To date, genetic alterations are still the easiest changes in cancer cells to detect and study experimentally. In the future, successful sequencing of an entire human cancer cell genome will certainly yield more important information for the further study of cancer. However, even with this data, many important alterations will be missed, since not all changes occur at the DNA sequence level and are instead occurring at a non-genetic level. For example, both epigenetic phenomena and post-translational modifications have critical roles in the regulation of important cellular capabilities that contribute to the neoplastic phenotype.
Alterations in gene expression that do not involve mutations of DNA sequences are epigenetic events. These arise during cell development and proliferation and serve as an additional method of adaptation to environmental and selective pressures. It has become clear in recent years, that epigenetic changes have an impact to the development of human cancers through silencing of tumor suppressors and DNA damage elements, chromosomal instability, and even activation of oncogenes (160,161).
Hypermethylation-mediated silencing of tumor suppressor genes may be important for tumor development since, among other advantages, it tends to lead to a selective cellular growth advantage (160,161). Methylation of cytosine residues at CpG dinu-cleotides occurs, and 70-80% of these dinucleotides are heavily methylated in human cells (162). Long GC-rich stretches of DNA in the human genome, termed CpG islands, are often uniquely associated with flanking genes and are protected from modification (163). These normally unmethylated CpG islands may become methylated in cancer cells, resulting in loss of expression of the flanking genes (160). This form ofmethylation-induced silencing affects tumor suppressors genes such as CDH1 (164) and P16(165), both implicated in cancer development. Epigenetic alterations found in familial and non-hereditary forms of breast and colon cancer offer further supportive evidence for the role of methylation in neoplastic formation (166).
Although the exact mechanism of abnormal epigenetic changes leading to neoplasia is unknown, likely candidates include changes in expression of the key enzymes that regulate DNA methylation, such as the DNA methyltransferases (DNMTs). Overexpression of DNMT mRNA levels have been found in malignancies of various histological origin, including lung (167), colon (168,169), and ovarian (170) cancer cells. Further evidence is the fact that overexpression of DNMT1 leads to de novo methy-lation of CpG islands (171), and can facilitate cellular transformation (172,173).
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