title: Epigenetic changes in solid and hematopoietic tumors.
abstract: There are three connected molecular mechanisms of epigenetic cellular memory in mammalian cells: DNA methylation, histone modifications, and RNA interference. The first two have now been firmly linked to neoplastic transformation. Hypermethylation of CpG-rich promoters triggers local histone code modifications resulting in a cellular camouflage mechanism that sequesters gene promoters away from transcription factors and results in stable silencing. This normally restricted mechanism is ubiquitously used in cancer to silence hundreds of genes, among which some critically contribute to the neoplastic phenotype. Virtually every pathway important to cancer formation is affected by this process. Methylation profiling of human cancers reveals tissue-specific epigenetic signatures, as well as tumor-specific signatures, reflecting in particular the presence of epigenetic instability in a subset of cancers affected by the CpG island methylator phenotype. Generally, methylation patterns can be traced to a tissue-specific, proliferation-dependent accumulation of aberrant promoter methylation in aging tissues, a process that can be accelerated by chronic inflammation and less well-defined mechanisms including, possibly, diet and genetic predisposition. The epigenetic machinery can also be altered in cancer by specific lesions in epigenetic effector genes, or by aberrant recruitment of these genes by mutant transcription factors and coactivators. Epigenetic patterns are proving clinically useful in human oncology via risk assessment, early detection, and prognostic classification. Pharmacologic manipulation of these patterns-epigenetic therapy-is also poised to change the way we treat cancer in the clinic.
authors.affiliation: Sapporo Medical University, Sapporo, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyota
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
mesh_terms: D000483:Alleles; D000818:Animals; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D019337:Hematologic Neoplasms / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D010641:Phenotype; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D014018:Tissue Distribution; D014158:Transcription, Genetic
chemical_list: D006657:Histones