Loss-of-function fibroblast growth factor receptor-2 mutations in melanoma.
We report that 10% of melanoma tumors and cell lines harbor mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. These novel mutations include three truncating mutations and 20 missense mutations occurring at evolutionary conserved residues in FGFR2 as well as among all four FGFRs. The mutation spectrum is characteristic of those induced by UV radiation. Mapping of these mutations onto the known crystal structures of FGFR2 followed by in vitro and in vivo studies show that these mutations result in receptor loss of function through several distinct mechanisms, including loss of ligand binding affinity, impaired receptor dimerization, destabilization of the extracellular domains, and reduced kinase activity. To our knowledge, this is the first demonstration of loss-of-function mutations in a class IV receptor tyrosine kinase in cancer. Taken into account with our recent discovery of activating FGFR2 mutations in endometrial cancer, we suggest that FGFR2 may join the list of genes that play context-dependent opposing roles in cancer.
Gartside
Michael G
MG
Division of Cancer and Cell Biology, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
Chen
Huaibin
H
Ibrahimi
Omar A
OA
Byron
Sara A
SA
Curtis
Amy V
AV
Wellens
Candice L
CL
Bengston
Ana
A
Yudt
Laura M
LM
Eliseenkova
Anna V
AV
Ma
Jinghong
J
Curtin
John A
JA
Hyder
Pilar
P
Harper
Ursula L
UL
Riedesel
Erica
E
Mann
Graham J
GJ
Trent
Jeffrey M
JM
Bastian
Boris C
BC
Meltzer
Paul S
PS
Mohammadi
Moosa
M
Pollock
Pamela M
PM
D002455:Cell Division; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008958:Models, Molecular; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000737:chemistry* / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology
C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2