DNA methylation and gastrointestinal malignancies: functional consequences and clinical implications

Evidence now suggests that the transcriptional silencing of selected genes by DNA methylation plays a crucial role in the development and progression of human gastrointestinal malignancies. To date, genes involved in the regulation of the cell cycle, DNA repair, angiogenesis, and apoptosis have all been shown to be inactivated by the hypermethylation of their respective 5' CpG islands. The specific causes and effects of the changes in DNA methylation that occur in cancer remain unknown, however. Nevertheless, recently developed techniques for detecting changes in DNA methylation have dramatically increased the amount of information available on the patterns of methylation that occur as cancers progress. One key process involved in aberrant methylation is related to aging, and because it affects a large number of CpG islands, age-related methylation may be a primary cause of the increased incidence of cancer seen among older individuals. Other patterns of methylation are cancer-specific and are detected only in a subset of tumors exhibiting the CpG island methylator phenotype (CIMP). In this regard, the majority of sporadic colorectal cancers, exhibiting microsatellite instability (MSI) appear to be associated with CIMP, which leads to aberrant methylation of human MutL homologue (hMLH1) and the loss of its expression. We anticipate that as the various components of the molecular machinery involved in aberrant DNA methylation become better understood, they will prove to be useful targets, serving as the basis for the development of new methods for the diagnosis and treatment of gastrointestinal malignancies.