Predicting favourable prognosis of urothelial carcinoma: gene expression and genome profiling Theodorus H. van der Kwast a and Bharati Bapat b Introduction Technological innovations like high throughput DNA and cDNA profiling have provided much information in recent years on the molecular-genetic changes in bladder cancer [1]. Techniques like high-resolution comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) array analysis have led to the dis- covery of many genetic alterations in the various stages of bladder cancer. cDNA profiling has yielded mRNA expression signatures, which have now been validated in a few large series for prognostication in individual patients [2]. In addition, the field of epigenetics is now also rapidly developing, and a picture of the importance of epigenetics in bladder carcinogenesis is emerging. To enable presentation of all this new information in a meaningful way for purpose of this review, we tried to correlate the expression array and (epi-)genetic data with the current model of bladder carcinogenesis. This two- pathway model is based on conventional histopathologi- cal and specific molecular-genetic features (Fig. 1). Clas- sically, this model distinguishes a hyperplasia, papillary low-grade carcinoma pathway with favourable prognosis, and a carcinoma in-situ high-grade carcinoma pathway with poor prognosis [3]. At the molecular level the hyperplasia – papillary low-grade urothelial carcinoma with favourable prognosis is characterized by a gain-of- function mutation in the fibroblast growth factor receptor a Department of Pathology, University Health Network and University of Toronto and b Pathology and Laboratory Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital and University of Toronto, Toronto, Canada Correspondence to Theodorus H. van der Kwast, Department of Pathology, Toronto General Hospital, 11th floor, University Health Network, 200 Elizabeth Street, Toronto, Ontario, M5G 2C5, Canada Tel: +1 416 340 4597; e-mail: theo.vdkwast@uhn.on.ca Current Opinion in Urology 2009, 19:516–521 Purpose of review 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. Recent findings 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. Summary 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. Keywords bladder cancer, cDNA profiling, epigenetics, genomics, methylation, microRNA, molecular pathways Curr Opin Urol 19:516–521 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 0963-0643 0963-0643 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MOU.0b013e32832eb45f