.lastname: Seigler
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Darrow
authors.forename: Hugh
authors.initials: H
authors.lastname: Paterson
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Marshall
authors.forename: Richard
authors.initials: R
authors.lastname: Wooster
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
mesh_terms: D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D006801:Humans; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017434:Protein Structure, Tertiary; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000276:immunology / Q000378:metabolism
chemical_list: C482119:BRAF protein, human; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins