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Prospective Study of FGFR3 Mutations As a Prognostic Factor in Nonmuscle Invasive Urothelial Bladder Carcinomas

Silvia Hernández, Elena López-Knowles, Josep Lloreta, Manolis Kogevinas, Alex Amorós, Adonina Tardón, Alfredo Carrato, Consol Serra, Núria Malats, Francisco X. Real

From the Universitat Pompeu Fabra, Institut Municipal d'Investigació Mèdica, Hospital del Mar, Barcelona; Universidad de Oviedo, Oviedo; Hospital General Universitario, Instituto Biología Molecular y Celular, U. Miguel Hernández, Elche; and the Consorci Hospitalari Parc Tauli, Sabadell, Spain, for the EPICURO Study Investigators

Address reprint requests to Francisco X. Real, MD, PhD, OR Núria Malats, MD, PhD, Institut Municipal d'Investigació Mèdica, Universitat Pompeu Fabra, Carrer del Dr. Aiguader 80, 08003-Barcelona, Spain; e-mail: preal{at}imim.es OR nuria{at}imim.es

PURPOSE: To determine the frequency and the prognostic value of fibroblast growth factor receptor 3 (FGFR3) mutations in patients with nonmuscle invasive bladder tumors according to tumor stage and grade.

PATIENTS AND METHODS: Seven hundred seventy-two patients with newly diagnosed bladder tumors were recruited. Tumors were reviewed by expert pathologists. Patients were prospectively followed-up (median, 62.6 months for disease-free patients) through review of hospital records and telephone interviews. The sequence of exons 7 and 10 of FGFR3 was analyzed by polymerase chain reaction and direct sequencing. We assessed the association of mutations with stage and grade. The predictive value of mutations for recurrence, progression, and mortality were assessed using Kaplan-Meier and Cox multivariable models.

RESULTS: Mutations were more common among low malignant potential neoplasms (LMPN; 77%) and TaG1/TaG2 tumors (61%/58%) than among TaG3 tumors (34%) and T1G3 tumors (17%). The S249C, Y375C, S248C, and G372C mutations accounted for 91.5% of all sequence changes. The A393E substitution was associated with LMPN (P < .001). The F386L polymorphism was more frequent among patients with low-grade tumors (odds ratio, 6.97; 95%CI, 1.40 to 47.06; P = .009). In the multivariable analysis of all superficial tumors, mutations were associated with increased risk of recurrence. However, in the stratified analyses only patients with TaG1 tumors had a significantly higher risk of recurrence (hazard ratio, 2.12; 95%CI, 1.28 to 3.53; P = .004).

CONCLUSION: The findings of this large study strongly support the notion that FGFR3 mutations characterize a subgroup of bladder cancers with good prognosis; patients with mutant TaG1 tumors have a higher risk of recurrence; and the F386L variant is selectively associated with low-grade tumors.

Supported in part by Grants No. FIS 00/0745, C03/009, C03/010, G03/160, and G03/174 from Instituto de Salud Carlos III, Ministerio de Sanidad. E.L. was supported by a predoctoral fellowship of the Ramón Areces Foundation, Madrid, Spain.

Presented in abstract format at the Annual Meeting of the American Association for Cancer Research, Chicago, IL, September 12-15, 2006.

N.M. and F.X.R. have contributed equally and share senior authorship.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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