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Greater exposure to estrogens is a risk factor for ovarian cancer. To investigate the role of estrogens in ovarian cancer, a spot urine sample and a saliva sample were obtained from 33 women with ovarian cancer and 34 age-matched controls. Thirty-eight estrogen metabolites, conjugates and DNA adducts were analyzed in the urine samples using ultraperformance liquid chromatography/tandem mass spectrometry, and the ratio of adducts to metabolites and conjugates was calculated for each sample. The ratio of depurinating estrogen–DNA adducts to estrogen metabolites and conjugates was significantly higher in cases compared to controls (p< 0.0001), demonstrating high specificity and sensitivity. DNA was purified from the saliva samples and analyzed for genetic polymorphisms in the genes for two estrogen-metabolizing enzymes. Women with two low-activity alleles of catechol-O-methyltransferase plus one or two high-activity alleles of cytochrome P450 1B1 had higher levels of estrogen–DNA adducts and were more likely to have ovarian cancer. These findings indicate that estrogen metabolism is unbalanced in ovarian cancer and suggest that formation of estrogen–DNA adducts plays a critical role in the initiation of ovarian cancer.When estrogen latches onto DNA, cancer often follows. This study investigated the role of estrogen metabolism in ovarian cancer by testing how often estrogen bound to DNA in women with and without ovarian cancer. They found more estrogen-DNA adducts in ovarian cancer patients than in age-matched controls. Further, the authors tested for polymorphisms in certain genes. Low-activity alleles of catechol-O-methyltransferase, as well as high-activity alleles of cytochrome P450 1B1, correlated with more estrogen-DNA adducts and more ovarian cancer. Estrogen metabolism, then, appears to be unbalanced in ovarian cancer, and estrogen-DNA adduct formation could spur the cancer's birth.