In this competing renewal, we propose to address additional questions on the role of endogenous steroid sex hormones in the development of endometrial cancer in our case-control study nested within three cohorts: the New York University Women's Health Study in New York, the Northern Sweden Health and Disease Study in Umea, Sweden, and the ORDET study in Milan, Italy. In the previous funding period we showed that the risk of endometrial cancer increased with increasing postmenopausal levels of estrogens (estradiol, estrone) and androgens (testosterone, androstenedione, DHEAS). These are the first prospective data on endogenous androgens and endometrial cancer risk. We now propose to examine endometrial cancer risk in relation to estrogen metabolites, some of which are thought to be more genotoxic than estrogens themselves, and to functional polymorphisms that impact estrogen biosynthesis, activity and metabolism. The specific hypotheses to be tested in this proposal are: (1) Circulating levels of 16alpha-hydroxyestrone are positively associated with risk of endometrial cancer, while the ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone is inversely associated with risk.
This aim will be restricted to women who were postmenopausal at enrollment; (2) Functional polymorphisms in selected genes coding for enzymes involved in estrogen synthesis or metabolism (CYP17, CYP1B 1, COMT) are associated with risk of endometrial cancer; and (3) Selected polymorphisms in the progesterone receptor gene are associated with risk of endometrial cancer. There are no studies on endometrial cancer and 2- and 16alpha-hydroxyestrone, and very few studies on estrogen-related polymorphisms. We estimate that we will accrue 444 incident cases of endometrial cancer and 888 controls. We will also further evaluate the functional importance of several gene polymorphisms by examining their associations with circulating levels of estrogens and estrogen metabolites. ? ?
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| Clendenen, Tess V; Rendleman, Justin; Ge, Wenzhen et al. (2015) Genotyping of Single Nucleotide Polymorphisms in DNA Isolated from Serum Using Sequenom MassARRAY Technology. PLoS One 10:e0135943 |
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| Zeleniuch-Jacquotte, A; Shore, R E; Afanasyeva, Y et al. (2011) Postmenopausal circulating levels of 2- and 16ýý-hydroxyestrone and risk of endometrial cancer. Br J Cancer 105:1458-64 |
| Zeleniuch-Jacquotte, Anne; Lundin, Eva; Micheli, Andrea et al. (2006) Circulating enterolactone and risk of endometrial cancer. Int J Cancer 119:2376-81 |
| Lukanova, Annekatrin; Zeleniuch-Jacquotte, Anne; Lundin, Eva et al. (2004) Prediagnostic levels of C-peptide, IGF-I, IGFBP -1, -2 and -3 and risk of endometrial cancer. Int J Cancer 108:262-8 |
| Lukanova, Annekatrin; Lundin, Eva; Micheli, Andrea et al. (2004) Circulating levels of sex steroid hormones and risk of endometrial cancer in postmenopausal women. Int J Cancer 108:425-32 |
