DESCRIPTION: (Applicant's Description) 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
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
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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