Abstract 1066: Racial disparities of genome-wide DNA methylation profiles and association with breast tissues biomarkers in healthy women

Abstract

Abstract Breast cancer is the most common cancer in women, with more aggressive disease observed among African Americans (AA) compared to European Americans (EA). It is a complex and heterogeneous disease, characterized by genetic and epigenetic alterations. Racial differences in DNA methylation have been shown in breast cancers, but it is not clear if these differences exist in healthy women who have not had breast cancer. We identified genome-wide differentially methylated (DM) CpGs by race, in order to: 1) understand methylation patterns of promoter and non-promoter related DM CpGs; 2) study their association with tissue biomarkers of proliferation and differentiation; and 3) examine if these correlations were similar for AA and EA. Normal breast tissues were collected from healthy women undergoing reduction mammoplasty (N = 83). Tissue DNA was analyzed using the Infinium HumanMethylation450 BeadChip for differential genome-wide methylation between AA (N = 22) and EA (N = 61). Analysis methods included age and BMI-adjusted Generalized Linear Regression models, hierarchical clustering and Principal Component Analysis (PCA). Correction for multiple comparisons was performed. We further evaluated the performance of the threshold for classification between EA and AA using the area under the curve (AUC) and by 10-fold cross validation. Biological functions of the DM genes were assigned using the Ingenuity Pathway Analysis (IPA). Partial correlation analysis was performed between the DM CpGs and proliferation (Ki-67, Leptin, IGF1, and IGFBP3) or differentiation (Adiponectin)-related tissue biomarkers. 485 or 23 DM CpGs were identified after FDR or Bonferroni correction at p<0.05, respectively. The AUC was 0.8 and 1 and% correct rates were 78% and 100%, respectively. A heat map and PCA showed distinct methylation patterns between EA and AA. A larger variation was observed in promoters while relatively consistent methylation levels were found in intergenic regions. IPA among 177 DM CpGs in promoter regions showed 136 genes associated with cancers that play roles in cell death and survival, cellular development, and cell-to-cell signaling. Of the 23 DM CpGs, 9 CpGs are known oncogenes or tumor suppressors in breast or other cancers. 8 CpGs were significantly correlated with at least one biomarker in EA (p<0.05), but not in AA. One CpG site was significantly correlated in AA only (p<0.05). 4 DM CpGs were differentially correlated between EA and AA at P-interaction<0.05. This is the first genome-wide study to show differences in methylation between AA and EA in normal breast tissues. A subset of the CpGs was correlated with breast tissue biomarkers of proliferation and differentiation and these correlation patterns were different by race. These findings may provide further insights on the contribution of DNA methylation differences as determinants of racial disparities in breast cancer. Citation Format: Min-Ae Song, Catalin Marian, Theodore M. Brasky, Daniel Weng, Cenny Taslim, Jo L. Freudenheim, Peter G. Shields. Racial disparities of genome-wide DNA methylation profiles and association with breast tissues biomarkers in healthy women. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1066. doi:10.1158/1538-7445.AM2015-1066