BRAF and RAS mutations in human lung cancer and melanoma.
BRAF encodes a RAS-regulated kinase that mediates cell growth and malignant transformation kinase pathway activation. Recently, we have identified activating BRAF mutations in 66% of melanomas and a smaller percentage of many other human cancers. To determine whether BRAF mutations account for the MAP kinase pathway activation common in non-small cell lung carcinomas (NSCLCs) and to extend the initial findings in melanoma, we screened DNA from 179 NSCLCs and 35 melanomas for BRAF mutations (exons 11 and 15). We identified BRAF mutations in 5 NSCLCs (3%; one V599 and four non-V599) and 22 melanomas (63%; 21 V599 and 1 non-V599). Three BRAF mutations identified in this study are novel, altering residues important in AKT-mediated BRAF phosphorylation and suggesting that disruption of AKT-induced BRAF inhibition can play a role in malignant transformation. To our knowledge, this is the first report of mutations documenting this interaction in human cancers. Although >90% of BRAF mutations in melanoma involve codon 599 (57 of 60), 8 of 9 BRAF mutations reported to date in NSCLC are non-V599 (89%; P < 10(-7)), strongly suggesting that BRAF mutations in NSCLC are qualitatively different from those in melanoma; thus, there may be therapeutic differences between lung cancer and melanoma in response to RAF inhibitors. Although uncommon, BRAF mutations in human lung cancers may identify a subset of tumors sensitive to targeted therapy.
Brose
Marcia S
MS
Department of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center, Philadelphia 19104, USA.
Volpe
Patricia
P
Feldman
Michael
M
Kumar
Madhu
M
Rishi
Irum
I
Gerrero
Renee
R
Einhorn
Eugene
E
Herlyn
Meenhard
M
Minna
John
J
Nicholson
Andrew
A
Roth
Jack A
JA
Albelda
Steven M
SM
Davies
Helen
H
Cox
Charles
C
Brignell
Graham
G
Stephens
Philip
P
Futreal
P Andrew
PA
Wooster
Richard
R
Stratton
Michael R
MR
Weber
Barbara L
BL
D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D003062:Codon; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D014407:Tumor Cells, Cultured
D003062:Codon; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases