Abstract
Bladder tumors develop through different molecular pathways. Recent reports suggest activating mutations of the fibroblast growth factor receptor 3 (FGFR3) gene as marker for the "papillary" pathway with good prognosis, in contrast to the more malignant "carcinoma in situ" (CIS) pathway. The aim of this clinical follow-up study was to investigate the role of FGFR3 mutations in bladder cancer development in a longitudinal study. We selected 85 patients with superficial bladder tumors, stratified into early (stage T(a)/grade 1-2, n = 35) and more advanced (either stage T(1) or grade 3, n = 50) developmental stages. The patients were followed prospectively, and metachronous tumors were included. We did screening for FGFR3 and TP53 mutations by direct bidirectional sequencing and for genome-wide molecular changes with microarray technology. A total of 43 of 85 cases (51%) showed activating mutations of FGFR3. The mutations were associated with papillary tumors of early developmental stage. However, after stratifying for developmental stage, FGFR3-mutated tumors showed the same malignant potential as wild-type tumors. Tumors with concomitant CIS were generally FGFR3 wild type. They were characterized by different patterns of chromosomal changes and gene expression signatures compared with FGFR3-mutated tumors, indicating different molecular pathways. FGFR3 mutations seem to have a central role in the early development of papillary bladder tumors. These tumors follow a common molecular pathway, which is different from tumors with concomitant CIS. FGFR3 mutations do not seem to play a role in bladder cancer progression.
Highlights
Bladder tumors develop through different molecular pathways
fibroblast growth factor receptor 3 (FGFR3) mutations are rarely found in carcinoma in situ’’ (CIS) [9], which is known to have a high frequency of TP53 mutations [7] and a high probability of progression
We found no correlation between FGFR3 mutation status and general chromosomal instability
Summary
Recent reports suggest activating mutations of the fibroblast growth factor receptor 3 (FGFR3) gene as marker for the ‘‘papillary’’ pathway with good prognosis, in contrast to the more malignant ‘‘carcinoma in situ’’ (CIS) pathway The aim of this clinical follow-up study was to investigate the role of FGFR3 mutations in bladder cancer development in a longitudinal study. Conclusions: FGFR3 mutations seem to have a central role in the early development of papillary bladder tumors.These tumors follow a common molecular pathway, which is different from tumors with concomitant CIS. Activating mutations of the fibroblast growth factor receptor 3 (FGFR3) gene have been shown in bladder tumors with high frequency [8] They are associated with early papillary lesions with low malignant potential [9, 10]. Metachronous tumors were examined in a subgroup of cases to show changes in developing tumors
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