Mutations of the BRAF gene in human cancer

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; Rachel Hawes; Jaime Hughes; Vivian Kosmidou; Andrew Menzies; Catherine Mould; Adrian Parker; Claire Stevens; Stephen Watt; 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

doi:10.1038/nature00766

Mutations of the BRAF gene in human cancer

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, Rachel Hawes, Jaime Hughes, Vivian Kosmidou, Andrew Menzies, Catherine MouldAdrian Parker, Claire Stevens, Stephen Watt, 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

Research output: Contribution to journal › Article › peer-review

8861 Citations (SciVal)

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.

Original language	English
Pages (from-to)	949-54
Number of pages	6
Journal	Nature
Volume	417
Issue number	6892
DOIs	https://doi.org/10.1038/nature00766
Publication status	Published - 27 Jun 2002

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

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This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/nature00766

Cite this

@article{af46117bbdf34627836e7354177c0eca,

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.",

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",

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

year = "2002",

month = jun,

day = "27",

doi = "10.1038/nature00766",

language = "English",

volume = "417",

pages = "949--54",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "6892",

}

Davies, H, Bignell, GR, Cox, C, Stephens, P, Edkins, S, Clegg, S, Teague, J, Woffendin, H, Garnett, MJ, Bottomley, W, Davis, N, Dicks, E, Ewing, R, Floyd, Y, Gray, K, Hawes, R, Hughes, J, Kosmidou, V, Menzies, A, Mould, C, Parker, A, Stevens, C, Watt, S, Wilson, R, Jayatilake, H, Gusterson, BA, Cooper, C, Shipley, J, Hargrave, D, Pritchard-Jones, K, Maitland, N, Chenevix-Trench, G, Riggins, GJ, Bigner, DD, Palmieri, G, Cossu, A, Flanagan, A, Nicholson, A, Ho, JWC, Leung, SY, Yuen, ST, Weber, BL, Seigler, HF, Darrow, TL, Paterson, H, Marais, R, Marshall, CJ, Wooster, R, Stratton, MR & Futreal, PA 2002, 'Mutations of the BRAF gene in human cancer', Nature, vol. 417, no. 6892, pp. 949-54. https://doi.org/10.1038/nature00766

TY - JOUR

T1 - Mutations of the BRAF gene in human cancer

AU - Davies, Helen

AU - Bignell, Graham R

AU - Cox, Charles

AU - Stephens, Philip

AU - Edkins, Sarah

AU - Clegg, Sheila

AU - Teague, Jon

AU - Woffendin, Hayley

AU - Garnett, Mathew J

AU - Bottomley, William

AU - Davis, Neil

AU - Dicks, Ed

AU - Ewing, Rebecca

AU - Floyd, Yvonne

AU - Gray, Kristian

AU - Hawes, Rachel

AU - Hughes, Jaime

AU - Kosmidou, Vivian

AU - Menzies, Andrew

AU - Mould, Catherine

AU - Parker, Adrian

AU - Stevens, Claire

AU - Watt, Stephen

AU - Wilson, Rebecca

AU - Jayatilake, Hiran

AU - Gusterson, Barry A

AU - Cooper, Colin

AU - Shipley, Janet

AU - Hargrave, Darren

AU - Pritchard-Jones, Katherine

AU - Maitland, Norman

AU - Chenevix-Trench, Georgia

AU - Riggins, Gregory J

AU - Bigner, Darell D

AU - Palmieri, Giuseppe

AU - Cossu, Antonio

AU - Flanagan, Adrienne

AU - Nicholson, Andrew

AU - Ho, Judy W C

AU - Leung, Suet Y

AU - Yuen, Siu T

AU - Weber, Barbara L

AU - Seigler, Hilliard F

AU - Darrow, Timothy L

AU - Paterson, Hugh

AU - Marais, Richard

AU - Marshall, Christopher J

AU - Wooster, Richard

AU - Stratton, Michael R

AU - Futreal, P Andrew

PY - 2002/6/27

Y1 - 2002/6/27

N2 - 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.

AB - 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.

KW - 3T3 Cells

KW - Amino Acid Sequence

KW - Animals

KW - Base Sequence

KW - Cell Division

KW - Cell Transformation, Neoplastic

KW - DNA Mutational Analysis

KW - Enzyme Activation

KW - Humans

KW - MAP Kinase Signaling System

KW - Melanoma

KW - Mice

KW - Mitogen-Activated Protein Kinases

KW - Molecular Sequence Data

KW - Mutation, Missense

KW - Neoplasms

KW - Protein Structure, Tertiary

KW - Proto-Oncogene Proteins B-raf

KW - Proto-Oncogene Proteins c-raf

KW - Tumor Cells, Cultured

KW - ras Proteins

U2 - 10.1038/nature00766

DO - 10.1038/nature00766

M3 - Article

C2 - 12068308

VL - 417

SP - 949

EP - 954

JO - Nature

JF - Nature

SN - 0028-0836

IS - 6892

ER -