Combined microsatellite and FGFR3 mutation analysis enables a highly sensitive detection of urothelial cell carcinoma in voided urine.
OBJECTIVE
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.


METHODS
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.
van Rhijn
Bas W G
BW
Department of Pathology, Josephine Nefkens Institute, Erasmus University, 3000 CA Rotterdam, the Netherlands.
Lurkin
Irene
I
Chopin
Dominique K
DK
Kirkels
Wim J
WJ
Thiery
Jean-Paul
JP
van der Kwast
Theo H
TH
Radvanyi
François
F
Zwarthoff
Ellen C
EC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000175:diagnosis / Q000235:genetics* / Q000652:urine; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics* / Q000378:metabolism; D014571:Urologic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000652:urine; D019459:Urothelium / Q000473:pathology
D017468:Receptors, Fibroblast Growth Factor; C496365:FGFR3 protein, human; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3