We propose to conduct detailed analyses of hormonal, dietary, and genetic risk factors for ovarian cancer using data collected from the Nurses' Health Study (NHS) since 1976 and from the Nurses' Health Study II (NHSII) since 1989. We expect that 857 cases in NHS and 163 cases in NHSII will be confirmed by the 2006 follow-up cycle; approximately 25% (n~250) of all cases will be premenopausal. Specifically we propose to evaluate early body shape (at ages 5 and 10), body mass index at age 18, adult waist-to-hip ratio, height, physical activity and inactivity, birthweight, dietary folate and related nutrients, and analgesic/anti-inflammatory medication use in relation to ovarian cancer risk. In addition, we will use previously measured plasma hormone levels from controls in prior case-control studies, we will examine whether birthweight, waist-to-hip ratio, and analgesic medication use are associated with sex hormones such as estradiol and testosterone. Further, using a nested case-control design, we will examine relationships of plasma c-reactive protein, interleukin-6, and TNF-a receptor 2 with ovarian cancer using blood samples collected from 32,826 NHS participants in 1989-1990 and 29,616 NHSII participants in 1996- 1998. Using germline DNAfrom archived buffy coat, buccal cell specimens, or non-tumor tissue, we propose to evaluate ovarian cancer risk in relation to a genetic polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene (677 C>T). We have established a bank of tumor tissue from women with incident ovarian cancer. Using this resource we propose to examine aberrant methylation of certain genes within ovarian tumors and to asses whether these aberrations are associated with dietary intake of folate and other related nutrients. For some exposures, such as physical activity and body mass index, we will be able to examine relationships to ovarian cancer in greater detail than previous studies; for other exposures, such as inflammatory markers, ours will be the first prospective study. A major strength of this proposal is our ability to examine these factors prospectively and the availability of over 25 years worth of questionnaire data, archived plasma and DNA samples and tumor tissue samples from ovarian cancer cases. Finally the project will not only improve our understanding of disease etiology, but also could have important public health implications because several of these risk factors are modifiable.