Abstract C003: Analysis of genetic control of differential DNA methylation between breast cancer patients of African and European ancestry

Abstract

Abstract Black women with significant African ancestry experience a disproportionately higher incidence of the most aggressive and invasive breast cancer subtypes, along with worse clinical outcomes across all population groups in the United States. These health disparities arise from complex interactions between genetic, sociocultural, and environmental factors. Although there is a critical need to understand how these non-genetic factors contribute to disease risk or etiology, they are difficult to measure reliably, and their long-term impacts are not well understood. Epigenetic mechanisms that regulate gene expression, such as DNA methylation (DNAm), have been proposed to capture the molecular impact of adverse environments on tumor biology. While DNAm levels can change in response to environmental cues, they are also regulated by individual genotypes at methylation quantitative trait loci (meQTLs), presenting a challenge for modeling environmental effects on cancer molecular phenotypes. We hypothesize that ancestry differential DNAm in breast cancer can be partially explained by ancestry differential genotype frequencies of SNPs at meQTL loci. We leveraged multi-omic data from The Cancer Genome Atlas (TCGA) breast cancer (BRCA) cohort to perform integrative analysis for patients of European and African ancestry (n=578), including ancestry-based differential methylation analysis, meQTL analysis and association testing of genotypes and ancestry. We identified 804 CpGs differentially methylated between European and African ancestry BRCA patients. meQTL analysis at these sites identified 130 cis-meQTLs and 1,019 trans-meQTLs. ~84% of the identified cis- and ~80% of the identified trans-meQTLs show evidence of differential genotype frequencies by ancestry. Gene set enrichment analysis of the meQTL target genes implicated genes involved in regulation of cell differentiation and developmental processes, phosphatase activity and phosphorylation processes. Our findings show that ancestry specific DNAm differences display strong genetic associations via ancestry associated meQTLs (a-meQTLs) affecting fundamental biological functions in breast cancer. This result points to the potential for confounding due to genetic ancestry in studies that use DNA methylation as a molecular readout of environmental exposures. Citation Format: Kyriaki Founta, Nyasha Chambwe. Analysis of genetic control of differential DNA methylation between breast cancer patients of African and European ancestry [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C003.