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Department of Pathology, Josephine Nefkens Institute, Erasmus University, 3000 DR Rotterdam, the Netherlands [B. W. G. v. R., I. L., T. H. v. d. K., E. C. Z.]; Department of Urology, Erasmus University and University Hospital, 3000 CA Rotterdam, the Netherlands [B. W. G. v. R., W. J. K.]; and Laboratoire de Morphogenèse Cellulaire et Progession Tumorale, UMR 144, Centre National de la Recherche Scientifique, Institut Curie, 75248 Paris Cedex 05, France [F. R.]
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ABSTRACT |
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 Top ABSTRACT IntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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54,400 new cases in the United States per year
(1)
. In the majority of patients, bladder cancer is
superficial (i.e.,
pTa-pT1) at first
presentation. After
TUR3
of superficial bladder cancer, patients are monitored by cystoscopy at
regular intervals because the recurrence rate of superficial bladder
cancer is up to 70% (2, 3, 4)
. Progression to invasive
disease occurs in around 15–20% of patients (2
, 3)
.
Clinical and histopathological factors for prediction of tumor
recurrence and progression of bladder cancer have been studied
extensively (2, 3, 4)
. Tumor grade, stage, and recurrence
rate are especially important. In addition, it has appeared that
mutations in the tumor suppressor genes TP53 and
RB are of additional value to assess aggressive tumor
behavior (5)
. The FGFR3 is a glycoprotein composed of
three extracellular immunoglobulin-like domains, a transmembrane
domain, and a split tyrosine-kinase domain. Several reports have shown
that constitutive activation of the FGFR3 gene by specific
point mutations leads to congenital anomalies such as achondroplasia
and thanatophoric dysplasia (6
, 7)
. A frequent
t(4;14)(p16.3;q32.3) chromosomal translocation with the breakpoint near
FGFR3 in multiple myelomas suggested an oncogenic
role for the FGFR3 gene (8)
. However, an
activating mutation in the FGFR3 gene occurred rarely in
multiple myeloma (9)
. The same missense mutations (R248C,
S249C, G372C, and K652E) that were observed in thanatophoric dysplasia
were recently found in 9 of 26 bladder carcinomas and 3 of 12 cervix
carcinomas (10)
. It has been shown that mutated
FGFR3 can transform NIH 3T3 cells when targeted to the cell
membrane (11)
. Because the FGFR3 gene is
expressed in bladder cancer and normal urothelium (10)
, it
is likely that the mutant gene has an oncogenic role in bladder cancer
pathogenesis. The present study assesses the possible prognostic value
of the FGFR3 mutation in bladder cancer. |
Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Sample Collection and DNA Extraction.
The bladder tumors were subjected to careful microdissection after
confirmation of the histopathological diagnosis. Venous blood (7 ml)
was obtained from every patient to be used as control. DNA from
paraffin-embedded, formalin-fixed neoplastic tissue was extracted using
DNeasy Tissue kit (Qiagen GmbH, Hilden, Germany) according to enclosed
protocol. DNA from venous blood was isolated using one-step DNAzol BD
Reagent (Life Technologies, Inc., Grand Island, NY). We checked the
accuracy of the microdissection procedure by LOH analysis in 18 of the
19 patients with 
pT1 tumors comparing the
allele intensities of normal and tumor DNA of the same samples that
were used for the FGFR3 mutation analysis. A 50% reduction
of allele intensity was considered LOH. We used 23 microsatellite
markers on 9 different chromosomes as described previously
(12)
. Every LOH was confirmed in a second PCR.
FGFR3 Mutation Analysis.
FGFR3 mutation analysis was performed by PCR-SSCA on tumor-
and control blood DNA of all of the patients. Three regions of interest
containing the four previously identified mutations were amplified by
PCR. The primer sequences were the same as used by Capellen et
al. (10)
. The following primer pairs were used: for
exon 7, 5'-AGTGGCGGTGGTGGTGAGGGAG-3' and
5'-TGTGCGTCACTGTACACCTTGCAG-3'; for exon 10, 5'-CAACGCCCATGTCTTTGCAG-3'
and 5'-CGGGAAGCGGGAGATCTTG-3'; and for exon 15,
5'-GACCGAGGACAACGTGATG-3' and 5'-GTGTGGGAAGGCGGTGTTG-3'. All of the
tumors with an aberrant band at SSCA were sequenced with T7 Sequenase
v2.0 (Amersham life Science, Inc., Cleveland, OH) on both strands to
check the identity of the mutations. Analysis of all of the samples was
carried out in a blinded fashion, without knowledge of clinical or
histopathological status.
Statistical Analysis.
