It has been suggested that cancer represents an alteration in DNA, heritable by progeny cells, that leads to the abnormally regulated expression of normal cellular genes. In the experiments proposed here, we wish to explore the idea that changes in the methylation status of genes represent one class of such DNA alterations in cancer. These experiments were prompted by two sets of observations. The first set comprises the large number of studies showing that changes in DNA methylation accompany the regulated expression of normal genes, and that induced decreases in DNA methylation lead to the expression of the hypomethylated genes. The second set of observations comprises our own studies on a small number of human cancer patients; we have found that specific genes are strikingly hypomethylated in some of the cancerous tissues when compared to their normal counterparts. We wish to extend these observations through a detailed study of DNA methylation in a common form of human cancer, colonic adenocarcinoma. We will study the methylation of several genes in a large number of these cancers to determine the prevalence of this form of DNA alteration in colon cancer. We will then determine whether changes in the methylation status of genes is associated with abnormal expression of these genes in the cancerous tissues. Finally, we will determine whether there is a correlation between alterations in DNA methylation and basic malignant processes such as tumor progression, metastasis, and heterogeneity.
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