Abstract P1-09-15: DNA methylation markers influenced by BMI are associated with breast cancer

Abstract

Abstract Body mass index (BMI) is a well-established risk factor for breast cancer. However, the underlying molecular mechanism through which BMI acts on breast cancer remain largely unknown. DNA methylation plays a critical role in regulating gene expression. Aberrant DNA methylation has been implicated in breast cancer development. We hypothesize that BMI influences DNA methylation that in turn leads to breast cancer. We therefore conducted a molecular epidemiological study to identify DNA methylation markers that are associated with BMI in healthy women and further determine the association of these DNA methylation changes with breast cancer development and occurrence. We analyzed 270 normal breast tissue from healthy women and 109 tumor tissue from breast cancer patients for genome-wide DNA methylation profiling using the Illumina Truseq® Methyl Capture EPIC sequencing technology. After data quality control, approximately 3 million CpG sites (sequencing depth≥10) were retained and included in further statistical analysis. Linear regression was performed to examine the association between BMI and each of CpG sites, adjusting for age and race. Bonferroni correction was used for control for multiple comparisons. We further investigated whether these BMI-associated DNA methylation markers were differentially methylated in normal and breast tissue. We found that 30 CpG sites were significantly associated with BMI (P< 1.5x 10-8) in normal breast tissue. Many of these GpG sites were also differentially methylated in tumor and normal breast tissue. Top CpG hits are near novel and putative cancer genes mainly involved in lipid metabolism and related reproductive phenotypes that increase breast cancer risk, including KIAA0232, SHZ2, LACTB, PAPPA, and DLGAP2. The most significant CpG site associated with BMI is on chr. 4 in KIAA0232 gene. Little is known about the function of this gene, but genetic variant near the gene are associated with platelet count and volume in GWAS. The second most significant hit is on chr.20 in gene TSHZ2. This gene is found downregulated in breast and prostate cancer. LACTB gene is a tumor suppressor that modulates lipid metabolism and cell state. Its mechanism of action involves alteration of mitochondrial lipid metabolism and differentiation of breast cancer cells. PAPPA gene plays a role in inflammation and promote invasion of cancer cells. DLGAP2 is an imprinted gene, and SNPs near DLGAP2 are associated with age at menarche in AA women. Our results suggest DNA methylation may intermediate the observed association between BMI and breast cancer. Further research is warranted to validate these findings in larger studies as well as to understand the regulatory network by linking data with gene expression. Citation Format: He C, Lin N, Castle J, Liu J, Liu Y, Wang C. DNA methylation markers influenced by BMI are associated with breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-09-15.