Role of FGFR3 in urothelial cell carcinoma: biomarker and potential therapeutic target

Abstract

Although non-invasive bladder tumours (pTa) are the most common group of bladder tumours at presentation, there has until recently been relatively little information on their molecular biology. Thus it was of great interest when mutations in the FGF receptor 3 (FGFR3) were identified in bladder tumours and it became apparent that these were most common in tumours of low grade and stage. Since the initial description of activating mutations of FGFR3, there have been numerous studies confirming the frequency and spectrum of these mutations in bladder cancers of all grades and stages. Mutation screening techniques have evolved and improved. FGFR3 mutation has been assessed as a predictive biomarker in tumour tissues and as a diagnostic biomarker in urine. Efforts have been made to understand the function of FGFR3 in urothelial and other cells. Although our understanding of FGFR3 function is incomplete, it is already apparent that this may represent an important therapeutic target not only in non-invasive bladder cancer but also in a significant number of invasive tumours. This review summarises the current state of knowledge of this interesting receptor in urothelial carcinoma (UC).

Figure 1.. Relative frequencies and positions of FGFR3 mutations in bladder cancers

Frequencies are the percentage of all FGFR3 mutations described to date. IgI, IgII, IgIII, immunoglobulin-like domains; TK-1, TK-2, split tyrosine kinase domain.

Figure 2.. Relationship of FGFR3 mutation to bladder tumour grade and stage

Data from [11, 20, 24, 45, 52, 61].

Figure 3.. Potential pathways of urothelial tumorigenesis.

Black arrows indicate likely pathways and grey arrows indicate uncertain relationships. Frequencies are given for mutations in FGFR3, TP53, Ras genes and PIK3CA and for chromosome 9 LOH. PIK3CA data are from a single study [53]. Figures for other genes and chromosome 9 are representative of a much larger literature. Low-grade papillary tumours (top) may arise via simple hyperplasia and minimal dysplasia and these are characterised at the molecular level by deletions of chromosome 9 and activating mutations of FGFR3. Invasive carcinoma (bottom) is believed to arise via the flat high-grade lesion CIS and in this case TP53 mutation occurs early and FGFR3 mutations are infrequent. There is limited data for chromosome 9 LOH in CIS. Muscle invasive tumours are usually genetically unstable and contain many genomic alterations in addition to those shown here. The finding of dysplasia in association with high-grade papillary tumours that lack TP53 mutation but have frequent chromosome 9 losses suggests that an independent route to high-grade papillary tumours may exist (centre). The pathway to development of T1 tumours is uncertain.

Figure 4.. Patterns of FGFR3 staining in normal urothelium and bladder tumours

Normal ureteric urothelium (A) and bladder tumour samples (B-D). A, staining pattern 1; B, staining pattern 0; C, staining pattern 2; D, staining pattern 3; bars = 100μm. Reproduced with permission from: DC Tomlinson, O Baldo, P Harnden and MA Knowles. FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. Journal of Pathology volume 213, 2007, Copyright Pathological Society of Great Britain and Ireland. Permission is granted by John Wiley & Sons Ltd on behalf of PathSoc.

Figure 5.. FGFR3 protein expression in relation to mutation and tumour stage

A. Distribution of high and low expression of FGFR3 protein in bladder tumours with and without mutation. B. Relationship of high-level expression of FGFR3 to tumour stage and mutation status. Data from [43].