Interest of methylated genes as biomarkers in urothelial cell carcinomas of the urinary tract.

Urothelial cell carcinomas (UCC), including bladder cancer and upper urinary tract cancer, are the second most common malignancy of the urogenital tract after prostate cancer. It is a critical issue to differentiate accurately those patients whose tumour will recur and/or progress after initial treatment from those without recurrence and/or progression because tumours with a similar morphology behave differently. Patients undergo lifelong cystoscopic and cytology surveillance to detect subsequent tumour recurrence. New noninvasive methods for the diagnosis and surveillance of UCCs are required. DNA methylation is an important epigenetic mechanism of gene regulation and plays essential roles in tumour initiation and progression. Currently, aberrant promoter hypermethylation has been investigated in specific genes, i.e. tumour-suppressor genes, proto-oncogenes, genes involved in cell adhesion, and genes of cell cycle regulation. E-cadherin has been shown to be an independent marker of prognosis. Other genes, e.g. APC, RASSF1a, TNFRSF25, EDNRB, and p14, are implicated in tumour progression. IGFBP3 and APAF-1 are independent markers of recurrence. APAF-1 is also correlated with tumour stage and grade. In urine, hypermethylation of DAPK, RARβ, E-cadherin and p16 has been shown to have a good sensitivity and specificity for bladder cancer detection. Several studies found that analysis of hypermethylation using a panel of tumour-suppressor genes yielded superior results to cytology in the detection of bladder cancer and its progression. Hence, the different panels (e.g. RASSF1a/APC/p14, RAR_/DAPK/E-cadh/p16, p16/p14/MGMT/GSTP1, and RASSF1a/E-cadh/APC) are of interest in the detection of bladder cancer. The last panel and RASSF1a/E-cadh/APC/TNFRSF25/EDNRB are also interesting for tumour progression. There is evidence that the extent of the mutator and methylator phenotypes in UCCs differs with tumour location, perhaps suggesting that carcinogens affect the urinary tract in different ways. For all loci studied except DAPK, there was more frequent methylation in UUT-UCCs than in the bladder cancers; this difference was statistically significant for hMLH1, RARB, E-cadherin, p16 and MINT31. In contrast to UUT-UCCs, hMLH1 and MINT31 were rarely methylated in bladder tumours, suggesting that they play a role in UUT carcinogenesis but not bladder cancer.