Background: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder condition characterized by oligomenorrhea and hyperandrogenism. PCOS is also associated with risk of metabolic disturbances including type 2 diabetes, insulin resistance, and metabolic syndrome, which may also influence cancer risk. Examining the association between PCOS, type II diabetes, and metabolic syndrome, and ovarian cancer by histologic subtype could further our understanding of the mechanism(s) behind these potential associations and help identify women at increased risk for ovarian cancer. Hypothesis/Specific Aims:
Our aim i s to examine the association between PCOS, type II diabetes, and components of these conditions overall and by histologic subtype of ovarian cancer. We will also examine the association between these conditions and tissue marker expression in ovarian cancer tumors. Finally, despite valid study design and analysis, confounding can be an issue in observational studies. Mendelian randomization, the random assortment of genes from parents to offspring, offers a method for examining the association between proposed exposures and outcomes without the distortion of confounding. We plan to test the following hypotheses: 1. PCOS is associated with increased ovarian cancer risk, specifically for the endometrioid subtype. 2. Type II diabetes and metabolic syndrome are associated with increased ovarian cancer risk, specifically with endometrioid and clear cell subtypes. 3. Using a Mendelian randomization approach, genetic variants associated with type II diabetes and PCOS are associated with increased ovarian cancer risk. 4. PCOS, type II diabetes, and their associated characteristics are associated with tumors expressing specific tissue markers (IGF-1R, PTEN, BAF250a (ARID1A), HOXA-10, IL8, PAX2, and MAPK). Study Design: The proposed project will utilize the New England Case-Control Study, a population based study of ovarian cancer (Aims 1-4), and the Ovarian Cancer Association Consortium, pooled data from 13 ovarian cancer case-controls studies (Aim 1). Questionnaire data will be utilized for examining PCOS, type II diabetes, and associated characteristics and ovarian cancer risk. Genome-wide association studies (GWAS) data will be used for the Mendelian randomization analyses. Tissue expression of molecular markers associated with PCOS or type II diabetes will also be examined.
The proposed study provides us with the opportunity to examine the association between polycystic ovary syndrome (PCOS) and type II diabetes, and ovarian cancer risk. Given the number of individuals with PCOS and type II diabetes, there may be a large public health impact from the development of targeted prevention and early detection guidelines for ovarian cancer for which women with these conditions may be a high-risk population.
