Mutations of the BRAF gene in human cancer.
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.
Davies
Helen
H
Cancer Genome Project, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
Bignell
Graham R
GR
Cox
Charles
C
Stephens
Philip
P
Edkins
Sarah
S
Clegg
Sheila
S
Teague
Jon
J
Woffendin
Hayley
H
Garnett
Mathew J
MJ
Bottomley
William
W
Davis
Neil
N
Dicks
Ed
E
Ewing
Rebecca
R
Floyd
Yvonne
Y
Gray
Kristian
K
Hall
Sarah
S
Hawes
Rachel
R
Hughes
Jaime
J
Kosmidou
Vivian
V
Menzies
Andrew
A
Mould
Catherine
C
Parker
Adrian
A
Stevens
Claire
C
Watt
Stephen
S
Hooper
Steven
S
Wilson
Rebecca
R
Jayatilake
Hiran
H
Gusterson
Barry A
BA
Cooper
Colin
C
Shipley
Janet
J
Hargrave
Darren
D
Pritchard-Jones
Katherine
K
Maitland
Norman
N
Chenevix-Trench
Georgia
G
Riggins
Gregory J
GJ
Bigner
Darell D
DD
Palmieri
Giuseppe
G
Cossu
Antonio
A
Flanagan
Adrienne
A
Nicholson
Andrew
A
Ho
Judy W C
JW
Leung
Suet Y
SY
Yuen
Siu T
ST
Weber
Barbara L
BL
Seigler
Hilliard F
HF
Darrow
Timothy L
TL
Paterson
Hugh
H
Marais
Richard
R
Marshall
Christopher J
CJ
Wooster
Richard
R
Stratton
Michael R
MR
Futreal
P Andrew
PA
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
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