Abstract 1326: Systems approach to identifying potential environmental exposures playing a role in ovarian carcinogenesis

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Other than an association of a small fraction with inherited mutations in BRCA1 and BRCA2, most cases of ovarian cancer (OvCa) are sporadic with cause unknown. Identifying environmental exposures that may contribute to ovarian carcinogenesis would provide the basis for epidemiological studies to determine other causes of OvCa. Environmental exposures are capable of inducing epigenetic changes that result in changes in gene expression. Most importantly, changes in microRNA expression may cause permanent changes in regulation of gene expression patterns leading to altered cellular phenotypes. These alterations in microRNAs represent dysregulation in the cancer cells and may be a manifestation of environmental exposures. Thus, we hypothesized that circulating microRNAs associated with OvCa are biomarkers of exposure and could be used to identify gene expression changes resulting from environmental exposures. We employed a systems approach utilizing publicly available data for elevated levels of circulating microRNAs associated with OvCa and for altered gene expression in ovarian cancers in conjunction with associations between chemical exposures and gene expression compiled in the Comparative Toxicogenomics Database (CTD) to identify chemicals that may play a role in ovarian carcinogenesis. Intersection of genes with altered expression in ovarian cancer and putative gene targets of microRNAs identified in plasmas of OvCa patients gave a list of candidate genes for chemical interactions. Ingenuity Pathway analyses of these genes show that they participate in pathways involved in cancer and other chronic diseases. This list of genes was submitted to the CTD and a list of chemicals with known interactions with these genes was collected. The list of chemicals interacting with the OvCa specific genes included known carcinogens (arsenic, asbestos, benzo[a]pyrene), co-carcinogens (tetrachlorodibenzodioxin, tetradecanoylphorbol acetate), peroxides, heavy metals (Cu, Zn), epigenotoxicants (hydralizine, valproic acid), inflammation inducers (zymosan, lipopolysaccharide), steroid hormones (estradiol, progesterone, dexamethasone), dietary chemopreventives (indole-3-carbinol, curcumin) and chemotherapeutics (doxorubicin, tamoxifen). While some of these chemicals and pathways have been implicated previously in ovarian carcinogenesis, many have not and their identification will enable the development of targeted epidemiological studies to determine the role of their exposure in inducing or preventing OvCa. This systems approach may be useful to identify environmental exposures contributing to cancer of other organs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1326. doi:10.1158/1538-7445.AM2011-1326