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Reversal of DNA hypomethylation by folic acid supplements: possible role in colorectal cancer prevention
  1. J C Mathers
  1. Correspondence to:
    Professor J C Mathers
    Human Nutrition Research Centre, School of Clinical Medical Sciences, University of Newcastle, Newcastle upon Tyne, NE1 7RU, UK;

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Low folate intake may predispose to a greater risk of colorectal cancer

The deranged gene expression that is causal for colorectal cancer (CRC) development results from unrepaired genomic damage which accumulates in successive generations of mucosal cells and which provides the neoplasm with a growth and/or survival advantage. Such damage includes disabling mutations in tumour suppressor (TS) genes and facilitates inappropriate expression of oncogenes. Approximately 25 years ago, evidence began to appear that changes in methylation status of DNA might be responsible for changes in gene expression. The potential importance of aberrant DNA methylation in tumorigenesis was signalled when, on 6 January 1983, Nature carried an article by Feinberg and Vogelstein1 reporting the first evidence of hypomethylation of some genes in tumours compared with “normal” tissue from the same individuals. That same year, Gama-Sosa and colleagues2 used high performance liquid chromatography to demonstrate that metastatic tumours had a significantly lower content of 5-methylcytosine than did benign neoplasms or normal tissues. Somewhat surprisingly, site specific hypermethylation of particular genes, including the classical TS the retinoblastoma gene, was observed a few years later (see Feinberg and Tycko3 for an excellent review). It is now clear that global genomic hypomethylation and hypermethylation of specific genes coexist in the same tumours but whether the genesis of the two phenomena is related remains uncertain.


Laird4 has argued that cancer may be as much a disease of misdirected epigenetics as it is of genetic mutations. Epigenetics describes non-coding changes to the genome which are transmitted through mitosis and alter gene expression. Although changes in other epigenetic markings, especially in post translational modifications of histones, are likely to be of considerable significance in tumour pathogenesis, much of the work to date has focussed on DNA methylation. Approximately 1% of DNA bases in the …

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