RT Journal
A1 Teschendorff, Andrew E.
A1 Menon, Usha
A1 Gentry-Maharaj, Aleksandra
A1 Ramus, Susan J.
A1 Weisenberger, Daniel J.
A1 Shen, Hui
A1 Campan, Mihaela
A1 Noushmehr, Houtan
A1 Bell, Christopher G.
A1 Maxwell, A. Peter
A1 Savage, David A.
A1 Mueller-Holzner, Elisabeth
A1 Marth, Christian
A1 Kocjan, Gabrijela
A1 Gayther, Simon A.
A1 Jones, Allison
A1 Beck, Stephan
A1 Wagner, Wolfgang
A1 Laird, Peter W.
A1 Jacobs, Ian J.
A1 Widschwendter, Martin
T1 Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer
JF Genome Research 
JO Genome Research 
YR 2010 
FD April 01 
VO 20 
IS 4 
SP 440 
OP 446 
DO 10.1101/gr.103606.109 
UL http://genome.cshlp.org/content/20/4/440.abstract 
AB 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 ∼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.