DESCRIPTION (provided by applicant): Among the various models of ovarian carcinogenesis that have been put forth, hormonal influences predominate. An important current challenge in ovarian cancer epidemiology is to better understand the role of ovarian stimulation by progestogens, estrogens, and androgens in the etiology of this disease. Studies of variation in genes involved in hormonal pathways may contribute importantly in this regard, as they may (perhaps in combination with interview-based measurements of hormonal exposures) provide an improved assessment of the extent of ovarian exposure to particular hormones throughout life. We propose to use haplotype tagging SNPs and putative functional SNPs to examine the effect of variation in genes involved in the biosynthesis or catabolism of, or response to, progestogens, estrogens, and androgens on risk of ovarian cancer. We hypothesize that gene variants related to (1) reduced progestogen stimulation or (2) increased estrogen or androgen stimulation of the ovarian epithelium will be associated with increased risk. Developing a large, well-defined, population-based resource is an important element of this application. The proposed study builds on our ongoing population-based case-control study of ovarian cancer in western Washington State that includes women aged 35-74 years who are diagnosed with epithelial ovarian cancer from 2002-2005. Through this application, we will extend case and control interviewing and specimen collection for an additional three years (2006-2008) to enroll a study population of 1120 women with invasive epithelial ovarian cancer and 1760 controls. In addition to the proposed research on hormonal pathways, the collected specimens and data will provide a foundation for planned future studies of additional genes and pathways relevant to other models of ovarian carcinogenesis. Progress towards prevention of ovarian cancer is hindered by an inadequate understanding of the protective or causative mechanisms through which various exposures exert their effects. The proposed study, by expanding our knowledge of the role of progestogens, estrogens, and androgens in the development of ovarian cancer, will inform efforts to develop effective strategies to prevent this disease.
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