Elsevier

European Urology

Volume 55, Issue 3, March 2009, Pages 650-658
European Urology

Bladder Cancer
FGFR3 Mutations Indicate Better Survival in Invasive Upper Urinary Tract and Bladder Tumours

https://doi.org/10.1016/j.eururo.2008.06.013Get rights and content

Abstract

Background

Promoter hypermethylation and microsatellite instability are frequent in tumours of the upper urinary tract (UTT) and infrequent in bladder tumours. FGFR3 mutations are common findings in bladder tumours and are associated with a good prognosis.

Objective

To investigate the occurrence of FGFR3 mutations in UTT and determine the prognostic effect of these genetic changes.

Design, setting, and participants

Tissue from the initial tumour was obtained from 280 patients (117 bladder tumours and 163 UTT). Patients were selected from pathologic archives to represent the disease spectrum of UCC throughout the urinary tract. Following UCC excision, patients underwent surveillance for a median of 56 mo (range 1–216 mo) or until death.

Measurements

FGFR3 mutation analysis was successfully performed on 252 of the 280 primary tumours using the SNaPshot method. Two-tailed statistical analyses were done using the χ2, Fisher exact tests, and log rank tests. Cox proportional hazard ratios were estimated to obtain risks of recurrence, progression, and death, and to find independent prognostic factors in a multivariate model.

Results and limitations

FGFR3 mutations occurred with the same frequency in bladder and upper tract tumours. Mutations were associated with low-stage tumours and a milder disease course in bladder, ureter, and renal pelvis tumours. Strikingly, our data suggest that these mutations indicate a better survival in patients with invasive tumours from the bladder and upper urinary tract.

Conclusions

FGFR3 mutation status might be used to select patients with invasive UCC who have a lower risk of death.

Introduction

The majority of urothelial cell carcinomas (UCC) occur in the bladder, with only 5% in the ureter or renal pelvis (defined as upper tract tumours [UTT]). Urothelial tumours from the upper and lower tract show histologic and morphologic similarities and were thought to develop similarly. However, several studies have shown that upper and lower tract tumours have genetic and epigenetic differences. For example, microsatellite instability (MSI) was found to be more frequent in upper tract tumours [1] while bladder tumours displayed more frequent nucleotide instability at selected tetranucleotides [2]. Analysis for hypermethylation at 11 CpG islands subsequently showed that promoter hypermethylation is both more frequent and more extensively present in UTT compared to bladder tumours [3]. Specifically, hypermethylation of the hMLH1 gene promoter appeared to explain the high frequency of MSI in UTT tumours. These molecular differences support the clinical observation that, in general, UTT tumours are of higher stage and grade to those in the bladder [4]. These data indicate that urothelial tumours of different anatomical location may have differing pathogenesis pathways.

Fibroblast growth factor receptor 3 (FGFR3) and TP53 mutations are the most frequent somatic mutations found in bladder UCC. FGFR3 mutations occur in 50% of primary bladder tumours, and are associated with low stage and grade tumours [5] and a good prognosis [6]. Hence, FGFR3 could be potentially useful as both a clinical biomarker and a therapeutic target [7]. Conversely, mutations in the TP53 gene, which are present in about 25% of tumours, occur primarily in invasive bladder tumours. Based on the mutual exclusivity of FGFR3 and TP53 mutations in bladder tumours, a two-pathway model has been proposed for urothelial carcinogenesis [8], [9]. In colon cancer, a difference in TP53 mutation frequency according to location has recently been reported: Distal colon tumours were found to have significantly more mutations than proximal colon tumours [10]. In addition, methylation and MSI also differ in frequency according to tumour site in this type of cancer [11], [12].

The aim of this study was to compare the frequency of FGFR3 mutations in urothelial tumours from the bladder and upper urinary tract, and correlate these results to disease course of UCCs of different locations.

Section snippets

Sample collection and DNA extraction

We studied 280 patients with primary UCC (Table 1) who underwent surgery at the Royal Hallamshire Hospital Sheffield, UK, or at the Institut Mutualiste de Montsouris, Hôpital Tenon, and Hôpital de St. Louis, Paris, France [3]. All clinical and follow-up data were obtained from a retrospective hospital case note review. Sociodemographic data were obtained from the patients or next of kin (in case of patient death) directly, through the use of a social, occupational, and risk factor

Mutations in FGFR3 occurred at the same frequency in bladder and upper tract tumours

FGFR3 mutations occurred in 46% (48/105) of bladder tumours and in 48% (71/147) of UTT (Table 1). Mutations were found in six different codons, and their frequencies were consistent for bladder tumours and UTT, respectively: The mutation in codon 249 (S249C) was the most frequent (62/58%), followed by Y375C (18/20%), R248C (10/14%), G372C (8/4%), K652M (2/3%), and A393E (0/1%). In one bladder tumour sample and one UTT sample, the double mutation S249C/Y375C was found.

The group of UTT consisted

Discussion

This study aimed to investigate FGFR3 mutations in bladder tumours versus UTT and their relationship with disease course. In invasive bladder tumours, genetic instability is frequent, as has been observed by numerous LOH and CGH analyses, and mutations in the TP53 gene are often present [19]. In non-invasive bladder tumours LOH of chromosome 9 predominates as well as activating point mutations in the FGFR3 gene [20]. We previously showed that in UTT microsatellite instability and CpG island

Conclusions

We have shown that mutations in FGFR3 occur at the same frequency in bladder tumours and UTT. The FGFR3 mutation seems to enhance disease-specific survival in patients with bladder, ureter, and renal pelvis tumours, and in ureter tumours FGFR3 is an independent predictor of survival. Furthermore, FGFR3 mutation status might be used to select invasive tumours with a lower risk.

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