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Combined Microsatellite and FGFR3 Mutation Analysis Enables a Highly Sensitive Detection of Urothelial Cell Carcinoma in Voided Urine¹

Department of Pathology, Josephine Nefkens Institute, Erasmus University [B. W. G. v. R., I. L., T. H. v. d. K., E. C. Z.], and Department of Urology, Erasmus University and University Hospital [B. W. G. v. R., W. J. K.], 3000 CA Rotterdam, the Netherlands; Service d’Urologie, Centre Hospitalier Universitaire Henri Mondor, 94010 Créteil Cedex, France [D. K. C.]; and Laboratoire de Morphogenèse Cellulaire et Progression Tumorale, UMR 144, Centre National de la Recherche Scientifique, Institut Curie, 75248 Paris Cédex 05, France [J-P. T., F. R.]

Purpose: Fibroblast growth factor receptor 3 (FGFR3) mutations were reported recently at a high frequency in low-grade urothelial cell carcinoma (UCC). We investigated the feasibility of combining microsatellite analysis (MA) and the FGFR3 status for the detection of UCC in voided urine.

Experimental Design: In a prospective setting, 59 UCC tissues and matched urine samples were obtained, and subjected to MA (23 markers) and FGFR3 mutation analysis (exons 7, 10, and 15). In each case, a clinical record with tumor and urine features was provided. Fifteen patients with a negative cystoscopy during follow-up served as controls.

Results: A mutation in the FGFR3 gene was found in 26 (44%) UCCs of which 22 concerned solitary pTaG1/2 lesions. These mutations were absent in the 15 G3 tumors. For the 6 cases with leukocyturia, 46 microsatellite alterations were found in the tumor. Only 1 of these was also detected in the urine. This was 125 of 357 for the 53 cases without leukocyte contamination. The sensitivity of MA on voided urine was lower for FGFR3-positive UCC (15 of 21; 71%) as compared with FGFR3 wild-type UCC (29 of 32; 91%). By including the FGFR3 mutation, the sensitivity of molecular cytology increased to 89% and was superior to the sensitivity of morphological cytology (25%) for every clinical subdivision. The specificity was 14 of 15 (93%) for the two (molecular and morphological) cytological approaches.

Conclusions: Molecular urine cytology by MA and FGFR3 mutation analysis enables a highly sensitive and specific detection of UCC. The similarity of molecular profiles in tumor and urine corroborate their clonal relation.

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