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Role of Activating Fibroblast Growth Factor Receptor 3 Mutations in the Development of Bladder Tumors

Authors' Affiliations: ¹ Molecular Diagnostic Laboratory, Department of Clinical Biochemistry; ² Department of Urology, Aarhus University Hospital; ³ Department of Theoretical Statistics, Faculty of Mathematical Sciences; and ⁴ Bioinformatics Research Center, Aarhus University, Aarhus, Denmark

Requests for reprints: Torben F. Ørntoft, Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital, Skejby, DK-8200 Aarhus N, Denmark. Phone: 45-8949-5100; Fax: 45-8949-6018; Email: orntoft{at}ki.au.dk.

Purpose: Bladder tumors develop through different molecular pathways. Recent reports suggest activating mutations of the fibroblast growth factor receptor 3 (FGFR3) gene as marker for the "papillary" pathway with good prognosis, in contrast to the more malignant "carcinoma in situ" (CIS) pathway. The aim of this clinical follow-up study was to investigate the role of FGFR3 mutations in bladder cancer development in a longitudinal study.

Experimental Design: We selected 85 patients with superficial bladder tumors, stratified into early (stage T_a/grade 1-2, n = 35) and more advanced (either stage T₁ or grade 3, n = 50) developmental stages. The patients were followed prospectively, and metachronous tumors were included. We did screening for FGFR3 and TP53 mutations by direct bidirectional sequencing and for genome-wide molecular changes with microarray technology.

Results: A total of 43 of 85 cases (51%) showed activating mutations of FGFR3. The mutations were associated with papillary tumors of early developmental stage. However, after stratifying for developmental stage, FGFR3-mutated tumors showed the same malignant potential as wild-type tumors. Tumors with concomitant CIS were generally FGFR3 wild type. They were characterized by different patterns of chromosomal changes and gene expression signatures compared with FGFR3-mutated tumors, indicating different molecular pathways.

Conclusions: FGFR3 mutations seem to have a central role in the early development of papillary bladder tumors. These tumors follow a common molecular pathway, which is different from tumors with concomitant CIS. FGFR3 mutations do not seem to play a role in bladder cancer progression.

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