Aberrant DNA methylation plays an important role in breast cancer initiation and progression. It is believed that changes in DNA methylation occur early in breast cancer development or even in normal tissue before tumor occurrence, and these changes could be a useful source for early detection, prognosis, and targeted therapy. DNA methylation is tissue-specific and is influenced by inherited genetic variations in the human genome. Genome-wide association studies (GWAS) have identified more than 600 single nucleotide polymorphisms (SNPs) associated with breast cancer risk and outcome. However, how these germline genetic variants influence DNA methylation in breast tissue, especially in normal breast tissue, remains largely unknown. We performed a methylation quantitative trait loci (meQTL) analysis to examine the association between the GWAS identified breast cancer risk loci and DNA methylation in 48 women with paired blood and breast tissue samples. Genotyping of SNPs was performed using blood-derived DNA and the Illumina HumanOmni 2.5-4v1_D array chip. Genome-wide DNA methylation was measured using breast tissue derived genomic DNA and the new Illumina TruSeq Methyl Capture EPIC sequencing technology. We found that GWAS-identified breast cancer risk loci were associated with DNA methylation sites close to genes enriched in pathways related to cell differentiation and morphogenesis, DNA damage, cell movement, and hormonal signaling pathways. We identified more cis-acting than trans-acting meQTLs, and the peak enrichment for meQTLs was in close proximity to transcription start sites. We further compared our results with those from the meQTL studies conducted with lymphoblastoid cell lines and peripheral blood samples. We found more than 60% of the identified association between genetic variants and DNA methylation in our study are tissue-type specific. Our study may provide a post-GWAS functional characterization of breast cancer risk loci and shed light on epigenetic mechanisms that underlie the observed GWAS association.

Citation Format: Nan Lin, Aditi Shendre, JinPeng Liu, Chi Wang, Yunlong Liu, Chunyan He. Genetic regulation of DNA methylation in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5319.