Sarah Holt

Interdisciplinary Training

Sarah Holt

"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.