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. 2015 Aug 4;7(1):67.
doi: 10.1186/s13148-015-0104-2. eCollection 2015.

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

Karin van Veldhoven #  1   2 , Silvia Polidoro #  2 , Laura Baglietto  2 , Gianluca Severi  2 , Carlotta Sacerdote  2 , Salvatore Panico  3 , Amalia Mattiello  3 , Domenico Palli  4 , Giovanna Masala  4 , Vittorio Krogh  5 , Claudia Agnoli  5 , Rosario Tumino  6 , Graziella Frasca  6 , Kirsty Flower  7 , Ed Curry  7 , Nicholas Orr  8 , Katarzyna Tomczyk  8 , Michael E Jones  9 , Alan Ashworth  10 , Anthony Swerdlow  8   9 , Marc Chadeau-Hyam  1 , Eiliv Lund  11 , Montserrat Garcia-Closas  10   9 , Torkjel M Sandanger  11 , James M Flanagan #  7 , Paolo Vineis #  1   2
Affiliations

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

Karin van Veldhoven et al. Clin Epigenetics. .

Abstract

Background: 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 β values over all probes were calculated as a measurement for epigenome-wide methylation.

Results: 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 %).

Conclusions: 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.

Keywords: Biomarker; Breast cancer; EWAS; Methylation; Peripheral blood; Risk.

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Figures

Fig. 1
Fig. 1
Log relative risk distribution of individuals in EPIC using the effect estimate of the logistic model of splined global methylation as it relates to case-control status. The log (RR) is presented on the x-axis, with density on the y-axis and with the median and 95 % range marked with the dotted line
Fig. 2
Fig. 2
Forest plot meta-analysis of three independent breast cancer case-control studies. The effect estimates are derived from the “per 1 SD odds ratio” and presented as a log of odds ratio. The p value for heterogeneity is p = 0.01 indicating significant heterogeneity in the populations. The number of subjects (cases and controls) in each study is reported. Data from Severi et al. [23] have been reported elsewhere
Fig. 3
Fig. 3
Kernel density estimate for samples collected less than 3.7 years before diagnosis and more than 3.7 years before diagnosis in EPIC. The p values refer to the significance level of the Kolmogorov-Smirnov test of equality in distribution between cases and controls.
See this image and copyright information in PMC

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