The role of DNA hypermethylation in human neoplasia

Cancer development and progression is dictated by a series of alterations i n genes such as oncogenes, tumor suppressor genes, DNA repair genes, and ot hers. DNA methylation is an epigenetic modification that is profoundly alte red in most cancers. Recently, hypermethylation of CpG-rich areas located i n the promoter of genes (CpG islands) has been shown to be commonly implica ted in silencing tumor suppressor genes in cancer. By cloning and character izing a large number of such CpG islands hypermethylated in colon cancer, w e found that two processes explain most of these events. Age-related CpG is land methylation in a subset of cells in normal tissues, followed by intens ification of methylation in cancer cells explains the majority of hypermeth ylation events in colon cancer and may provide a mechanistic link between a ging and cancer formation. Most of the other CpG islands methylated in colo n cancer can be explained by a newly described phenotype, the CpG island me thylator phenotype (CIMP) which results in multiple methylation events in a subset of cancers. CIMP accounts for the majority of sporadic colon cancer s characterized by microsatellite instability, as well as most tumors with k-ras mutations. Understanding further the factors that lead to, and modula te, aberrant methylation in cancer may provide novel avenues for prevention and treatment of this disease.