title: Loss-of-function fibroblast growth factor receptor-2 mutations in melanoma.
abstract: 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.
authors.affiliation: Division of Cancer and Cell Biology, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Gartside
authors.forename: Huaibin
authors.initials: H
authors.lastname: Chen
authors.forename: Omar A
authors.initials: OA
authors.lastname: Ibrahimi
authors.forename: Sara A
authors.initials: SA
authors.lastname: Byron
authors.forename: Amy V
authors.initials: AV
authors.lastname: Curtis
authors.forename: Candice L
authors.initials: CL
authors.lastname: Wellens
authors.forename: Ana
authors.initials: A
authors.lastname: Bengston
authors.forename: Laura M
authors.initials: LM
authors.lastname: Yudt
authors.forename: Anna V
authors.initials: AV
authors.lastname: Eliseenkova
authors.forename: Jinghong
authors.initials: J
authors.lastname: Ma
authors.forename: John A
authors.initials: JA
authors.lastname: Curtin
authors.forename: Pilar
authors.initials: P
authors.lastname: Hyder
authors.forename: Ursula L
authors.initials: UL
authors.lastname: Harper
authors.forename: Erica
authors.initials: E
authors.lastname: Riedesel
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Mann
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Trent
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.forename: Moosa
authors.initials: M
authors.lastname: Mohammadi
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Pollock
mesh_terms: 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
chemical_list: C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2