Feinberg and Tyco Nat Reviews 2004

Feinberg and Tyco Nat Reviews 2004 - PERSPECTIVES abnormal...

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Unformatted text preview: PERSPECTIVES abnormal during fetal development, thereby predisposing to paediatric cancers, and they can change during normal ageing and con- tribute 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 dinu- cleotides 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 intro- duced the two investigators. At the time, many groups were excited by observations that DNA methylation might be linked to tis- sue-specific gene silencing, so Feinberg and Vogelstein searched for differences between cancers and normal tissues. They used Southern blotting to analyse DNA that had been digested with methylation-sensitive restriction enzymes and found that a sub- stantial proportion of CpGs that were methylated in normal tissues were unmethy- lated in cancer cells 1 . Ehrlich and colleagues then carried out similar investigations using high-performance liquid chromatography to show that the 5-methylcytosine content was globally reduced 2 (see TIMELINE). The loss of methylation involved every tumour type studied, both benign and malignant; fur- thermore, pre-malignant adenomas also universally had altered DNA methylation 3,4 . Hypomethylation of DNA has mechanis- tic implications. First, it can lead to gene acti- vation. It has been found recently that many CpG islands are normally methylated in somatic tissues 5 .These methylated islands can become hypomethylated in cancer and nearby genes become activated. Examples of genes that are affected by hypomethylation include oncogenes such as HRAS 6 and the ‘CT’genes — those that are expressed normally in the testis and aberrantly in tumours. Their hypomethylation leads, for example, to MAGE expression in melanoma — a promis- ing target of immunotherapy 7 . The related cancer/testis antigen CAGE was also shown to be activated by hypomethylation, which was confirmed using 5-aza-2 ′-deoxycytidine (5-azaCdR), an inhibitor of DNA methyla- tion,as well as promoter reporter transfection experiments; hypomethylation of CAGE was found to precede the development of stomach and liver cancer at high frequency 8 .Although hypomethylation was the originally identified epigenetic change in cancer,it was overlooked in preference of hypermethylation for many years and is only now undergoing a renais- sance.This is,in part,because of previous bias in experimental design; if one looks for altered methylation only at sites that are normally...
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Feinberg and Tyco Nat Reviews 2004 - PERSPECTIVES abnormal...

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