Sequence analysis of the protein kinase gene family in human testicular germ-cell tumors of adolescents and adults.
The protein kinase gene family is the most frequently mutated in human cancer. Previous work has documented activating mutations in the KIT receptor tyrosine kinase in testicular germ-cell tumors (TGCT). To investigate further the potential role of mutated protein kinases in the development of TGCT and to characterize the prevalence and patterns of point mutations in these tumors, we have sequenced the coding exons and splice junctions of the annotated protein kinase family of 518 genes in a series of seven seminomas and six nonseminomas. Our results show a remarkably low mutation frequency, with only a single somatic point mutation, a K277E mutation in the STK10 gene, being identified in a total of more than 15 megabases of sequence analyzed. Sequencing of STK10 in an additional 40 TGCTs revealed no further mutations. Comparative genomic hybridization and LOH analysis using SNP arrays demonstrated that the 13 TGCTs mutationally screened through the 518 protein kinase genes were uniformly aneuploid with consistent chromosomal gains on 12p, 8q, 7, and X and losses on 13q, 18q, 11q, and 4q. Our results do not provide evidence for a mutated protein kinase implicated in the development of TGCT other than KIT. Moreover, they demonstrate that the general prevalence of point mutations in TGCT is low, in contrast to the high frequency of copy number changes.
Bignell
Graham
G
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, United Kingdom.
Smith
Raffaella
R
Hunter
Chris
C
Stephens
Philip
P
Davies
Helen
H
Greenman
Chris
C
Teague
Jon
J
Butler
Adam
A
Edkins
Sarah
S
Stevens
Claire
C
O'Meara
Sarah
S
Parker
Adrian
A
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
Andy
A
Gillis
Ad J M
AJ
Stoop
Hans J
HJ
van Gurp
Ruud J H L M
RJ
Oosterhuis
J Wolter
JW
Looijenga
Leendert H J
LH
Futreal
P Andrew
PA
Wooster
Richard
R
Stratton
Michael R
MR
D000293:Adolescent; D000328:Adult; D002869:Chromosome Aberrations; D005091:Exons; D018628:Gene Dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics*; D017354:Point Mutation; D011494:Protein Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D018239:Seminoma / Q000235:genetics*; D013736:Testicular Neoplasms / Q000235:genetics*
D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C474806:STK10 protein, human