) Women who smoke cigarettes have about half the risk of endometrial cancer of non-smokers. Female smokers have been observed to have an increase in 2-hydroxylation of estrogens, and this increased 2-hydroxylation has been suggested as a mechanism to explain the apparent antiestrogenic effect of cigarette smoke. Polymorphisms in several genes involved in metabolizing potential carcinogens in cigarette smoke have been related to an increased risk of lung cancer. One of these genes is also involved in 2-hydroxylation of estrogens. Thus, it might be anticipated that women who have the high-risk genotypes, in terms of lung cancer, would have a reduced risk of a condition such as endometrial cancer, whose incidence is reduced by cigarette smoking. However, in a recent small case-control study, a strong, positive relationship between the presence of some of the polymorphisms in these genes and endometrial cancer risk was reported. In our proposed population-based case-control study, we will explore whether polymorphisms in some of these genes are associated with endometrial cancer risk. The genes of interest are: cytochrome P450 1A1 (CYP1A1), glutathione-S-transferases M1 (GSTM1) and T1 (GSTT1), and catechol-O-methyltransferase (COMT). Cases and controls will be drawn from our funded study of continuous combined hormone replacement therapy and endometrial cancer. Cases are women ages 50-69 years with incident endometrial cancer diagnosed between 6/l/97 and 7/31/00, who reside in western Washington. Controls are women recruited through random-digit dialing (ages 50-64 years) and Health Care Financing Administration files (ages 65-69 years), who reside in the same geographic area. In the proposed study, 175 cases and 175 controls will be asked to provide a blood specimen at the time of interview. Using purified DNA from these blood samples, the genotypes of interest will be assayed using PCR and RFLPs. Differences in the distributions of genotypes between cases and controls will be assessed in the whole study population, as well as in sub-groups of women defined by cigarette smoking history and use of hormone replacement therapy (HRT). Since endometrial cancer is strongly hormone-related, the results of this study could have relevance for other, more common cancers whose relation to hormones is not so straightforward. Additionally, this information potentially could be used to predict a woman's sensitivity to the carcinogenic effects of HRT, and thus bear on a woman's decision regarding long-term use of HRT.
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