First reported in 1949, methylcytosine in DNA sequences has only relatively recently received attention in the development, progression, diagnosis, and management of human cancers Methylcytosine is created post-replication by the addition of a methyl group to the 5 position of the cytosine ring when a cytosine is followed by a guanine (CpG) in sequence. The addition is made by DNA methyltransferases (DNMTs) using the methyl donor s-adenosyl methionine. Across mammalian genomes, CpG dinucleotides are relatively rare events. Sporadically, CpG may be found in high density in constructs called CpG islands that are frequently associated with the control regions of genes. Hypermethylation of these islands was originally thought to result in persistent silencing of the associated gene. New work has demonstrated, however, that chromatin marks on histones are responsible for the active silencing of the gene, which can often be expressed even when methylated. These hypermethylated genes will revert to a silenced state in relatively short order when the signal for the histone changes recedes.2 Recently, a third concept of CpGs has emerged. The CpGs residing in the lower density regions near CpG islands are considered to reside on the "shores" of those islands and appear to play a significant role in cell development and stem cell function. The first reported examination of DNA methylation in canine cancer was in 2003 when lymphomas were shown to be characterized by the same global loss of DNA methylationseen in human lymphomas.3 Subsequently, the often hypermethylated FHITgene was studied in canine lymphoma cell lines and found to be aberrantly expressed, but hypermethylation could not be documented to be the cause.4 Conversely, the DLC1 gene was shownto be significantly hypermethylated in canine lymphoma patient samples, but no effect on the expression of the gene could be identified.5 Put most simply, epigenetic changes like DNA methylation are the mechanism by which a liver cell remains a liver cell and a skin cell remains a skin cell, yet they share identical DNA within the same body. Certain sets of genes in each cell are mostly permanently turned on or off to limit the set of proteins that can be expressed. These mechanisms become disrupted inthe course of carcinogenesis, changing the gene sets available to cancer cells and resulting in significant genetic and epigenetic plasticity.
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