Breast Tissue-Specific Dna Methylation Levels Predicted By Genetic Variants In Association With Breast Cancer.

Abstract Aberrant DNA methylation (DNAm) contributes to the development of breast cancer. Both genetic and environmental factors influence DNAm levels in a tissue-specific fashion. Previously studies have reported that genetically predicted DNAm levels at CpGs were associated with breast cancer risk. However, the prediction models were built based on DNAm measured in blood, which may not be the most relevant tissue for breast cancer. In this study, we aim to build statistical models to predict breast tissue-specific DNAm levels using genetic data and DNAm sequencing data of normal breast tissue from healthy women (N=293). We applied these models to the GWAS data from the Breast Cancer Association Consortium that includes 46,785 breast cancer patients and 42,892 controls. We evaluated the association of genetically predicted breast tissue-specific DNAm levels at CpGs with breast cancer risk using MetaXcan. Due to our small sample size of normal breast tissue samples, we restricted our statistical models to those that were well-validated and highly correlated between predicted and measured DNAm levels (r≥0.6). We thus identified 45 CpGs that were significantly associated with breast cancer risk after correction for multiple testings, and many of these CpGs were also differentially methylation between breast tumor and normal tissue samples. Genes annotated to these CpG sites are enriched in Wnt signaling, cell cycle, and stem cell proliferation pathways, including known genes such as FGFR2, KLF4, CASC8, TERT, and EMBP1. We also identified novel putative DNAm markers for the development of breast cancer. Our study provides insight into tissue-specific genetic regulation of DNAm in normal breast tissue. Citation Format: Chunyan He, James Castle, Nan Lin, Jinpeng Liu, Chi Wang, Yunlong Liu. Breast tissue-specific DNA methylation levels predicted by genetic variants in association with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2087.