Abstract P4-03-26: Blood DNA Methylation and Breast Cancer: a Prospective Case-Control Analysis in the Breast Cancer Prospective Family Study Cohort

Abstract Breast cancer has increased dramatically in young women < 50 years in the US over the past decade. DNA methylation is a type of epigenetic change that plays an important role in cancer etiology by silencing tumor suppressor genes or DNA repair-related genes through hypermethylation or activating oncogenes through hypomethylation. Previous genome-wide association studies have suggested DNA methylation in blood is a potential epigenetic markers of breast cancer risk. In this study, we applied targeted methyl-seq to examine the DNA methylation profile in regulatory sequences of 57 known DNA repair pathway genes, together with 123 other genes, located in immune-related loci and genome-wide association peaks for breast cancer. We used a nested case-control design within the Breast Cancer Prospective Family Study Cohort (FroF-SC) and examined DNA methylation profile in DNA from the blood of breast cancer cases (N=293) and age-matched controls (N=327). In the preliminary data analysis, we observed that the methylation levels in 5 genes were statistically significantly different between cases and controls using Wilcoxon Rank Sum Test (Table 1). Some candidate loci show methylation values spanning a wide range (Std Dev) in both cases and controls, suggesting the presence of genotype-dependent allele-specific methylation (ASM). We then conducted generalized estimating equations (GEE model) adjusting for age at blood draw and calculated the odds ratios (ORs) and 95%CI for the association between methylation levels in the 90th and 10th percentiles of differentially methylated genes (90% vs 10% methylation) and breast cancer risk. The ORs (95% CI) from the GEE models were 1.26 (0.97, 1.63, p=0.08) for CD6, 1.27 (0.85, 1.91, p=0.24) for SDCCAG3, 1.12 (0.85, 1.48, p=0.40) for DCLRE1B, 1.29 (0.88, 1.90, p=0.20) for IP09, and 1.63 (1.08, 2.45, p=0.02) for GNPDA1 (Table 2). The associations were not different by age group. Our preliminary results suggest that DNA methylation measured in blood may be a biomarker of breast cancer susceptibility. Citation Format: HuiChen Wu, Angelica Castano, Yuyan Liao, Regina Santella, David Brenner, Mary Beth Terry, Benjamin Tycko. Blood DNA Methylation and Breast Cancer: a Prospective Case-Control Analysis in the Breast Cancer Prospective Family Study Cohort [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-26.