"Ovarian Cancer Risk Associated with Polymorphisms Involved in
the Synthesis
of Estrogen Intermediates"
While ovulation has consistently been linked with the risk of epithelial
ovarian cancer, the mechanisms of this effect are not well understood. During
menstrual cycles, the epithelium proliferates at times when estrogenic influences
are relatively high. At ovulation, the ovarian epithelium is bathed in follicular
fluid that contains estradiol in concentration 10,000 times higher than circulating
levels. Exposure of the epithelium to high levels of estradiol or its oxidative
metabolites during periods of increased mitotic activity may enhance the
risk of genetic mutation occurring.
We propose to conduct a population-based case-control study to examine the
risk of epithelial ovarian cancer associated with polymorphisms in genes
involved in determining metabolic pathways of estrogen. The 4-hydroxylation
of estradiol results in catechol intermediates that can cause oxidative damage,
lipid peroxidation and formation of DNA adducts. Polymorphisms influencing
estridiol hydroxylation and levels of potentially carcinogenic catechol intermediates
will be studied: CYP1A1 m1, m2, m3, m4; CYP1B1 Arg48Gly, Ala119Ser,
Leu432Val, Asn453Ser; COMT Val158Me; SULT1A1 Arg213His; and a microsatellite
polymorphism in UGT1A1.
This interdisciplinary research will address a novel hypothesis using a comprehensive
panel of polymorphisms related to estrogen metabolism, in a relatively large
study population of 310 cases and 543 controls. Results of this study will
enhance our understanding of both the role of estrogen metabolism in ovarian
carcinogenesis and a possible mechanism of genetic susceptibility to this
disease.
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