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Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer

Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer
Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer
Polycomb group proteins (PCGs) are involved in repression of genes that are required for stem cell differentiation. Recently, it was shown that promoters of PCG target genes (PCGTs) are 12-fold more likely to be methylated in cancer than non-PCGTs. Age is the most important demographic risk factor for cancer, and we hypothesized that its carcinogenic potential may be referred by irreversibly stabilizing stem cell features. To test this, we analyzed the methylation status of over 27,000 CpGs mapping to promoters of approximately 14,000 genes in whole blood samples from 261 postmenopausal women. We demonstrate that stem cell PCGTs are far more likely to become methylated with age than non-targets (odds ratio = 5.3 [3.8-7.4], P < 10(-10)), independently of sex, tissue type, disease state, and methylation platform. We identified a specific subset of 69 PCGT CpGs that undergo hypermethylation with age and validated this methylation signature in seven independent data sets encompassing over 900 samples, including normal and cancer solid tissues and a population of bone marrow mesenchymal stem/stromal cells (P < 10(-5)). We find that the age-PCGT methylation signature is present in preneoplastic conditions and may drive gene expression changes associated with carcinogenesis. These findings shed substantial novel insights into the epigenetic effects of aging and support the view that age may predispose to malignant transformation by irreversibly stabilizing stem cell features.
1088-9051
440-446
Teschendorff, Andrew E.
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Menon, Usha
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Gentry-Maharaj, Aleksandra
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Ramus, Susan J.
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Weisenberger, Daniel J.
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Shen, Hui
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Campan, Mihaela
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Noushmehr, Houtan
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Bell, Christopher G.
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Maxwell, A Peter
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Savage, David A.
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Mueller-Holzner, Elisabeth
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Marth, Christian
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Kocjan, Gabrijela
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Gayther, Simon A.
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Jones, Allison
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Beck, Stephan
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Wagner, Wolfgang
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Laird, Peter W.
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Jacobs, Ian J.
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Widschwendter, Martin
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Teschendorff, Andrew E.
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Menon, Usha
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Gentry-Maharaj, Aleksandra
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Ramus, Susan J.
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Weisenberger, Daniel J.
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Shen, Hui
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Campan, Mihaela
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Noushmehr, Houtan
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Bell, Christopher G.
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Maxwell, A Peter
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Savage, David A.
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Mueller-Holzner, Elisabeth
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Marth, Christian
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Kocjan, Gabrijela
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Gayther, Simon A.
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Jones, Allison
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Beck, Stephan
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Wagner, Wolfgang
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Laird, Peter W.
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Jacobs, Ian J.
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Widschwendter, Martin
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Teschendorff, Andrew E., Menon, Usha, Gentry-Maharaj, Aleksandra, Ramus, Susan J., Weisenberger, Daniel J., Shen, Hui, Campan, Mihaela, Noushmehr, Houtan, Bell, Christopher G., Maxwell, A Peter, Savage, David A., Mueller-Holzner, Elisabeth, Marth, Christian, Kocjan, Gabrijela, Gayther, Simon A., Jones, Allison, Beck, Stephan, Wagner, Wolfgang, Laird, Peter W., Jacobs, Ian J. and Widschwendter, Martin (2010) Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Research, 20 (4), 440-446. (doi:10.1101/gr.103606.109). (PMID:20219944)

Record type: Article

Abstract

Polycomb group proteins (PCGs) are involved in repression of genes that are required for stem cell differentiation. Recently, it was shown that promoters of PCG target genes (PCGTs) are 12-fold more likely to be methylated in cancer than non-PCGTs. Age is the most important demographic risk factor for cancer, and we hypothesized that its carcinogenic potential may be referred by irreversibly stabilizing stem cell features. To test this, we analyzed the methylation status of over 27,000 CpGs mapping to promoters of approximately 14,000 genes in whole blood samples from 261 postmenopausal women. We demonstrate that stem cell PCGTs are far more likely to become methylated with age than non-targets (odds ratio = 5.3 [3.8-7.4], P < 10(-10)), independently of sex, tissue type, disease state, and methylation platform. We identified a specific subset of 69 PCGT CpGs that undergo hypermethylation with age and validated this methylation signature in seven independent data sets encompassing over 900 samples, including normal and cancer solid tissues and a population of bone marrow mesenchymal stem/stromal cells (P < 10(-5)). We find that the age-PCGT methylation signature is present in preneoplastic conditions and may drive gene expression changes associated with carcinogenesis. These findings shed substantial novel insights into the epigenetic effects of aging and support the view that age may predispose to malignant transformation by irreversibly stabilizing stem cell features.

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Published date: April 2010
Organisations: Human Development & Health, Centre for Biological Sciences, MRC Life-Course Epidemiology Unit

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Local EPrints ID: 400991
URI: http://eprints.soton.ac.uk/id/eprint/400991
ISSN: 1088-9051
PURE UUID: c915b54a-91cc-48cc-98de-9dfd0dbbe66c
ORCID for Christopher G. Bell: ORCID iD orcid.org/0000-0003-4601-1242

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Date deposited: 03 Oct 2016 10:14
Last modified: 14 Sep 2021 17:55

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Contributors

Author: Andrew E. Teschendorff
Author: Usha Menon
Author: Aleksandra Gentry-Maharaj
Author: Susan J. Ramus
Author: Daniel J. Weisenberger
Author: Hui Shen
Author: Mihaela Campan
Author: Houtan Noushmehr
Author: Christopher G. Bell ORCID iD
Author: A Peter Maxwell
Author: David A. Savage
Author: Elisabeth Mueller-Holzner
Author: Christian Marth
Author: Gabrijela Kocjan
Author: Simon A. Gayther
Author: Allison Jones
Author: Stephan Beck
Author: Wolfgang Wagner
Author: Peter W. Laird
Author: Ian J. Jacobs
Author: Martin Widschwendter

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