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The history of cancer epigenetics
Andrew P. Feinberg and Benjamin Tycko
Since its discovery in 1983, the epigenetics of human cancer has been in the shadows of human cancer genetics. But this area has become increasingly visible with a growing understanding of specific epigenetic mechanisms and their role in cancer, including hypomethylation, hypermethylation, loss of imprinting and chromatin modification. This timeline traces the field from its conception to the present day. It also addresses the genetic basis of epigenetic changes an emerging area that promises to unite cancer genetics and epigenetics, and might serve as a model for understanding the epigenetic basis of human disease more generally.
Epigenetic inheritance is defined as cellular information, other than the DNA sequence itself, that is heritable during cell division. There are three main, inter-related types of epigenetic inheritance: DNA methylation, genomic imprinting and histone modification (BOX 1).Epigenetic inheritance accounts for unusual phenomena such as position-effect variegation in flies, telomere and mating-type silencing in yeast, and transgene-induced gene silencing in plants and animals. However, it has become increasingly apparent that epigenetic inheritance is important in many physiological and pathophysiological conditions. It is key to our understanding of the differences between growing, senescent and immortal cells, tumour and normal cells, various differentiated cells, and ageing cells. Epigenetic templates that control gene expression are transmitted to daughter cells independently of the DNA sequence. These metastable patterns can sometimes become
abnormal during fetal development, thereby predisposing to paediatric cancers, and they can change during normal ageing and contribute to common cancer risk in adults. They can also support clonal evolution in human cancers, contributing to tumour progression.
But how was this key role for epigenetics in cancer development discovered, how has it come to rival genetics and what else do we need to know?
Hypomethylation and gene activation
Loss of DNA methylation at CpG dinucleotides was the first epigenetic abnormality to be identified in cancer cells. At a symposium at Johns Hopkins in 1982 on tumour-cell heterogeneity,Andy Feinberg and Bert Vogelstein wondered what mechanism accounted for high-frequency mutations, adaptation to tumour microenvironment and plasticity in some cancers. The conference was organized by Donald Coffey, who had introduced the two investigators. At the time, many groups were excited by observations that DNA...