Abstract 2772: Hormone replacement therapy and genome-wide DNA methylation among post-menopausal women

Abstract

Abstract Hormone replacement therapy (HRT) has been associated with increased risks of cancers of the breast, ovary, endometrium and colon. The exact mechanism underlying these associations remains unknown, though changes to DNA methylation have been suggested to play a role. To explore this compelling mechanism, we examined genome-wide DNA methylation in blood among 92 women with and without a history of long-term HRT use that were recruited as controls for a previous case-control study of breast cancer. HRT exposure was defined as estrogen use for at least 10 years among women with hysterectomy (n = 23) and as estrogen and progesterone use for at least 5 years among women without hysterectomy (n = 23). Women with and without hysterectomy and no history of HRT use were selected for comparison (n = 46). Genome-wide methylation was measured in DNA from blood using the Illumina Infinium HumanMethylation450 BeadChip platform. After excluding loci on sex chromosomes, loci with detection p-values <0.01 in ≥20% of samples, loci within 50 base pairs of at least one variant with a minor allele frequency of >1%, and loci with cross-reactive probes, 343,349 loci were included for analysis. Separately for the hysterectomy and non-hysterectomy groups, the M-value for each locus (defined as the logit of methylated probe intensity and overall intensity using a 0.001 threshold) was regressed against HRT status in linear models to adjust for age and BMI. The Significance Analysis of Microarrays (SAM) method was used to account for multiple comparisons by controlling the false discovery rate. Preliminary analyses have revealed significant differential methylation at four loci, including cg19987229, cg22610211, cg08440572, and cg11372436. For example, estrogen and progesterone users among women without hysterectomy were found to have 74% greater methylation at a locus near the transcription start site of the SOD3 gene (q<0.001). This may lead to decreased expression of the SOD3 gene which is involved in oxidative stress response. Data analyses at the level of gene, gene region, and CpG island are currently in progress. Differentially methylated loci identified in this study should be evaluated in association with breast cancer risk in a prospective study of breast cancer with detailed data on HRT use. If significant associations are observed, these loci could conceivably be used in screening efforts to identify HRT users that may be particularly susceptible to developing breast cancer. Citation Format: Kristina M. Jordahl, David R. Doody, Yuzheng Zhang, Donghui Yan, Timothy W. Randolph, Lisa G. Johnson, Christopher I. Li, Karl Kelsey, E. Andres Houseman, Pei Wang, Kathleen E. Malone, Parveen Bhatti. Hormone replacement therapy and genome-wide DNA methylation among post-menopausal 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 2772. doi:10.1158/1538-7445.AM2015-2772