The epigenetics of cancer etiology.
Epigenetic dysregulation is central to cancer development and progression. This dysregulation includes hypomethylation leading to oncogene activation and chromosomal instability, hypermethylation and tumor suppressor gene silencing, and chromatin modification acting directly, and cooperatively with methylation changes, to modify gene expression. In addition, disrupted genomic imprinting appears to contribute to colorectal cancer risk, and serves as a gatekeeper in Wilms tumor. A cancer predisposing disorder, Beckwith-Wiedemann syndrome, usually arises from epigenetic errors, solidifying the causal role of epigenetics in cancer. While cancer epigenetics has been reviewed extensively elsewhere, the main focus of this review will be to present the view that epigenetics and genetics are complementary in the area of cancer etiology, the focus of this volume. I propose a hypothesis in which epigenetic alterations contribute to tumor progression, but they also increase the probability that genetic changes, when they occur, will lead to cancer initiation. This hypothesis could contribute to a new understanding of the role of environmental carcinogens that may not be fully explained through a purely genetic view or by tests, such as bacterial mutation frequency, that ignore epigenetic factors.
Epigenetics Unit, Departments of Medicine, Oncology, and Molecular Biology and Genetics, Johns Hopkins University School of Medicine, 1064 Ross, Johns Hopkins Medical School, 720 Rutland Ave., Baltimore, MD 21205, USA. afeinberg@jhu.edu
Andrew P
AP
Feinberg
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D004777:Environment; D044127:Epigenesis, Genetic / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D009369:Neoplasms / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics* / Q000473:pathology
D002273:Carcinogens