Absence of FGFR3 mutations in urinary bladder tumours of rats and mice treated with N-butyl-N-(-4-hydroxybutyl)nitrosamine.
Frequent activating mutations of FGFR3 (fibroblast growth factor receptor 3) are found in human urothelial cell carcinomas, particularly in superficial papillary tumours (in 74%-84% of pTaG1-G2), but not in carcinomas in situ (CIS) and at a low rate in invasive tumours (in 16%-21% of pT1-4). In mice and rats, BBN (N-butyl-N-(4-hydroxybutyl)nitrosamine) specifically induces bladder tumours. In rats, superficial papillary tumours are mostly observed. In mice, tumour progression follows the CIS pathway: CIS are first observed, followed by tumours that invade surrounding muscle. Therefore, we looked for FGFR3 mutations in these two animal models of bladder cancer. Only the FGFR3b isoform is expressed in human urothelium and derived tumours. We identified the FGFR3b isoform in rats for the first time and showed that this is the main isoform expressed in the bladder urothelium and derived carcinomas in mice and rats, as in humans. SSCP and sequence analysis of FGFR3b showed sequence changes (polymorphisms or silent mutations) in four BBN-induced rat and mouse bladder tumours. The absence of activating mutations of FGFR3 in the mouse model was in agreement with the fact that mouse BBN-induced bladder tumour progression mimics the CIS pathway. The absence of FGFR3 mutations in the rat bladder tumours suggests that, at least at the genetic level, rat superficial papillary tumours differ from their human counterparts.
Dunois-Lardé
Claire
C
Laboratoire de Morphogenèse Cellulaire et Progression Tumorale, UMR 144, Centre National de la recherche Scientifique, Institut Curie, Section de Recherche, Paris, France.
Levrel
Olivier
O
Brams
Aude
A
Thiery
Jean Paul
JP
Radvanyi
François
F
D000818:Animals; D001483:Base Sequence; D002085:Butylhydroxybutylnitrosamine / Q000633:toxicity; D002277:Carcinoma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000187:drug effects / Q000235:genetics; D009153:Mutagens / Q000633:toxicity; D009154:Mutation / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D020033:Protein Isoforms / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D017422:Sequence Analysis, DNA; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology
D004273:DNA, Neoplasm; D009153:Mutagens; D020033:Protein Isoforms; D017468:Receptors, Fibroblast Growth Factor; D002085:Butylhydroxybutylnitrosamine; C496365:FGFR3 protein, human; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3