Epigenetic Biomarkers in Bladder Cancer

1.1 Epigenetics and cancer: An overview Genetic and epigenetic alterations are hallmarks of human cancer. In the last few decades, it has been well established that epigenetic changes are important events in human cancer development and progression in addition to genetic alterations (such as chromosomal rearrangements, aneuploidies and point mutations). Epigenetics refers to the study of changes in gene expression that are determined by mechanisms other than changes in the DNA sequence. Epigenetic phenomena include X-chromosome inactivation, genomic imprinting, cellular differentiation and the maintenance of cell identity. These events are mediated by several molecular mechanisms, including DNA methylation, post-translational histone modifications and various RNA-mediated processes. Many studies in the field of epigenetics have focused on the effects of histone modifications and DNA methylation in the transcription process because these mechanisms are often linked and interdependent (Ballestar, 2011). A variety of methods are currently being applied to detect epigenetic changes, and the past two decades have shown an exponential increase in novel approaches aimed at elucidating the molecular basis of epigenetic inheritance. DNA methylation is the most well studied epigenetic modification in human diseases (Fernandez et al., 2011). It involves the addition of a methyl group to the 5 carbon of a cytosine that is immediately followed by one guanine; i.e., DNA methylation typically occurs in a CpG dinucleotide context. CpG dinucleotides are generally underrepresented in the genome due to the increased mutation frequencies of the methylcytosines that are spontaneously converted to thymines. However, within the regions that are known as CpG islands, these dinucleotides are found at higher frequencies than is expected. It is believed that the human genome is comprised of approximately 38,000 CpG islands, and a large proportion of them (~37%) are located in the 5’ gene regulatory regions (promoters). The aberrant content of DNA methylation (global genome hypomethylation) and patterns of cytosine methylation, especially hypermethylation in promoter-associated CpG islands, are known to be associated with cancer. Gene-specific promoter hypermethylation causes the breakdown of normal cell physiology by silencing tumor suppressor genes, while DNA hypomethylation can reactivate oncogenes and repetitive sequences of the genome and lead to chromosomal instability (Sawan et al., 2008).