Abstract DP-007: POLYCYSTIC OVARY SYNDROME AND OVARIAN CANCER RISK: A MENDELIAN RANDOMIZATION ANALYSIS

Abstract BACKGROUND: Polycystic ovary syndrome (PCOS), a complex endocrine disorder that has an estimated prevalence of 4-21% in reproductive aged women, is characterized by oligomenorrhea (i.e. infrequent or irregular periods) and abnormal hormone levels including hyperandrogenism, hyperinsulinemia, and gonadotropin imbalance which could influence ovarian cancer risk. Recently, the Ovarian Cancer Association Consortium (OCAC) reported a non-significant decreased risk of invasive ovarian cancer among women with self-reported PCOS. When infrequent and irregular periods were examined as a proxy for PCOS, women reporting these characteristics had a decreased risk of invasive ovarian cancer that was consistent across most histotypes. However, given the limitations of self-reported PCOS, potential confounding, and that oligomenorrhea only captures one facet of PCOS, the causality of these observed associations remains uncertain. Therefore, we sought to use Mendelian randomization (MR), the analytical method that capitalizes on the random assortment of genes from parents to offspring, to examine the association between PCOS and ovarian cancer independent of exposure misclassification and confounding variables. METHODS: We conducted a literature search to identify single nucleotide polymorphisms (SNPs) associated with PCOS for use as instrumental variables. Using summary statistics from a previously conducted genome wide association study (GWAS) of ovarian cancer among European ancestry women within OCAC (22,406 invasive cases and 40,941 controls), we assessed the association between genetically predicted PCOS and ovarian cancer risk using an inverse-variance weighted method. The associations were examined overall and by histotype. In addition, as oral contraceptives have a well-established protective effect on ovarian cancer risk and are a first-line treatment for women with PCOS to manage menstrual irregularities, hyperandrogenism, and acne, we evaluated the association between PCOS-associated SNPs and oral contraceptive use using publicly available GWAS data. RESULTS: We identified 7 SNPs that were associated with PCOS on genome-wide significance levels in European populations. A statistically significant inverse association was observed between genetically predicted PCOS and invasive ovarian cancer risk with an odds ratio (OR) of 0.89 (95% confidence interval [CI] = 0.82-0.97; p=0.006). When results were examined by histotype, there was a statistically significant inverse association between genetically predicted PCOS and the high-grade serous (OR=0.88; 95% CI=0.79-0.97; p=0.012; cases=13,307) and endometrioid (OR=0.73; 0.60-0.88; p=0.001; cases=2,810) histotypes. None of our instrument SNPs were associated with ever use of oral contraceptives after adjusting for number of tests. We conducted a sensitivity analyses of our MR analyses excluding two SNPs that showed nominal association (p<0.05) with oral contraceptives and the association with ovarian cancer was not materially changed. CONCLUSION: Our study provides evidence for a causal relationship between PCOS and ovarian cancer risk, with PCOS reducing risk of most histotypes of ovarian cancer. These results lend support to our previous observational study results. Future studies are needed to understand the mechanisms underlying this association. Citation Format: Holly R. Harris, Kara L. Cushing-Haugen, Sara Lindström, Kathryn L. Terry. POLYCYSTIC OVARY SYNDROME AND OVARIAN CANCER RISK: A MENDELIAN RANDOMIZATION ANALYSIS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr DP-007.