Hypermethylation in bladder cancer: biological pathways and translational applications

A compelling body of evidences sustains the importance of epigenetic mechanisms in the development and progression of cancer. Assessing the epigenetic component of bladder tumors is strongly improving our understanding of their biology and clinical behavior. In terms of DNA methylation, cancer cells show genome-wide hypomethylation and site-specific CpG island promoter hypermethylation. In the context of other epigenetic alterations, this review will focus on the hypermethylation of CpG islands in promoter regions, as the most widely described epigenetic modification in bladder cancer. CpG islands hypermethylation is believed to be critical in the transcriptional silencing and regulation of tumor suppressor and crucial cancer genes involved in the major molecular pathways controlling bladder cancer development and progression. In particular, several biological pathways of frequently methylated genes include cell cycle, DNA repair, apoptosis, and invasion, among others. Furthermore, translational aspects of bladder cancer methylomes described to date will be discussed towards their potential application as bladder cancer biomarkers. Several tissue methylation signatures and individual candidates have been evidenced, that could potentially stratify tumors histopathologically, and discriminate patients in terms of their clinical outcome. Tumor methylation profiles could also be detected in urinary specimens showing a promising role as non-invasive markers for cancer diagnosis towards an early detection and potentially for the surveillance of bladder cancer patients in a near future. However, the epigenomic exploration of bladder cancer has only just begun. Genome-scale DNA methylation profiling studies will further highlight the relevance of the epigenetic component to gain knowledge of bladder cancer biology and identify those profiles and candidates better correlating with clinical behavior.