In bladder carcinoma, we recently identified FGFR3 mutations in 41% of tumours, making this the most frequently mutated putative oncogene identified in bladder cancer to date.
In summary, alternative splicing of FGFR3 IIIb in NHU cells represents a normal mechanism to generate a transcript that regulates proliferation and in bladder cancer, the ratio of FGFR3 isoforms is significantly altered.
An example of a TM domain pathogenic mutation is the Ala391-->Glu mutation in fibroblast growth factor receptor 3 (FGFR3), linked to Crouzon syndrome with acanthosis nigricans, as well as to bladder cancer.
The findings of this large study strongly support the notion that FGFR3 mutations characterize a subgroup of bladder cancers with good prognosis; patients with mutant TaG1 tumors have a higher risk of recurrence; and the F386L variant is selectively associated with low-grade tumors.
The phenotypic consequences of constitutive activation of FGFR3 in bladder cancer have not been elucidated and further studies are required to confirm the consequences of inhibiting receptor activity in urothelial cells.
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.
The identification of mutations of FGF receptor 3 (FGFR3) in most noninvasive bladder tumors and the recent finding of overexpression of this receptor not only in superficial tumors but also in many invasive bladder cancers has generated optimism that therapies targeting this receptor tyrosine kinase may have major application in the treatment of urothelial cancers.
The two most important developments are the identification of a mutation in the fibroblast growth factor receptor 3 gene in more than 50% of urothelial carcinomas and the discovery of cDNA profiles characteristic of different subsets of bladder cancer.
These studies provide in vivo evidence demonstrating an oncogenic role of FGFR3 in bladder cancer and support antibody-based targeting of FGFR3 in hematologic and epithelial cancers driven by WT or mutant FGFR3.