Statistical package for social sciences 8.0 (SPSS Inc., Chicago, IL)
and StatXact version 2 (Cytel Software Corporation, Cambridge, MA)
computer software were used for data documentation and analysis.
Fisher’s exact test was used to analyze the FGFR3 mutation
in relation to stage, grade, highest stage, and prediction of tumor
recurrence. Logistic regression analysis with the backward elimination
method was used for comparison of variables to predict recurrence. All
of the Ps are two sided. Statistical significance was
assumed if P < 0.05.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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SSCA detected aberrant bands (Fig. 1)
in DNA samples from 34 tumors but not in DNA from corresponding venous
blood, indicating the somatic nature of FGFR3 mutations in
bladder cancer. Thirty mutations concerned the already described codon
249 mutation (S249C). Codon 248 (R248C) and 372 (G372C) mutations were
found once and twice, respectively (Fig. 1, A, C, and D)
. An additional mutation, not observed in bladder
cancer previously, was also detected (Fig. 1E)
. DNA sequence
analysis revealed the point mutation leading to A393E, previously known
in a hereditary skeletal syndrome (13)
. The two mutations,
R248C and S249C, can be found in one amplification region. This region
represented 91% of the observed FGFR3 mutations in our
group of bladder cancers. The identity of all of the mutations was
confirmed by DNA sequence analysis. Five samples from blood DNA were
also sequenced as negative controls. No mutations were found in these
samples. Fig. 1
shows that the five detected mutations can easily be
identified by SSCA.
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A). Furthermore, all of the tumors with a mutation in the
FGFR3 gene were grade 1 or 2. The mutation did not occur in
19 grade 3 tumors (P < 0.0001). The stages
of these 19 G3 tumors were
pTa in 3, pT1 in 1, and
pT2 in 15 cases, respectively. When we compared
the patient’s history (median history of 5.4 years; range, 0.8–26.9
years) with histopathological and FGFR3 mutation status, we
observed that patients with only a pTa history,
had a mutation in 33 (73%) of 45 cases. In patients whose history
revealed at least 1 pT1 tumor, the
FGFR3 mutation occurred in only 1 (8%) of 12 tumors
(P < 0.0001; Table 1B
). These results
suggest that the FGFR3 mutations are linked with a disease
course in which lower-staged (i.e.,
pTa) tumors prevail.
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). It should be noted that only patients (n = 57) diagnosed with superficial bladder cancer (i.e.,
pTa, pT1) at time of
mutation analysis were included in this follow-up analysis because
patients with invasive tumors underwent cystectomy or radiotherapy.
Moreover, in logistic regression analysis with the backward elimination
method, using recurrence as a dependent variable and tumor stage,
grade, highest stage, and FGFR3 mutation status as
independent variables, the FGFR3 mutation status remained as
the only significant (P = 0.008) predictor of
recurrence.
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pT2) disease after 3
months. They were removed from subsequent cystoscopical follow-up. On
the other hand, in 7 of the 34 patients with a mutation in their
initial tumor, only 8 TURs revealed recurrent bladder cancer
(pTaG1 in 6 and
pTaG2 in 2). All of
the eight analyzed tumors retained the FGFR3 mutation that
was initially observed. Consequently, 24 (28%) of 86 cystoscopies were
positive in the FGFR3 wild-type group, resulting in a
recurrence rate per year of 1.12. In the FGFR3 mutant group,
only 8 (6%) of 136 cystoscopies were positive after 12 months of
follow-up, resulting in a recurrence rate per year of 0.24. The
recurrence rate per year was calculated at the 3-, 6-, 9-, and 12-month
cystoscopical evaluation points (Fig. 2)
. We also performed a subset analysis of primary and recurrent
superficial tumors. The recurrence rates were higher shortly after TUR
(3 months) for both patient groups (Fig. 2)
. The recurrence rates per
year were similar if the patients were divided into cases with primary
and recurrent cancers (results not shown). In addition, we observed a
difference in mutation frequencies between primary and recurrent
superficial tumors; when 18 (72%) of 25 primary superficial tumors had
a mutation in the FGFR3 gene, the mutation frequency was
only 16 (50%) of 32 for the recurrent tumors.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Our results show that FGFR3 mutations occur in nearly 50% of bladder cancers. The mutations were exclusively observed in superficial tumors and absent from invasive carcinomas. Moreover, bladder cancer recurrence rates were dramatically lower for tumors with a mutant FGFR3 gene. We, therefore, conclude that the FGFR3 mutations identify a large cohort of bladder cancer patients with favorable disease characteristics. As a consequence, molecular FGFR3 mutation analysis represents a novel, technically simple, and potentially powerful tool for the adjustment of clinical management in bladder cancer. Nowadays, all patients undergo frequent cystoscopy to monitor their disease. Our results suggest that the frequency of this uncomfortable, invasive, and expensive diagnostic procedure can be reduced considerably in patients with FGFR3-positive tumors.
