The epigenetic events that regulate gene expression have clearly emerged as a fundamental mechanism in developmental biology and in the pathogenesis of human disease. For example, multiple genes that affect numerous cellular pathways are silenced by hypermethylation in cancer, and studying these genes has increased our understanding of how cancer develops and progresses. A majority of studies, however, focus on methylation of a single gene or panel of genes, without detailed investigation of the functional relevance of the gene silencing. With the advent of genome-wide microarray platforms, the ‘methylome’ will be further defined. The molecular information gained from epigenetic studies, in conjunction with other genetic information, could be used to develop a novel classification system for tumors and diseases. This theoretical classification system could be designed to reflect so-called ‘tumor biology’ that could predict clinical outcomes such as overall prognosis, risk of recurrence after surgery, or response to chemotherapy.
Naturally, with the increased knowledge regarding the pathogenesis of disease, there is hope for the development of a new era of novel therapeutic agents that may effectively treat patients. The beauty of epigenitic modifications to DNA is that they are potentially preventable or even reversible. For example, blocking DNA methylation by inhibiting DNMTs results in demethylation of CpG islands in daughter cells, with subsequent restored expression of tumor suppressor genes and abrogation of tumor growth. There are several DNA demethylating compounds that are actively being investigated, including 5-azacytidine (AzaC), 5-aza-2′-deoxycytidine, zebularine, procainamide, and procaine [8
]. Unfortunately, toxicity has been a major limiting feature of these medications, and they are currently only indicated in patients with advanced myelodysplastic syndromes [21
]. Rather than systemically administered therapeutics, specialized delivery systems that specifically target aberrant methylation in tumors are actively being developed and studied. Abnormal promoter methylation has also been shown to correlate with chemotherapy and radiation resistance [22
]. In the future, it is conceivable that demethylating agents could be used to enhance the effectiveness of traditional chemotherapy [21
There are also a host of histone deacetylase (HDAC) inhibitors that are being studied for the treatment of cancer. Examples of these HDAC inhibitors include suberoylanilide hydroxamic acid, trichostatin A, valproic acid, and sodium butyrate [8
]. These agents result in an increase of histone acetylation by blocking the action of multiple HDACs, and are commonly used in laboratory experiments to reverse epigenetic-induced gene silencing.
Many of the epigenetic events described have been detected in human samples in preneoplastic tissues. In particular, some hypermethylated genes may even be detected in the serum of patients prior to clinical detection of malignancy. Another example is the prediction of the development of dyplasia progression in Barrett's associated adenocarcinoma of the esophagus. In a randomized, double-blinded, multicenter study, a panel of eight hypermethylated genes predicted the progression of dyplasia better than traditional clinical risk factors [23
]. For this reason, DNA methylation, hypomethylation, or histone modification are potential candidates for biomarkers for the early detection of disease.
In summary, epigentics has emerged as a crucial link between nature and nurture. With an incredible degree of complexity, epigenetic phenomena exert a profound influence on the regulation of how genetic information is transcribed and translated into proteins and phenotypes. With advanced technologies and knowledge, future discoveries regarding the pathogenesis of multifactorial and previously idiopathic diseases are possible.