Cancer incidence increases with age, but it is not clear why. Age-related changes in methylation have been reported in small studies of blood DNA, prompting us to explore associations between age and DNA methylation. We used data from our Sister Study case-cohort study of breast cancer to assess age-related methylation change at 27,578 CpGs. The women in the study ranged in age from 35 to 76 and all women were cancer-free at the time of enrollment. We found that almost a third of the CpGs were significantly associated with age. Using three small public methylation data sets on blood, we constructed a subset of 749 high confidence age-related CpGs that showed consistent age effects across all data sets. Using new publicly-available data from The Cancer Genome Atlas, we demonstrate that the aging sites we identified in blood are also broadly applicable across multiple human tissues. We noted that increasingly methylated age-related CpGs were in the promoter regions of a number of genes that are key regulators of cell differentiation/development programs. These genes included Cdx2 (Trophectoderm), Gata4 (primitive endoderm), Sox17 (endoderm), T (mesoderm), MyoD1 (muscle), Sox1 (neuroectoderm), and Hox genes (A, C, and D clusters, embryo body plan). Developmental regulatory genes are of particular interest for the epigenetics of cancer, and in relation to the cancer stem cell hypothesis: Although developmental genes are transcriptionally repressed in both normal cells and cancer cells, they undergo epigenetic switching from less stable, histone-based, gene repression to permanent DNA-methylation silencing. This permanent silencing may provide an evolutionary advantage to a cancer cell, allowing it to proliferate but not to differentiate. Based on an epigenetic switching hypothesis we predicted that increasingly-methylated age-associated CpG sites would be associated with the repressive H3K27me3 histone mark. To test this hypothesis we obtained publicly available ENCODE CHIP-seq data for histone modifications in a human embryonic stem cell (HESC), and in a normal differentiated lymphoblastoid cell line (GM12878) . In both HESC and lymphoblastic cells about 80% of increasingly-methylated age-related CpGs had the repressive H3K27me3 mark. This was significantly higher (p<10-50) than the 40% frequency at other sites on the array, and provides evidence that, like many developmental genes, the age-related methylation sites often coincide with the H3K27me3 histone mark in both embryonic stem and differentiated cells. We next predicted that these increasingly-methylated age-related sites should also be targets for overmethylation in tumor tissues. We analyzed publicly available methylation data for normal-tumor pairs from The Cancer Genome Atlas project that had data for 7 cancers. We found that the direction of change at age-related sites was a powerful predictor of significant methylation change in all 7 tumor types. These finding suggest an extension to the cancer-stem cell hypothesis: The association between increasing cancer incidence and age may in part be attributable to intermediate age-related methylation change at certain genes. Epigenome-wide studies have identified five loci where there is decreased blood DNA methylation associated with adult smoking. We examined smoking history in relation to DNA methylation in women from our 27K CpG methylation study and in women from our 450K CpG study of DES. We confirm smoking associations for four previously identified smoking-related CpGs in F2RL3, GPR15, AHRR and an intergenic region of chromosome 2. In addition we provide the first report of an association between a CpG in the coproporphyrinogen oxidase (CPOX) gene. CPOX codes for an enzyme involved in heme biosynthesis that is localized to the intermembrane space of the mitochondria, and mutations in CPOX are a cause of hereditary coproporphyria. In order to validate this locus we designed a pyrosequencing assay for the CpG shore site in the first intron of CPOX, and replicated our smoking result in an independent set of 476 women from the Sister Study. We found that relative to the levels in never smokers, there was lower methylation in former smokers (p <2x10-6) and even lower methylation levels among current smokers (p <2x10-18). These results suggest that the oxidative stress or the increased heme biosynthesis associated with smoking might lead to persistent decreased methylation in the first intron of CPOX. In addition we have completed a study epigenetic changes in blood of babies born to mothers who smoke. Maternal smoking during pregnancy is associated with significant infant morbidity and mortality, and may influence later disease risk. One mechanism by which smoking (and other environmental factors) might have long-lasting effects is through epigenetic modifications such as DNA methylation. We analyzed blood collected from 889 infants shortly after delivery and examined the DNA using the Illumina 450K methylation chip. BWe identified 185 CpGs with altered methylation in infants of smokers at genome-wide significance. These correspond to 110 gene regions, of which 7 have been previously reported and 10 are newly confirmed using publically-available results. Among these 10 the most noteworthy are FRMD4A, ATP9A, GALNT2, and MEG3, implicated in processes related to nicotine dependence, smoking cessation, and placental and embryonic development. The methylation changes identified in newborns may mediate the association between in utero maternal smoking exposure and later health outcomes.
| O'Brien, Katie M; Sandler, Dale P; Xu, Zongli et al. (2018) Vitamin D, DNA methylation, and breast cancer. Breast Cancer Res 20:70 |
| Herceg, Zdenko; Ghantous, Akram; Wild, Christopher P et al. (2018) Roadmap for investigating epigenome deregulation and environmental origins of cancer. Int J Cancer 142:874-882 |
| Wu, Lang; Shi, Wei; Long, Jirong et al. (2018) A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer. Nat Genet 50:968-978 |
| Felix, Janine F; Joubert, Bonnie R; Baccarelli, Andrea A et al. (2018) Cohort Profile: Pregnancy And Childhood Epigenetics (PACE) Consortium. Int J Epidemiol 47:22-23u |
| O'Brien, Katie M; Sandler, Dale P; Shi, Min et al. (2018) Genome-Wide Association Study of Serum 25-Hydroxyvitamin D in US Women. Front Genet 9:67 |
| O'Brien, Katie M; Sandler, Dale P; Kinyamu, H Karimi et al. (2017) Single-Nucleotide Polymorphisms in Vitamin D-Related Genes May Modify Vitamin D-Breast Cancer Associations. Cancer Epidemiol Biomarkers Prev 26:1761-1771 |
| Wilson, L E; Harlid, S; Xu, Z et al. (2017) An epigenome-wide study of body mass index and DNA methylation in blood using participants from the Sister Study cohort. Int J Obes (Lond) 41:194-199 |
| Harlid, Sophia; Adgent, Margaret; Jefferson, Wendy N et al. (2017) Soy Formula and Epigenetic Modifications: Analysis of Vaginal Epithelial Cells from Infant Girls in the IFED Study. Environ Health Perspect 125:447-452 |
| Michailidou, Kyriaki (see original citation for additional authors) (2017) Association analysis identifies 65 new breast cancer risk loci. Nature 551:92-94 |
| Sandler, Dale P; Hodgson, M Elizabeth; Deming-Halverson, Sandra L et al. (2017) The Sister Study Cohort: Baseline Methods and Participant Characteristics. Environ Health Perspect 125:127003 |
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