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DNA methylation and gene silencing in cancer: which is the guilty party?

Oncogene volume 21, pages 5380–5387 (2002)Cite this article

Abstract

The DNA methylation pattern of a cell is exquisitely controlled during early development resulting in distinct methylation patterns. The tight control of DNA methylation is released in the cancer cell characterized by a reversal of methylation states. CpG island associated genes, in particular tumour suppressor or related genes, are often hypermethylated and this is associated with silencing of these genes. Therefore methylation is commonly convicted as a critical causal event in silencing this important class of genes in cancer. In this review, we argue that methylation is not the initial guilty party in triggering gene silencing in cancer, but that methylation of CpG islands is a consequence of prior gene silencing, similar to the role of methylation in maintaining the silencing of CpG island genes on the inactive X chromosome. We propose that gene silencing is the critical precursor in cancer, as it changes the dynamic interplay between de novo methylation and demethylation of the CpG island and tilts the balance to favour hypermethylation and chromatin inactivation.

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Acknowledgements

We would like to thank Clare Stirzaker, Jenny Song, Peter Warnecke and Peter Molloy for valuable comments. This work was supported in part by grants from NH&MRC (9937987, 000454 and 202907).

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Authors and Affiliations

  1. Sydney Cancer Centre, Kanematsu Laboratories, Royal Prince Alfred Hospital, Missenden Road, Camperdown, 2050, NSW, Australia

    Susan J Clark & John Melki

  2. Faculty of Medicine, University of Sydney, Sydney, 2050, NSW, Australia

    Susan J Clark & John Melki

  3. CSIRO, Molecular Science, Sydney Laboratory, PO Box 184, North Ryde, NSW 1670, Australia

    Susan J Clark & John Melki

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Correspondence to Susan J Clark.

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Clark, S., Melki, J. DNA methylation and gene silencing in cancer: which is the guilty party?. Oncogene 21, 5380–5387 (2002). https://doi.org/10.1038/sj.onc.1205598

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