title: Mutations in TP53, but not FGFR3, in urothelial cell carcinoma of the bladder are influenced by smoking: contribution of exogenous versus endogenous carcinogens.
abstract: Smoking is a major risk factor for urothelial cell carcinoma of the bladder (UCC). Mutations in the FGFR3 and TP53 genes have been shown to define two distinct pathways in superficial papillary and invasive UCC disease, respectively. We investigated the relationship between smoking and these mutations by means of denaturing high performance liquid chromatography and sequencing for 110 primary UCC of the bladder. This study included 48 current smokers, 31 ex-smokers and 31 non-smokers. Thirty-five of the tumors were stage pTa, 40 pT1 and 35 > or =pT2. Fourteen of the tumors were grade 1, 37 were grade 2 and 59 grade 3. Smoking was associated with high stage (P = 0.03) and high grade tumors (P = 0.006). Twenty-two of the 110 tumors studied harbored TP53 mutations (20%) and 43 harbored FGFR3 mutations (39%). Odds ratios (OR) were higher for TP53 mutations in current smokers [OR, 2.25; 95% confidence interval (95% CI), 0.65-7.75] and ex-smokers (OR, 1.62; 95% CI, 0.41-6.42) than in non-smokers. Double TP53 mutations and the A:T-->G:C TP53 mutation pattern was found only in current smokers. Patients with the FGFR3(wild-type)/TP53(mutated) genotype had significantly higher levels of tobacco consumption, as measured in pack-years (P = 0.01). Smoking influenced neither the frequency nor the pattern of FGFR3 mutations. Our results suggest that smoking is associated with invasive and high grade UCCs, at initial presentation, and influenced TP53 or the molecular pathway defined by these mutations. In contrast, FGFR3 mutations are not affected by smoking and probably result from endogenous alterations. These data have potential implications for clinical management and prevention strategies.
authors.affiliation: EMI INSERM 03-37 and Service d'Urologie, Université Paris XII, AP-HP, Hôpital Henri Mondor, 94000 Créteil, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Wallerand
authors.forename: Ashraf A
authors.initials: AA
authors.lastname: Bakkar
authors.forename: Sixtina Gil Diez
authors.initials: SG
authors.lastname: de Medina
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Pairon
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Yang
authors.forename: Dimitri
authors.initials: D
authors.lastname: Vordos
authors.forename: Hugues
authors.initials: H
authors.lastname: Bittard
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fauconnet
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Kouyoumdjian
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Jaurand
authors.forename: Zuo-Feng
authors.initials: ZF
authors.lastname: Zhang
authors.forename: François
authors.initials: F
authors.lastname: Radvanyi
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Thiery
authors.forename: Dominique K
authors.initials: DK
authors.lastname: Chopin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002273:Carcinogens; D002295:Carcinoma, Transitional Cell / Q000209:etiology* / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D016158:Genes, p53 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000235:genetics*; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000187:drug effects / Q000235:genetics*; D012907:Smoking / Q000009:adverse effects*; D001749:Urinary Bladder Neoplasms / Q000209:etiology* / Q000235:genetics
chemical_list: D002273:Carcinogens; D017468:Receptors, Fibroblast Growth Factor; C496365:FGFR3 protein, human; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3