This article is part of a special issue on epigenomics.

Open Access Research

Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns

Duncan Sproul12, Robert R Kitchen13, Colm E Nestor12, J Michael Dixon1, Andrew H Sims1, David J Harrison14, Bernard H Ramsahoye15 and Richard R Meehan12*

Author Affiliations

1 Breakthrough Breast Cancer Research Unit and Division of Pathology, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK

2 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK

3 Yale University School of Medicine, Department of Molecular Biophysics & Biochemistry and Department of Psychiatry, 266 Whitney Ave, New Haven, CT 06511, USA

4 University of St Andrews School of Medicine, Medical and Biological Sciences Building, University of St Andrews, North Haugh, St Andrews KY16 9TF, UK

5 Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK

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Genome Biology 2012, 13:R84  doi:10.1186/gb-2012-13-10-r84

Published: 3 October 2012

Abstract

Background

Aberrant CpG island promoter DNA hypermethylation is frequently observed in cancer and is believed to contribute to tumor progression by silencing the expression of tumor suppressor genes. Previously, we observed that promoter hypermethylation in breast cancer reflects cell lineage rather than tumor progression and occurs at genes that are already repressed in a lineage-specific manner. To investigate the generality of our observation we analyzed the methylation profiles of 1,154 cancers from 7 different tissue types.

Results

We find that 1,009 genes are prone to hypermethylation in these 7 types of cancer. Nearly half of these genes varied in their susceptibility to hypermethylation between different cancer types. We show that the expression status of hypermethylation prone genes in the originator tissue determines their propensity to become hypermethylated in cancer; specifically, genes that are normally repressed in a tissue are prone to hypermethylation in cancers derived from that tissue. We also show that the promoter regions of hypermethylation-prone genes are depleted of repetitive elements and that DNA sequence around the same promoters is evolutionarily conserved. We propose that these two characteristics reflect tissue-specific gene promoter architecture regulating the expression of these hypermethylation prone genes in normal tissues.

Conclusions

As aberrantly hypermethylated genes are already repressed in pre-cancerous tissue, we suggest that their hypermethylation does not directly contribute to cancer development via silencing. Instead aberrant hypermethylation reflects developmental history and the perturbation of epigenetic mechanisms maintaining these repressed promoters in a hypomethylated state in normal cells.