Epigenetic Alterations as Contributors to the Pathogenesis, Detection, Prognosis and Treatment of Human Pre-invasive Neoplasia

The study of molecular processes driving human neoplasia development is achieving critical gains in terms of better detection and treatment. Current medicine already benefits from discovering genetic signatures of distinct cancers, and therapies have become more specifically targeted to the molecular aberrations defining parti­cular cancers (e.g.: chronic myelogenous leukemia is now diagnosed by detecting the t(9;22)(q34;q11) translocation, and therapy is based on inhibitors of the aberrant bcr-abl kinase). Epigenetic processes complement the genetic determinants of the cellular phenotype, and their study is of great interest for cancer researchers. The primary physiologic role of epigenetics is to govern cellular differentiation. Epigenetics have particular importance in organogenesis and also in maintaining the proper phenotypic profile of each cell in distinct organs and systems. The vast majority of current studies address DNA methylation changes pertinent to different tumor types. The global hypomethylation occurring in cancer results in genetic instability and may trigger enhanced expression of particular oncogenes. In contrast, aberrant promoter hypermethylation may reduce the expression of proteins that are critical for tissue homeostasis. This mechanism may reduce the expression of important tumor suppressor genes or the level of proteins critically involved in DNA maintenance and repair, cellular adhesion and intracellular signaling. Apart from methylation, neoplasia related perturbations were identified in virtually all of the epigenetic machinery. Proteins controlling DNA conformation (such as histone– modifying enzymes, or components of ATP-dependent remodeling and poly-ADP ribosylation) show reduced expression or activity in several distinct tumor types, providing evidence that epigenetics are critically involved in cancer development. The dynamic profile of epigenetic changes provides valuable background for clinical applications. Based on the particular epigenetic signatures described for different tumors, current studies focus on the development of epigenetic tests not only to diagnose cancer in early stages including pre-invasive disease, but also to identify patients at risk for tumor development. In addition, neoplasia-related epigenetic changes open a new therapeutic approach in human cancers, with drugs that undergo or have already passed clinical trials. Epigenetics are therefore emerging as a promising field for both diagnostic and therapeutic approaches of human neoplasia and pre-invasive disease.