Predicting favourable prognosis of urothelial carcinoma: gene expression and genome profiling.
OBJECTIVE
During the past few years, information on (epi)genetic and expression profiling of urothelial carcinomas has expanded, allowing a better appreciation of their correlation with clinicopathological features of bladder cancer.


RESULTS
The two-pathway model of bladder carcinogenesis separating a favourable pathway characterized by mutations in the fibroblast growth factor 3 gene (FGFR3) and a clinically unfavourable pathway characterized by genetic instability and mutations in the p53 gene is now well established. Noninvasive (pTa), superficially invasive (pT1) and muscle invasive (pT2) bladder cancers can be separated statistically on the basis of extent of genomic instability. Expression (cDNA) array analyses are able to define mRNA signatures specifically associated with the two pathways of bladder carcinogenesis. Currently, attention is shifting to the role of epigenetic alterations in bladder carcinogenesis, including promoter hypermethylation of specific genes and aberrant expression of microRNAs. The level of promoter hypermethylation gradually increases from morphologically normal urothelium to invasive carcinoma. Aberrant expression of specific microRNAs is specifically related to the FGFR3 mutant defined bladder carcinogenesis pathway.


CONCLUSIONS
Quantitative genomic (DNA) alterations are associated with the two major molecular pathways of bladder carcinogenesis, defined by FGFR3 and p53 mutations. Chromosomal alterations, cancer specific mRNA expression signature and promoter hypermethylation may precede clinically and histopathologically detectable bladder cancer. As gene expression signature, promoter hypermethylation of selected genes and aberrant expression of some microRNAs are promising as bladder cancer biomarkers, future studies should explore their potential clinical significance taking into account their robustness and cost-effectiveness.
van der Kwast
Theodorus H
TH
Department of Pathology, University Health Network and University of Toronto, Canada. theo.vdkwast@uhn.on.ca
Bapat
Bharati
B
D002277:Carcinoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011401:Promoter Regions, Genetic; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism
D035683:MicroRNAs