Abstract
BackgroundInterest 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.ResultsIn 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 %).ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0104-2) contains supplementary material, which is available to authorized users.
Highlights
Interest in the potential of DNA methylation in peripheral blood as a biomarker of cancer risk is increasing
Epigenome-wide hypomethylation is associated with risk of breast cancer Using European Prospective Investigation into Cancer and Nutrition (EPIC)-Italy, the first data set we investigated, the mean β value between matched breast cancer cases (53.00 %) and controls (53.18 %) was 0.18 % lower in cases
Conditional logistic regression analysis using categorical methylation in quartiles is reported in Table 1 and shows a marked decrease of breast cancer risk with increasing mean β values
Summary
Interest in the potential of DNA methylation in peripheral blood as a biomarker of cancer risk is increasing. It was not the presence of repetitive sequences but rather of these hypomethylated blocks across unique sequences, which caused most of the overall hypomethylation in tumours [11, 12] For this reason, we hypothesised that it would be possible to use the Illumina Infinium HumanMethylation450 (HM450) BeadChip array to assess genome-wide methylation levels. We hypothesised that it would be possible to use the Illumina Infinium HumanMethylation450 (HM450) BeadChip array to assess genome-wide methylation levels This array measures DNA methylation at approximately 485,000 CpG sites distributed across the entire genome, including CpGs on islands, shores, and shelves, as well as gene promoters and bodies, intergenic regions, and other areas [13]. This covers ~1.5 % of the 28 million CpG sites known in the genome
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