Abstract 3382: Methylation status and microRNA expression changes in women with breast cancer stratifying by DNA repair capacity

Abstract

Abstract The American Cancer Society estimates 252,710 new breast cancer (BC) cases and 40,610 cancer related-deaths in the US, only in 2017. In addition to the well-established BC risk factors, our studies during the last decade have shown that women having a low DNA repair capacity (DRC) as measured through the nucleotide excision repair pathway is associated with higher BC risk. This finding allows us to study BC etiology based on DRC rather than using the ordinary stratification; for example, we found an association between DRC levels and estrogen receptor status. Since DRC has been associated with different clinical aspects of BC and it is known that it can be regulated through epigenetic mechanisms, more studies regarding the effect of epigenetic changes on DRC in BC are needed. Therefore, the main objective of this study is to identify epigenetic mechanisms that could be influencing DRC levels in women with BC through gene silencing. The main hypothesis consists in testing whether the epigenetic changes such as methylation and microRNA (miRNA) levels can be used to stratify BC patients by DRC levels. Plasma and tumor samples were randomly selected from our BC cohort. DRC values were previously measured in lymphocytes using the host cell reactivation assay. BC cases and controls were divided in two categories: low (≤3.8%) and high (>3.8%) DRC. MicroRNAs were extracted from 56 plasma samples (27 BC cases and 29 controls) to perform an expression profile analysis using the Human MicroRNA A Cards v 2.0 assay. Relative miRNA expression was calculated using the 2-ΔCt method. Methylation status of tumors was obtained through an epigenome-wide DNA methylation analysis stratifying by DRC using the Illumina Human Methylation EPIC 850K array. After unbiased selection and pathologist evaluation, 56 formalin-fixed paraffin-embedded tumors were selected and sectioned for DNA extraction. Based on the DRC, the samples were divided in low (n=24) and high (n=32) using the established cut-off. A significant association between miR-323-3p, miR-29b, and miR-159a expression and the BC outcome was found (p<0.01). Using the DRC categories, all three miRs were found to be differentially expressed when comparing cases and controls with high and low DRC (p<0.05, KW). The methylation data was analyzed using the bump hunting method. The epigenome-wide analysis of the BC methylome revealed 23 regions that were significantly differentially methylated between tumors with low and high DRC (p<0.05). Although DRC levels are low when the BC malignancy is developed, whether these changes occur during carcinogenesis or due to a preexisting epigenetic disposition is still unknown. However, our results lead us to conclude that epigenetic changes such as methylation and miRNA expression can influence the DRC levels in BC. This study was supported by: S06GM008239-20, 9SC1CA182846-04, U54CA163068, 2U54CA163071-06, and R003050/MD007579. Citation Format: Carmen M. Ortiz-Sanchez, Jarline Encarnacion, Rafael Guerrero, Jaime Matta. Methylation status and microRNA expression changes in women with breast cancer stratifying by DNA repair capacity [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 3382.