ABSTRACT
Many genetic and environmental factors contribute to development of cancer. Traditional approaches to identification of cancer suppressor genes focused on structural changes in genes, including point mutations, gene deletions, and rearrangements and it is now well recognized that acquired mutations in key genes, for example p53 in multiple cancer types and B-raf, most strikingly in malignant melanoma, are important genetic changes in tumorigenesis in many cancer types. Furthermore, the unequivocal association of high penetrance germ-line alleles in genes such as BRCA1 (breast cancer) and p53 (Li Fraumeni syndrome) with cancer clearly confirm the importance of genetic changes in contributing to neoplasia. However, one of the major emerging themes of the last 10 years has been the recognition of the importance in carcinogenesis of downregulation of gene expression through transcriptional silencing. A large volume of experimental evidence now suggests that transcriptional silencing, via epigenetic mechanisms, is a mode of gene inactivation at least as common as the disruption of classic tumor-suppressor genes in human cancer by mutation, and possible more so [1]. For example, although germ-line mutations in BRCA1 are strongly associated with increased predisposition to familial breast cancer, somatically acquired mutations in the gene are exceedingly rare in sporadic breast and ovarian cancers, and the gene is more frequently inactivated by transcriptional silencing.
