European-American (EA) woman have a higher overall incidence of breast cancer than African American (AA) women, yet AA woman have poorer survival outcome, even after controlling for factors related to socioeconomic status. AA women are diagnosed at a younger age with aggressive breast tumors, more frequently ‘triple negative’ due to lack of estrogen and progesterone receptor (ER and PR) expression and negative for HER-2 amplification, as well as, high proliferative indices. These ‘triple negative’ breast cancers are most lethal since hormonal- or anti-HER2 therapy are not effective; therefore, fewer treatment options are available. Currently, the reason for racial disparities in breast cancer biology and early age of onset in AA women is largely unknown. Previous studies using a panel of 5 cancer-associated genes demonstrated a higher frequency of methylation in ER-negative tumors from younger AA women compared to EA women. We hypothesize that DNA methylation is one potential molecular mechanism that drive differences in breast cancer etiology between AA and EA women. Utilizing the Illumina Infinium Human Methylation 450K bead array, we surveyed DNA methylation at greater than 485,000 CpG sites across the genome at single-nucleotide resolution in breast tumor DNA from 138 (58 AA, 80EA) women and normal breast tissue DNA from 124 (22 AA, 102 EA) women undergoing reduction mammoplasty. Following filtering for ambiguously mapping probes and probes containing known SNPs, unsupervised hierarchical cluster analysis of the most varied CpG loci among tumor tissues distinguished three major clusters: Normal, ER-positive tumors and ER-negative tumors. We identified 157 CpG sites that are differentially methylated between tumors from AA and EA women (Δβ>0.17, FDR<0.05). Of these, 50 CpG were uniquely differentially methylated in ER-negative tumors, while 28 CpG sites were specific to ER-positive tumors. We are currently examining these loci in more depth to determine their biological significance and potential contribution to differences in breast cancer etiology between AA and EA women. Future analyses include screening a larger cohort of 1000 FFPE tumor DNAs to effectively compare differential methylation with age at onset, and a variety of tumor characteristics and risk factors. Funded by 1 R01 CA133264 to CBA, KD, and MJH, and by Cancer Center Support Grant CA16056 to RPCI.
Citation Format: Allyson C. Young, Christine B. Ambrosone, Lara Sucheston, Dan Wang, Li Yan, Song Liu, Li Tang, Jo L. Freudenheim, Peter G. Shields, Carl D. Morrison, Kitwa Demissie, Saraswati Sukumar, Michael J. Higgins. Genome-wide methylation patterns suggest differences in breast cancer biology in American women of African and European ancestry. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3641. doi:10.1158/1538-7445.AM2013-3641