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Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns
University of Edinburgh, Western General Hospital, UK .
University of Edinburgh, Western General Hospital, UK .
Breakthrough Breast Cancer Research Unit and Division of Pathology, University of Edinburgh, Western General Hospital, Edinburgh, UK; 2 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
University of Edinburgh, Western General Hospital, UK .
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2012 (English)In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 13, no 10Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
BioMed Central, 2012. Vol. 13, no 10
National Category
Genetics
Identifiers
URN: urn:nbn:se:liu:diva-100012DOI: 10.1186/gb-2012-13-10-r84ISI: 000313183900003PubMedID: 23034185OAI: oai:DiVA.org:liu-100012DiVA: diva2:659352
Available from: 2013-10-25 Created: 2013-10-25 Last updated: 2017-12-06Bibliographically approved

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