Microarray expression profiling in melanoma reveals a BRAF mutation signature.
We have used microarray gene expression profiling and machine learning to predict the presence of BRAF mutations in a panel of 61 melanoma cell lines. The BRAF gene was found to be mutated in 42 samples (69%) and intragenic mutations of the NRAS gene were detected in seven samples (11%). No cell line carried mutations of both genes. Using support vector machines, we have built a classifier that differentiates between melanoma cell lines based on BRAF mutation status. As few as 83 genes are able to discriminate between BRAF mutant and BRAF wild-type samples with clear separation observed using hierarchical clustering. Multidimensional scaling was used to visualize the relationship between a BRAF mutation signature and that of a generalized mitogen-activated protein kinase (MAPK) activation (either BRAF or NRAS mutation) in the context of the discriminating gene list. We observed that samples carrying NRAS mutations lie somewhere between those with or without BRAF mutations. These observations suggest that there are gene-specific mutation signals in addition to a common MAPK activation that result from the pleiotropic effects of either BRAF or NRAS on other signaling pathways, leading to measurably different transcriptional changes.
Pavey
Sandra
S
Queensland Institute of Medical Research, 300 Herston Rd, Herston, Queensland 4006, Australia.
Johansson
Peter
P
Packer
Leisl
L
Taylor
Jennifer
J
Stark
Mitchell
M
Pollock
Pamela M
PM
Walker
Graeme J
GJ
Boyle
Glen M
GM
Harper
Ursula
U
Cozzi
Sarah-Jane
SJ
Hansen
Katherine
K
Yudt
Laura
L
Schmidt
Chris
C
Hersey
Peter
P
Ellem
Kay A O
KA
O'Rourke
Michael G E
MG
Parsons
Peter G
PG
Meltzer
Paul
P
Ringnér
Markus
M
Hayward
Nicholas K
NK
D019943:Amino Acid Substitution; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics
C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins