Abstract 1380: Genome-wide fingerprinting of regulatory chromatin to evaluate the tissue specific origins of high-grade serous ovarian cancer

Abstract

Abstract The normal precursor tissue origins of high grade serous epithelial ovarian cancers (HSOC) are likely to be the fallopian tube epithelium (FTE) and/or the ovarian surface epithelium (OSE). To address this hypothesis, we used FAIRE-seq and ChIP-seq to evaluate the genome wide regulatory profiles of both tissue types and compared these profiles to well characterized HSOC cell lines (CaOV3 and UWB1.289). This analysis provided, for the first time, global high-resolution annotation of open chromatin and histone H3K27 acetylation and H3K4 monomethylation marks for these tissues types, which are consistent with sites of transcriptional regulation. Using these data, we identified over 10,000 non-promoter associated FAIRE/ChIP signal sites that represent candidate functional enhancers. The regulatory features provided a cell type-specific fingerprint for each cell type. While there were many similarities between OSE and FTE compared to other normal cell types, we also were also able to use these profiles to functionally distinguish OSE from FTE. When we compared profiles of HSOC cells, we observed stronger similarities in the regulatory chromatin landscape between FTE and HSOC cell types than between OSE and FTE. Supervised pathway analysis of genes located closest to putative enhancer sites provided additional evidence of signaling pathways that may underlie the neoplastic initiation and progression from normal tissue to HSOC phenotypes. Our results demonstrate the utility of this approach for identifying precursor tissue types for HSOC and other cancers based on the cell type specific chromatin datasets. Citation Format: Howard C. Shen, Simon Coetzee, Dennis J. Hazelett, Gerhard A. Coetzee, Houtan Noushmehr, Simon A. Gayther. Genome-wide fingerprinting of regulatory chromatin to evaluate the tissue specific origins of high-grade serous ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1380. doi:10.1158/1538-7445.AM2014-1380