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Epigenome-wide association study reveals decreased average methylation levels years before breast cancer diagnosis.

ABSTRACT: Interest in the potential of DNA methylation in peripheral blood as a biomarker of cancer risk is increasing. We aimed to assess whether epigenome-wide DNA methylation measured in peripheral blood samples obtained before onset of the disease is associated with increased risk of breast cancer. We report on three independent prospective nested case-control studies from the European Prospective Investigation into Cancer and Nutrition (EPIC-Italy; n?=?162 matched case-control pairs), the Norwegian Women and Cancer study (NOWAC; n?=?168 matched pairs), and the Breakthrough Generations Study (BGS; n?=?548 matched pairs). We used the Illumina 450k array to measure methylation in the EPIC and NOWAC cohorts. Whole-genome bisulphite sequencing (WGBS) was performed on the BGS cohort using pooled DNA samples, combined to reach 50× coverage across ~16 million CpG sites in the genome including 450k array CpG sites. Mean ? values over all probes were calculated as a measurement for epigenome-wide methylation.In EPIC, we found that high epigenome-wide methylation was associated with lower risk of breast cancer (odds ratio (OR) per 1 SD?=?0.61, 95 % confidence interval (CI) 0.47-0.80; -0.2 % average difference in epigenome-wide methylation for cases and controls). Specifically, this was observed in gene bodies (OR?=?0.51, 95 % CI 0.38-0.69) but not in gene promoters (OR?=?0.92, 95 % CI 0.64-1.32). The association was not replicated in NOWAC (OR?=?1.03 95 % CI 0.81-1.30). The reasons for heterogeneity across studies are unclear. However, data from the BGS cohort was consistent with epigenome-wide hypomethylation in breast cancer cases across the overlapping 450k probe sites (difference in average epigenome-wide methylation in case and control DNA pools?=?-0.2 %).We conclude that epigenome-wide hypomethylation of DNA from pre-diagnostic blood samples may be predictive of breast cancer risk and may thus be useful as a clinical biomarker.

SUBMITTER: van Veldhoven K

PROVIDER: S-EPMC4524428 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Epigenome-wide association study reveals decreased average methylation levels years before breast cancer diagnosis.

van Veldhoven Karin K Polidoro Silvia S Baglietto Laura L Severi Gianluca G Sacerdote Carlotta C Panico Salvatore S Mattiello Amalia A Palli Domenico D Masala Giovanna G Krogh Vittorio V Agnoli Claudia C Tumino Rosario R Frasca Graziella G Flower Kirsty K Curry Ed E Orr Nicholas N Tomczyk Katarzyna K Jones Michael E ME Ashworth Alan A Swerdlow Anthony A Chadeau-Hyam Marc M Lund Eiliv E Garcia-Closas Montserrat M Sandanger Torkjel M TM Flanagan James M JM Vineis Paolo P

Clinical epigenetics 20150804

<h4>Background</h4>Interest in the potential of DNA methylation in peripheral blood as a biomarker of cancer risk is increasing. We aimed to assess whether epigenome-wide DNA methylation measured in peripheral blood samples obtained before onset of the disease is associated with increased risk of breast cancer. We report on three independent prospective nested case-control studies from the European Prospective Investigation into Cancer and Nutrition (EPIC-Italy; n = 162 matched case-control pair ...[more]

PMID: 26244061

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Project description:Epigenetic mechanisms integrate both genetic variability and environmental exposures. However, comprehensive epigenome-wide analysis has not been performed across major childhood allergic phenotypes. We examined the association of epigenome-wide DNA methylation in mid-childhood peripheral blood (Illumina HumanMethyl450K) with mid-childhood atopic sensitization, environmental/inhalant and food allergen sensitization in 739 children in two birth cohorts (Project Viva-Boston, and the Generation R Study-Rotterdam). We performed covariate-adjusted epigenome-wide association meta-analysis and employed pathway and regional analyses of results. Seven-hundred and five methylation sites (505 genes) were significantly cross-sectionally associated with mid-childhood atopic sensitization, 1411 (905 genes) for environmental and 45 (36 genes) for food allergen sensitization (FDR<0.05). We observed differential methylation across multiple genes for all three phenotypes, including genes implicated previously in innate immunity (DICER1), eosinophilic esophagitis and sinusitis (SIGLEC8), the atopic march (AP5B1) and asthma (EPX, IL4, IL5RA, PRG2, SIGLEC8, CLU). In addition, most of the associated methylation marks for all three phenotypes occur in putative transcription factor binding motifs. Pathway analysis identified multiple methylation sites associated with atopic sensitization and environmental allergen sensitization located in/near genes involved in asthma, mTOR signaling, and inositol phosphate metabolism. We identified multiple differentially methylated regions associated with atopic sensitization (8 regions) and environmental allergen sensitization (26 regions). A number of nominally significant methylation sites in the cord blood analysis were epigenome-wide significant in the mid-childhood analysis, and we observed significant methylation - time interactions among a subset of sites examined. Our findings provide insights into epigenetic regulatory pathways as markers of childhood allergic sensitization.

Project description:BackgroundPhysical activity (PA) prior to and during pregnancy may have intergenerational effects on offspring health through placental epigenetic modifications. We are unaware of epidemiologic studies on longitudinal PA and placental DNA methylation.ObjectivesWe evaluated the association between PA before and during pregnancy and placental DNA methylation.MethodsPlacental tissues were obtained at delivery and methylation was measured using HumanMethylation450 Beadchips for participants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons among 298 participants. Using the Pregnancy Physical Activity Questionnaire, women recalled periconception PA (past 12 mo) at 8-13 wk of gestation and PA since last visit at 4 follow-up visits at 16-22, 24-29, 30-33, and 34-37 wk. We conducted linear regression for associations of PA at each visit with methylation controlling for false discovery rate (FDR). Top 100 CpGs were queried for enrichment of functional pathways using Ingenuity Pathway Analysis.ResultsPericonception PA was significantly associated with 1 CpG site. PA since last visit for visits 1-4 was associated with 2, 2, 8, and 0 CpGs (log fold changes ranging from -0.0319 to 0.0080, after controlling for FDR). The largest change in methylation occurred at a site in TIMP2 , which is known to encode a protein critical for vasodilation, placentation, and uterine expansion during pregnancy (log fold change: -0.05; 95% CI: -0.06, -0.03 per metabolic equivalent of task-h/wk at 30-33 wk). Most significantly enriched pathways include cardiac hypertrophy signaling, B-cell receptor signaling, and netrin signaling. Significant CpGs and enriched pathways varied by visit.ConclusionsRecreational PA in the year prior and during pregnancy was associated with placental DNA methylation. The associated CpG sites varied based on timing of PA. If replicated, the findings may inform the mechanisms underlying the impacts of PA on placenta health. This study was registered at clinicaltrials.gov as NCT00912132.

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Epigenome-wide association study reveals decreased average methylation levels years before breast cancer diagnosis.

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Epigenome-wide association study reveals decreased average methylation levels years before breast cancer diagnosis.

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