Browsing by Author "A Bakkar, Ashraf"

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Mutations in TP53 , but not FGFR3 , in urothelial cell carcinoma of the bladder are influenced by smoking: contribution of exogenous versus endogenous carcinogens
(Oxford University Press, 2005) Wallerand, Hervé; A Bakkar, Ashraf; Gil Diez De Medina, Sixtina; Pairon, Jean-Claude; Ching Yang, Yu; Vordos, Dimitri; Bittard, Hugues; Fauconnet, Sylvie; Kouyoumdjian, Jean-Claude; Claude Jaurand, Marie; Feng Zhang, Zuo; Radvanyi, François; Thiery, Jean-Paul; K Chopin, Dominique
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 ≥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 FGFR3wild-type / TP53mutated 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.
Occupational exposure to polycyclic aromatic hydrocarbons influenced neither the frequency nor the spectrum of FGFR3 mutations in bladder urothelial carcinoma
(Wiley Subscription Services, Inc., A Wiley Company, 2010) A Bakkar, Ashraf; Allory, Yves; Iwatsubo, Yuriko; Gil Diez De Medina, Sixtina; Maille, Pascale; Khreich, Nathalie; Riou, Audrey; Leroy, Karen; Vordos, Dimitrios; C Abbou, Claude; Andujar, Pascale; Billebaud, Thierry; Chammings, Soizick; Conso, Françoise; De La Taille, Alexandre; Fontaine, Eric; Gattegno, Bernard; Ravery, Vincent; Sibony, Mathilde; Radvanyi, François; K Chopin, Dominique; Pairon, Jean‐Claude
Occupational exposure to polycyclic aromatic hydrocarbons (PAH) is associated with an increased risk of urothelial carcinoma (UC). FGFR3 is found mutated in about 70% of Ta tumors, which represent the major group at diagnosis. The influence of PAH on FGFR3 mutations and whether it is related to the emergence or shaping of these mutations is not yet known. We investigated the influence of occupational PAH on the frequency and spectrum of FGFR3 mutations. We included on 170 primary urothelial tumors from five hospitals from France. Patients (median age, 64 yr) were interviewed to gather data on occupational exposure to PAH, revealing 104 non‐ and possibly PAH exposed patients, 66 probably and definitely exposed patients. Tumors were classified as follows: 75 pTa, 52 pT1, and 43 ≥pT2. Tumor grades were as follows: 6 low malignant potential neoplasms (LMPN) and 41 low‐grade and 123 high‐grade carcinomas. The SnaPshot method was used to screen for the following FGFR3 mutations: R248C, S249C, G372C, Y375C, A393E, K652E, K652Q, K652M, and K652T. Occupational PAH exposure was not associated with a particular stage or grade of tumors. Thirty‐nine percent of the tumors harbored FGFR3 mutations. After adjustment for smoking, occupational exposure to PAH did not influence the frequency [OR, 1.10; 95% CI, 0.78–1.52], or spectrum of FGFR3 mutations. Occupational exposure to PAH influenced neither the frequency nor the spectrum of FGFR3 mutations and there was no direct relationship between these mutations and this occupational hazard
Sensitive Allele-Specific PCR Assay Able to Detect FGFR3 Mutations in Tumors and Urine from Patients with Urothelial Cell Carcinoma of the Bladder
(Oxford University Press, 2005) A Bakkar, Ashraf; Quach, Viviane; Le Borgne, Anaïg; Toublanc, Marianne; Henin, Dominique; Wallerand, Hervé; Radvanyi, François; Bittard, Hugues; Ravery, Vincent; Boccon Gibod, Laurent; Gil Diez de Medina, Sixtina; K Chopin, Dominique; Grandchamp, Bernard
Activating somatic point mutations in exons 7, 10, and 15 of the FGFR3 gene are frequently observed in urothelial cell carcinoma (UCC) (1)(2). These mutations have been found primarily in superficial papillary pTa tumors and were absent in carcinoma in situ (3).