Alterations in DNA methylation are regarded as epigenetic and not genetic changes, because although epigenetic changes affect the structure of DNA, they do not materially affect the genetic code. In recent years, numerous studies have demonstrated that a close correlation exists between methylation and transcriptional inactivation, supporting the notion that not only genetic changes, but also epigenetic changes can contribute to the carcinogenic process (Strathdee et al., 2002; Yan et al., 2001). The pattern of methylation observed in cancer generally shows a dramatic shift compared with that of normal tissue. The methylation pattern in tumors consists of a global hypomethylation, in conjunction with localized hypermethylation at CpG islands (Goelz et al., 1985). This regional hypermethylation at CpG islands is associated with the transcriptional inactivation of cancer related genes (Momparler and Bovenzi, 2000).
Recent studies have demonstrated that hypermethylation of CpG islands may be implicated in tumorigenesis, acting as a mechanism to inactivate specific gene expression of a diverse array of genes (Baylin et al., 2001). Genes that have been reported to be regulated by CpG hypermethylation, include tumor suppressor genes, cell cycle related genes, DNA mismatch repair genes, hormone receptors and tissue or cell adhesion molecules (Yan et al., 2001). For example, tumor-specific deficiency of expression of the DNA repair genes MLH1 and MGMT (Herman, 1998; Simpkins, 1999) and the tumor suppressors, p16, CDKN2 and MTS1, has been directly correlated to hypermethylation (Jones, 1999; Merlo et al., 1995). Increased CpG island methylation can result in the inactivation of these genes resulting in increased levels of genetic damage, predisposing cells to later genetic instability which then contributes to tumor progression (Strathdee and Brown, 2002).
Hypermethylation is now the most well characterized epigenetic change to occur in tumors, and it is found in virtually every type of human neoplasm. Promoter hypermethylation is as common as the disruption of classic tumor-suppressor genes in human cancer by mutation and possibly more so (Baylin and Herman, 2000). Approximately 50% of the genes that cause familial forms of cancer when mutated in the germ line are also known to undergo methylation-associated silencing in various sporadic forms of cancer (Jones and Baylin, 2002).
In cancer, the dynamics of genetic and epigenetic gene silencing are very different. Somatic genetic mutation leads to a block in the production of functional protein from the mutant allele. If a selective advantage is conferred to the cell, the cells expand clonally to give rise to a tumor in which all cells lack the capacity to produce protein. In contrast, epigenetically mediated gene silencing occurs gradually. It begins with a subtle decrease in transcription, fostering a decrease in protection of the CpG island from the spread of flanking heterochromatin and methylation into the island. This loss results in gradual increases of individual CpG sites, which vary between copies of the same gene in different cells (Jones and Baylin, 2002).