Somatic mutations of the protein kinase gene family in human lung cancer.
Protein kinases are frequently mutated in human cancer and inhibitors of mutant protein kinases have proven to be effective anticancer drugs. We screened the coding sequences of 518 protein kinases (approximately 1.3 Mb of DNA per sample) for somatic mutations in 26 primary lung neoplasms and seven lung cancer cell lines. One hundred eighty-eight somatic mutations were detected in 141 genes. Of these, 35 were synonymous (silent) changes. This result indicates that most of the 188 mutations were "passenger" mutations that are not causally implicated in oncogenesis. However, an excess of approximately 40 nonsynonymous substitutions compared with that expected by chance (P = 0.07) suggests that some nonsynonymous mutations have been selected and are contributing to oncogenesis. There was considerable variation between individual lung cancers in the number of mutations observed and no mutations were found in lung carcinoids. The mutational spectra of most lung cancers were characterized by a high proportion of C:G > A:T transversions, compatible with the mutagenic effects of tobacco carcinogens. However, one neuroendocrine cancer cell line had a distinctive mutational spectrum reminiscent of UV-induced DNA damage. The results suggest that several mutated protein kinases may be contributing to lung cancer development, but that mutations in each one are infrequent.
Davies
Helen
H
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, United Kingdom.
Hunter
Chris
C
Smith
Raffaella
R
Stephens
Philip
P
Greenman
Chris
C
Bignell
Graham
G
Teague
Jon
J
Butler
Adam
A
Edkins
Sarah
S
Stevens
Claire
C
Parker
Adrian
A
O'Meara
Sarah
S
Avis
Tim
T
Barthorpe
Syd
S
Brackenbury
Lisa
L
Buck
Gemma
G
Clements
Jody
J
Cole
Jennifer
J
Dicks
Ed
E
Edwards
Ken
K
Forbes
Simon
S
Gorton
Matthew
M
Gray
Kristian
K
Halliday
Kelly
K
Harrison
Rachel
R
Hills
Katy
K
Hinton
Jonathon
J
Jones
David
D
Kosmidou
Vivienne
V
Laman
Ross
R
Lugg
Richard
R
Menzies
Andrew
A
Perry
Janet
J
Petty
Robert
R
Raine
Keiran
K
Shepherd
Rebecca
R
Small
Alexandra
A
Solomon
Helen
H
Stephens
Yvonne
Y
Tofts
Calli
C
Varian
Jennifer
J
Webb
Anthony
A
West
Sofie
S
Widaa
Sara
S
Yates
Andrew
A
Brasseur
Francis
F
Cooper
Colin S
CS
Flanagan
Adrienne M
AM
Green
Anthony
A
Knowles
Maggie
M
Leung
Suet Y
SY
Looijenga
Leendert H J
LH
Malkowicz
Bruce
B
Pierotti
Marco A
MA
Teh
Bin T
BT
Yuen
Siu T
ST
Lakhani
Sunil R
SR
Easton
Douglas F
DF
Weber
Barbara L
BL
Goldstraw
Peter
P
Nicholson
Andrew G
AG
Wooster
Richard
R
Stratton
Michael R
MR
Futreal
P Andrew
PA
D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics; D002276:Carcinoid Tumor / Q000201:enzymology / Q000235:genetics; D018287:Carcinoma, Large Cell / Q000201:enzymology / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics*; D009154:Mutation; D011494:Protein Kinases / Q000235:genetics*
D011494:Protein Kinases