The role of CpG island methylation in the development and progression of cancer

An altered pattern of DNA hypermethylation involving de novo methylation of normally unmethylated promoter regions of specific genes has been observed in nearly all human cancers. Multiple studies have shown that hypermethylation of promoter region CpG islands is associated with transcriptional silencing of the gene in which this modification occurs. The purpose of this thesis was to evaluate the hypothesis that aberrant promoter methylation is a frequent and critical event in the development of cancer. This was accomplished through a series of four studies designed to examine methylation in specific genes and tumor types and transcriptional regulation of a single gene. The first study examined the frequency and timing of methylation of the p16 gene in a rat model of hepatocellular carcinoma. The second study defined the role of methylation of the O6 -methylguanine-DNA methyltransferase gene in human lung adenocarcinomas associated with exposure to cigarette smoke, radon, and in tumors from never-smokers. The third study used an animal model to examine the relationship between carcinogen exposures and methylation by determining the frequency of methylation of the death associated protein-kinase gene in murine lung tumor cell lines, hyperplasias, and tumors associated with several environmental and occupational carcinogens. Finally, the fourth study began identifying the mechanisms involved in methylation-induced gene silencing. Specifically, this study examined transcriptional regulation of the human death associated protein-kinase promoter and elucidated critical factors involved in aberrant methylation of the gene.; These studies confirmed that methylation is a frequent and often early event in cancer development, and demonstrated that exposure to carcinogens may play a critical role in aberrant methylation of many genes. These studies also demonstrated that aberrant promoter region methylation is associated with transcriptional inactivity of the gene in which it occurs and that the presence of specific regulatory factors within a cell may have a strong impact on mediating a gene's sensitivity towards methylation-induced transcriptional silencing.; These studies significantly contributed to our understanding of the role methylation plays in cancer initiation and development and provided new information on the mechanisms by which aberrant methylation contributes to transcriptional silencing.