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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Career Transition Award (K22)
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Subcommittee I - Transistion to Independence (NCI)
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Jakowlew, Sonia B
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Fred Hutchinson Cancer Research Center
United States
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Harris, H R; Eke, A C; Chavarro, J E et al. (2018) Fruit and vegetable consumption and risk of endometriosis. Hum Reprod 33:715-727
Harris, Holly R; Rice, Megan S; Shafrir, Amy L et al. (2018) Lifestyle and Reproductive Factors and Ovarian Cancer Risk by p53 and MAPK Expression. Cancer Epidemiol Biomarkers Prev 27:96-102
Harris, Holly R; Babic, Ana; Webb, Penelope M et al. (2018) Polycystic Ovary Syndrome, Oligomenorrhea, and Risk of Ovarian Cancer Histotypes: Evidence from the Ovarian Cancer Association Consortium. Cancer Epidemiol Biomarkers Prev 27:174-182
Peres, Lauren C; Cushing-Haugen, Kara L; Anglesio, Michael et al. (2018) Histotype classification of ovarian carcinoma: A comparison of approaches. Gynecol Oncol 151:53-60
Yamamoto, Ayae; Harris, Holly R; Vitonis, Allison F et al. (2018) A prospective cohort study of meat and fish consumption and endometriosis risk. Am J Obstet Gynecol 219:178.e1-178.e10
Mu, Fan; Harris, Holly R; Rich-Edwards, Janet W et al. (2018) A Prospective Study of Inflammatory Markers and Risk of Endometriosis. Am J Epidemiol 187:515-522
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Harris, Holly R; Terry, Kathryn L (2016) Polycystic ovary syndrome and risk of endometrial, ovarian, and breast cancer: a systematic review. Fertil Res Pract 2:14