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
