Activation of the Fibroblast Growth Factor Receptor 3 in Bladder Cancer

The identification of frequent FGFR3 mutations in superficial bladder cancer suggests that mutation of the FGFR3 gene is a key genetic event in the development of noninvasive bladder tumors. Furthermore, FGFR3 mutations were associated with a good prognosis, suggesting that the activation of FGFR3 has a beneficial effect during urothelial tumor formation. In this thesis, two aspects of FGFR3 mutations in bladder cancer have been investigated. First, the potential use of FGFR3 mutations in bladder cancer diagnosis, prognosis, and in surveillance of patients with bladder cancer has been explored. The second, more important aim was to get insight in the functional role of mutant FGFR3 in bladder carcinogenesis. For clinical studies, a simple and fast method for FGFR3 mutation detection was developed that is fast, easy, more sensitive and less laborious than previous techniques. With this technique, several studies described in this thesis were done on the role of FGFR3 in bladder carcinogenesis and patient outcome. We analyzed FGFR3 mutations in urothelial hyperplasia, a precursor of low-grade papillary carcinoma, and found that FGFR3 mutations are already present in hyperplastic lesions. Furthermore, we reported a low number of chromosomal aberrations in bladder tumors with an FGFR3 mutation, which suggests that FGFR3 mutated tumors are genetically stable, in contrast to most tumors that do not carry this mutation, and we showed that this genetic stability of FGFR3 mutant tumors was paralleled by a normal differentiation of urothelial cells, since a normal staining pattern for cytokeratin 20, a marker for terminal differentiation of urothelium, was correlated with bladder cancers carrying the FGFR3 mutation. We also described the relation of molecular markers to bladder cancer patient outcome. The subset of FGFR3 mutated tumors with a normal CK20 staining pattern rarely progressed, providing a combination of two molecular markers that is able to define the group of prognostically favorable low-grade noninvasive papillary tumors. Upper urinary tract tumors (i.e. in the ureter and renal pelvis) may be genetically different from bladder tumors. The FGFR3 mutation frequency was, however, equally high (~50%) in all urothelial tract tumors, and FGFR3 mutation status was an independent predictor for progression and disease-specific survival in tumors from the ureter. Finally, we report the results of an experimental study analyzing the expression of a mutant FGFR3 receptor transfected in a human bladder cancer cell line. The most striking effect was that cells expressing the mutant FGFR3 receptor display both loss of integrin expression and increased apoptosis when cultured in Matrigel. This would suggest that interaction of bladder cancer cells expressing mutant FGFR3 with Matrigel (i.e. basement membrane substances) does not permit their survival. The latter would also explain the clinical finding that FGFR3 mutant bladder cancers have a comparatively low tendency to become invasive. In conclusion, this thesis describes both clinical and functional aspects of the activation of FGFR3 in bladder cancer. The results confirm the association of mutant FGFR3 with well-differentiated, noninvasive bladder tumors with few genetic alterations and a good prognosis.

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