Low frequency of epigenetic events in urothelial tumours from young patients

Introduction & Objectives: The incidence of Urothelial cell carcinoma of the bladder (UCC) increases with age. Tumours are uncommon in young patients and consequently little is known regarding their biology. We recently reported a series of tumours in patients less than 20 years of age at diagnosis and performed an exhaustive genetic screen for molecular alterations. Few events typical for UCC were detected. As many molecular carcinogenic events occur at the epigenetic rather than genetic level, here we analyse the same tumours for alterations in DNA hyperméthylation. We compare this sample with two other cohorts stratified by age and matched for pathological stage.
Material & Methods: We analysed 76 UCC from three groups stratified for age at diagnosis (<19 years, 20-45 years and >46 years (median age 74)) and matched for low grade and non-muscle invasive stage. Due to the rarity of young cases, we collected specimens from multiple centres, with appropriate ethics committee approvals. We used bisulphite conversion and quantified methyl specific PCR to investigate the promoter méthylation status of 8 tumour suppressor genes implicated in urothelial carcinogenesis.
Results: Tumours in the youngest age group had the lowest frequency of global hyperméthylation when compared to the other tumours (Methyl index: 37.5% vs. 62.5% vs. 50%, ANOVA p=0.009). When individual loci were analysed, younger patients had a significantly lower frequency and concentration of méthylation at APC, Bcl2, MGMT and E-Cadherin promoters when compared to the older groups (p<0.05). Few differences were present between the two older cohorts, although the concentration ofAPC and MGMT méthylation increased with age.
Conclusions: Urothelial tumours in patients under 19 years old have low rates of epigenetic alteration. Tumours in patients older than 20 years have a similar epigenetic profile to tumours in the typical UCC age population.