Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host

• Published in: Nature reviews. Cancer Vol. 13; no. 7; pp. 497 - 510
• Main Authors: Timp, Winston, Feinberg, Andrew P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2013; Nature Publishing Group
• Subjects: 70; Analysis; Biomedicine; Cancer; Cancer Research; Chromatin Assembly and Disassembly - physiology; Epigenesis, Genetic - physiology; Epigenetic inheritance; Genetic aspects; Health aspects; Heterochromatin - physiology; Humans; Medicin och hälsovetenskap; Neoplasms - genetics; Neoplasms - pathology; Neoplasms - therapy; opinion-2; United States
• ISSN: 1474-175X; 1474-1768; 1474-1768
• DOI: 10.1038/nrc3486

Feinberg and Timp review cancer-associated epigenetic alterations and propose that epigenetic dysregulation is an initiating force in tumorigenesis that promotes the selection of cancer-associated phenotypes and that can cooperate with genetic alterations, indicating that the gene-centric view of cancer biology is not the whole story. Although at the genetic level cancer is caused by diverse mutations, epigenetic modifications are characteristic of all cancers, from apparently normal precursor tissue to advanced metastatic disease, and these epigenetic modifications drive tumour cell heterogeneity. We propose a unifying model of cancer in which epigenetic dysregulation allows rapid selection for tumour cell survival at the expense of the host. Mechanisms involve both genetic mutations and epigenetic modifications that disrupt the function of genes that regulate the epigenome itself. Several exciting recent discoveries also point to a genome-scale disruption of the epigenome that involves large blocks of DNA hypomethylation, mutations of epigenetic modifier genes and alterations of heterochromatin in cancer (including large organized chromatin lysine modifications (LOCKs) and lamin-associated domains (LADs)), all of which increase epigenetic and gene expression plasticity. Our model suggests a new approach to cancer diagnosis and therapy that focuses on epigenetic dysregulation and has great potential for risk detection and chemoprevention.