cancer epigenetics NEJM 2008

cancer epigenetics NEJM 2008 - The n e w e ng l a n d j o u...

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review article T h e new engl and journal o f medicine n engl j med 358;11 march 1 3, 2008 1148 Molecular Origins of Cancer Epigenetics in Cancer Manel Esteller, M.D., Ph.D. From the Cancer Epigenetics Laboratory, Spanish National Cancer Research Center, Madrid. Address reprint requests to Dr. Esteller at the Cancer Epigenetics Labo- ratory, Spanish National Cancer Research Center, Melchor Fernandez Almagro 3, 28029 Madrid, Spain, or at mesteller@ N Engl J Med 2008;358:1148-59. Copyright © 2008 Massachusetts Medical Society. C lassic genetics alone cannot explain the diversity of pheno- types within a population. Nor does classic genetics explain how, despite their identical DNA sequences, monozygotic twins 1 or cloned animals 2 can have different phenotypes and different susceptibilities to a disease. The concept of epi- genetics offers a partial explanation of these phenomena. First introduced by C.H. Waddington in 1939 to name “the causal interactions between genes and their prod- ucts, which bring the phenotype into being,” 3 epigenetics was later defined as heri- table changes in gene expression that are not due to any alteration in the DNA se- quence. 4 The best-known epigenetic marker is DNA methylation. The initial finding of global hypomethylation of DNA in human tumors 5 was soon followed by the identifi- cation of hypermethylated tumor-suppressor genes, 6-11 and then, more recently, the discovery of inactivation of microRNA (miRNA) genes by DNA methylation. 12,13 These and other demonstrations of how epigenetic changes can modify gene expression have led to human epigenome projects 14 and epigenetic therapies. 15 Moreover, we now know that DNA methylation occurs in a complex chromatin network and is influ- enced by the modifications in histone structure that are commonly disrupted in cancer cells. 16-19 Epigenetic research uses powerful techniques for the study of DNA methylation, such as sodium bisulfite modification associated with polymerase-chain-reaction pro- cedures. 20,21 Terms used in epigenetic research are defined in the Glossary. Compre- hensive epigenomic techniques 22 have yielded preliminary descriptions of the epi- genomes of human cancer cells. 23-25 This review summarizes new developments concerning hypermethylation of the promoter regions of tumor-suppressor genes 26 and describes possible applications of epigenetics to the treatment of patients with cancer. Epigenetic Features of a Normal Cell DNA methylation has critical roles in the control of gene activity and the architecture of the nucleus of the cell. In humans, DNA methylation occurs in cytosines that pre- cede guanines; these are called dinucleotide CpGs. 26,27
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cancer epigenetics NEJM 2008 - The n e w e ng l a n d j o u...

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