title: FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma.
abstract: Fibroblast growth factor receptor 3 (FGFR3) mutations are frequent in superficial urothelial cell carcinoma (UCC). Ras gene mutations are also found in UCC. As oncogenic activation of both FGFR3 and Ras is predicted to result in stimulation of the mitogen-activated protein kinase (MAPK) pathway, we hypothesized that these might be mutually exclusive events. HRAS mutation has been widely studied in UCC, but all three Ras gene family members have not been screened for mutation in the same sample series. We screened 98 bladder tumours and 31 bladder cell lines for mutations in FGFR3, HRAS, NRAS and KRAS2. FGFR3 mutations were present in 54 tumours (55%) and three cell lines (10%), and Ras gene mutations in 13 tumours (13%) and four cell lines (13%). These included mutations in all three Ras genes; ten in HRAS, four in KRAS2 and four in NRAS and these were not associated with either tumour grade or stage. In no cases were Ras and FGFR3 mutation found together. This mutual exclusion suggests that FGFR3 and Ras gene mutation may represent alternative means to confer the same phenotype on UCC cells. If these events have biological equivalence, Ras mutant invasive UCC may represent a novel subgroup.
authors.affiliation: Cancer Research UK Clinical Centre, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Adel H
authors.initials: AH
authors.lastname: Jebar
authors.forename: Carolyn D
authors.initials: CD
authors.lastname: Hurst
authors.forename: Darren C
authors.initials: DC
authors.lastname: Tomlinson
authors.forename: Colin
authors.initials: C
authors.lastname: Johnston
authors.forename: Claire F
authors.initials: CF
authors.lastname: Taylor
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Knowles
mesh_terms: D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D011905:Genes, ras; D006801:Humans; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000502:physiology*; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics* / Q000502:physiology*; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D017468:Receptors, Fibroblast Growth Factor; C496365:FGFR3 protein, human; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3