Abstract 3230: Genome-wide blood DNA methylation and breast cancer risk: A meta-analysis of four prospective studies
Authors: Bodelon Clara , Ambatipudi Srikant , Dugué Pierre-Antoine , Johansson Annelie , Sampson Joshua N. , Southey Melissa C. , Giles Graham G. , Polidoro Silvia , Herceg Zdenko , Flanagan James M. , Milne Roger L. , Garcia-Closas Montserrat 
Published: August 2018

Abstract
Background. Environmental and genetic factors play an important role in the etiology of breast cancer; however the potential epigenetic component to the risk remains largely unexplored. DNA methylation in blood cells could serve as a biomarker for exposure and breast cancer risk. Several small blood-based DNA methylation studies have reported risk associations with individual CpGs and average methylation levels; however, these findings require validation in larger prospective cohort studies. To investigate the role of blood DNA methylation on breast cancer risk, we conducted a meta-analysis of four prospective cohort studies, including a total of 1,941 cases and 1,952 controls, the largest study of blood DNA methylation and breast cancer risk to date.
Methods. We assessed associations with methylation at 365,589 CpGs present in the HumanMethylation450 Beadchip, after excluding CpGs that did not pass quality controls in all studies. Each of the four cohorts (the Melbourne Collaborative Cohort Study, the Italian and IARC cohorts of the European Prospective Investigation into Cancer and Nutrition and the Prostate, Lung, Colorectal and Ovarian screening trial) estimated odds ratios (ORs) and 95% confidence intervals (CI) for the association between each individual CpG and breast cancer risk. In addition, each study assessed the association between average methylation measures and breast cancer risk, adjusted and unadjusted for cell-type composition. Study-specific ORs were combined using fixed-effect meta-analysis with inverse variance weights. The false discovery rate (q-value) was used to account for multiple testing.
Results. Methylation measured at individual CpGs in blood DNA was not associated with breast cancer risk (q-value&gt;0.6). In addition, higher average methylation level was not associated with risk of breast cancer (OR=0.94, 95% CI=0.85, 1.04; P=0.25; P for study heterogeneity=0.83). We found no evidence of modification of this association by age at diagnosis, time since blood collection or CpG location (P-heterogeneity&gt;0.05).
Conclusions. Overall, our data indicates that DNA methylation measured in blood prior to breast cancer diagnosis is unlikely to be associated with substantial breast cancer risk. Larger studies are needed to determine if modest to weak associations exist between blood DNA methylation and breast cancer risk.
Citation Format: Clara Bodelon, Srikant Ambatipudi, Pierre-Antoine Dugué, Annelie Johansson, Joshua N. Sampson, Melissa C. Southey, Graham G. Giles, Silvia Polidoro, Zdenko Herceg, James M. Flanagan, Roger L. Milne, Montserrat Garcia-Closas. Genome-wide blood DNA methylation and breast cancer risk: A meta-analysis of four prospective studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3230.