We propose to use a molecular epidemiologic approach in a case-control study to identify interindividual differences in susceptibility to tobacco-induced carcinogenesis as predictors of BC risk. This will include assessing susceptibility at several aspects of tobacco-induced carcinogenesis, including the genetically modulated activation and detoxification of tobacco mutagens and chromosome sensitivity to these mutagens. We will accrue 200 patients with superficial BC and 200 patients with invasive BC of any age and ethnicity and of either sex who have not received chemotherapy or radiotherapy. We will also prospectively select 400 controls from a potential large control pool identified from the rosters of the largest multispecialty healthcare group practice in the Houston metropolitan area. These controls will be matched to the patients by sex, age (plus /minus 5 years), and ethnicity. Comprehensive epidemiologic profiles will be constructed for these patients and controls.
The specific aims are: 1) To assess in patients with BC and in controls two mutagen sensitivity susceptibility assays performed in parallel, one that quantifies the number of lymphocytic chromatid breaks induced by in vitro exposure to bleomycin (a radiomimetic agent) and another that quantifies the number of breaks induced by in vitro exposure to benzo[a]pyrene diol-epoxide (BPDE; the activated form of benzo[alpha]pyrene, a tobacco carcinogen). Our hypothesis is that subjects who show increased bleomycin- and BPDE- chromosome sensitivity are at greater risk for BC than are those who do not show these sensitivities. Using the two tobacco mutagen sensitivity assays in parallel will improve our ability to identify populations at high-risk for BC (case-control analysis) and for invasive compared with superficial BC (case-case analysis); 2) To determine in patients and controls the frequencies of polymorphisms in those genes that regulate the metabolism of carcinogens in tobacco smoke, such as cytochrome P450 (CYP) 1A1, CYP2E1, glutathione-S-transferase (GST) mu and theta, epoxide hydrolase 3 (EPHX3) EPHX4, myeloperoxidase (MPO), N-acetyltransferase (NAT)1, and NAT2. Our hypothesis is that an inherent susceptibility to BC is associated with metabolic enzyme genetic polymorphisms that modulate activation and detoxification of tobacco carcinogen. 3) To explore the associations between the cytogenetic and molecular components and epidemiologic covariates (age, sex, ethnicity, cigarette smoking status, alcohol use and dietary intake, and family history of cancer) in risk of BC overall and by subtype. We will integrate epidemiologic data with the genetic data from the studies described in Specific Aims 1 and 2. Our long-term plan is to refine our risk assessment in patients with BC so that we can identify high-risk subgroups of candidates for primary and secondary prevention measures.
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