We observed a difference in mutation frequencies between primary and
recurrent superficial tumors in our study. It has been noted by others
that patients who already have recurrent disease continue to develop
recurrences more often than patients with a primary tumor (2
, 4)
. We suggest that this difference in mutation percentage is
caused by the fact that patients who are cured after a single TUR,
30%, do not, by definition, take part in the group of patients with
recurrent disease. Combining these observations, we feel that it is
likely that the group of patients with primary bladder cancer
containing a FGFR3 mutation encompasses patients who will
not develop a recurrence at all. Thus, the FGFR3 mutation
itself, being an indicator of superficial bladder cancer with a low
recurrence rate, is at least part of the explanation of the differences
between these groups. Capellen et al. (10)
were
the first to report on somatic FGFR3 mutations in bladder
cancer. They found 9 mutations in 26 tumors. Three of the nine
mutations occurred in invasive (i.e.,
pT2) tumors. The stage distribution of the
wild-type tumors was not given in their study. In contrast, we found no
mutations in invasive tumors. In addition, the correlation between the
presence of a mutation and low stage was highly significant in our
study. To ensure that no mutations were missed by contamination of
benign cells in the invasive tumors, we also performed LOH analysis on
these DNA samples. Multiple allelic losses were observed in 17 of 18
evaluable tumors (results not shown). These losses supported the
hypothesis that the DNA samples used for mutation and LOH analysis
indeed contained DNA that was derived mainly from tumor cells.
Thus, the apparent discrepancy between our study and that of Capellen
et al. (10)
remains difficult to explain. It
may be attributable to the relatively small number of tumors
examined by Capellen et al. (10)
.
The finding that tumors with FGFR3 mutations are less likely to lead to recurrences can be explained by the hypothesis that such tumors shed cells with a lower frequency than those tumors that do not carry a FGFR3 mutation. In the seven patients with recurrence in the mutant FGFR3 group, six of eight tumors occurred at the same region in the bladder, and six of eight recurrent lesions were single growths. In contrast, in most of the 14 patients who had recurrence in the nonmutant group, multiple tumors were found, and these tumors occupied several different sites in the bladder. These preliminary data indeed suggest that superficial bladder tumors without a FGFR3 mutation shed cells more easily and/or that these cells are better equipped to reimplant into the bladder epithelium. In addition, it may be possible that the FGFR3-mutated tumors proliferate not as fast as the nonmutated tumors. Additional experiments are required to test these hypotheses.
Molecular markers for bladder cancer may provide information to be used in clinical decision making. The incidence of TP53 gene mutations and an altered expression of the RB gene product appeared to be much higher in invasive, high-grade bladder cancers than in superficial low-grade ones (14 , 15) . These reports suggest that these molecular markers are relatively late events in disease pathogenesis and identify tumors with aggressive biological behavior. The clinical value of these two tumor suppressor genes is of importance to patients presenting with invasive bladder cancer (15 , 16) and for prediction of progression in patients with high-grade superficial bladder cancer. Barton Grossman et al. (5) advocated stratification of pT1 bladder cancer patients based on TP53 and RB status. Their results suggest that patients with normal protein expression for both genes can be managed conservatively, whereas patients with alterations in one, and particularly in both genes, require more aggressive treatment to prevent progression to invasive disease (5) . In contrast, chromosome 9q deletions, determined by LOH analysis, are found with similar frequency in superficial and invasive bladder cancer (17 , 18) and, therefore, cannot be used for prognostic purposes. The FGFR3 gene is the first gene identified in bladder cancer to be mutated selectively in those cancers that are characterized by favorable clinical parameters. Future studies should determine whether a combination of TP53, RB, and FGFR3 gene analyses could lead to a more accurate prediction of the disease course with regard to recurrence and progression. Furthermore, treatment strategies may also be determined based on these molecular markers.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by the University Hospital Rotterdam
as part of a top-down revolving fund project (FED 0930) and by a grant
from the Maurits and Anna de Kok foundation. 
2 To whom requests for reprints should be
addressed, at Department Pathology, Josephine Nefkens Institute,
Erasmus University, P. O. Box 1738, 3000 DR Rotterdam, the
Netherlands. Phone: 31-104087929; Fax: 31-104089487; E-mail: zwarthoff{at}path.fgg.eur.nl
3 The abbreviations used are: TUR,
trans-urethral resection; RB, retinoblastoma; FGFR3,
fibroblast growth factor receptor 3; LOH, loss of heterozygosity; SSCA,
single-strand conformation analysis.
Received 9/ 5/00. Accepted 1/ 4/01.
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