Sequence survey of receptor tyrosine kinases reveals mutations in glioblastomas.
It is now clear that tyrosine kinases represent attractive targets for therapeutic intervention in cancer. Recent advances in DNA sequencing technology now provide the opportunity to survey mutational changes in cancer in a high-throughput and comprehensive manner. Here we report on the sequence analysis of members of the receptor tyrosine kinase (RTK) gene family in the genomes of glioblastoma brain tumors. Previous studies have identified a number of molecular alterations in glioblastoma, including amplification of the RTK epidermal growth factor receptor. We have identified mutations in two other RTKs: (i) fibroblast growth receptor 1, including the first mutations in the kinase domain in this gene observed in any cancer, and (ii) a frameshift mutation in the platelet-derived growth factor receptor-alpha gene. Fibroblast growth receptor 1, platelet-derived growth factor receptor-alpha, and epidermal growth factor receptor are all potential entry points to the phosphatidylinositol 3-kinase and mitogen-activated protein kinase intracellular signaling pathways already known to be important for neoplasia. Our results demonstrate the utility of applying DNA sequencing technology to systematically assess the coding sequence of genes within cancer genomes.
Rand
Vikki
V
Department of Neurosurgery, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, Baltimore, MD 21224, USA.
Huang
Jiaqi
J
Stockwell
Tim
T
Ferriera
Steve
S
Buzko
Oleksandr
O
Levy
Samuel
S
Busam
Dana
D
Li
Kelvin
K
Edwards
Jennifer B
JB
Eberhart
Charles
C
Murphy
Kathleen M
KM
Tsiamouri
Alexia
A
Beeson
Karen
K
Simpson
Andrew J G
AJ
Venter
J Craig
JC
Riggins
Gregory J
GJ
Strausberg
Robert L
RL
D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics*; D002648:Child; D019143:Evolution, Molecular; D005260:Female; D023281:Genomics / Q000379:methods; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D008297:Male; D008957:Models, Genetic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D017422:Sequence Analysis, DNA
D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020796:Receptor, Platelet-Derived Growth Factor alpha