[The roles of DNA methylation in human neoplasms]

Recent data suggested that cancer appears to be a process that is fuelled both by genetic alterations and by epigenetic mechanisms. Epigenetics refer to the study of changes in gene expression that can be mitotically inherited, but is not associated with the changes in the coding sequence of the affected genes. DNA methylation, the best understood mechanism in epigenetics, is an enzyme-mediated chemical modification that adds methyl (CH3) groups at selected sites on DNA. In humans and most mammals, DNA methylation only affects the cytosine base (C), when it is followed by a guanosine (G). DNA methylation in the promoter regions is a powerful mechanism for the suppression of gene activity. It was thought formerly that two pathways by which tumor suppressor genes became disabled were intragenic mutations and loss of chromosomal material [(loss of heterozygosity (LOH) or homozygous deletion)]. More recent studies have firmly established methylation as one potential hit and represent a third mechanism by which tumor suppressor genes are inactivated, and that, in some cases, methylation is the sole mechanism responsible for the inactivation of a tumor suppressor gene. There is clearly a tumor-specific methylation pattern in many types of tumor. An individual tumor within a single patient may have characteristic set of gene with an increased propensity to become methylated as compared with a tumor of the same type in a different patient. Methylation changes appear to precede apparent malignancy in many cases. Therefore, methylation can distinguish tumor types and subtypes, and should be useful in improving early detection of potentially cancerous cells. Methylation markers may also be used to predict response to chemotherapy or duration of patient survival. The efficacy of hypomethylating agents (e.g. 5-aza-2'-deoxycytidine) as antineoplastic agents has been attributed to two distinct mechanism: cytotoxicity and induction of hypomethylation. Some clinical trials with them have been performed in solid tumors and malignant hematologic disease. In general, the response rates were not satisfactory. A variety of methods are used to evaluate the methylation status of genes. MSP (methylation-specific PCR) is very sensitive and has been widely used. It takes advantage of the DNA sequence difference existing between methylated and unmethylated DNA after bisulfite treatment.