Role of activating fibroblast growth factor receptor 3 mutations in the development of bladder tumors.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


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. FGFR3 mutations do not seem to play a role in bladder cancer progression.
Zieger
Karsten
K
Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University, Denmark.
Dyrskjøt
Lars
L
Wiuf
Carsten
C
Jensen
Jens L
JL
Andersen
Claus L
CL
Jensen
Klaus Møller-Ernst
KM
Ørntoft
Torben Falck
TF
D002278:Carcinoma in Situ / Q000235:genetics / Q000378:metabolism; D002874:Chromosome Mapping; D016000:Cluster Analysis; D004247:DNA / Q000737:chemistry; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019656:Loss of Heterozygosity; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D012306:Risk; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
D016159:Tumor Suppressor Protein p53; D004247:DNA; D051498:Receptor, Fibroblast Growth Factor, Type 3