Bladder CancerFGFR3 Mutations Indicate Better Survival in Invasive Upper Urinary Tract and Bladder Tumours
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.
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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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2021, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :In total, 9,229 patients with available survival or response to cancer treatment data were included in 62 studies. Seventeen studies [9,14–29] were designed prospectively and 45 [30–74] were retrospective. Most studies evaluated the prognostic value of FGFR3 and only 4 [30,52,55,62] and 1 [52] studies assessed FGFR1 and FGFR4 as prognosticators, respectively.