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Measuring carcinogen metabolite levels in long-term smokers and estimating the risk of lung cancer

Principal Investigator
Name
Timothy Church
Degrees
-
Institution
University of Minnesota
Position Title
-
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
2005-0029
Initial CDAS Request Approval
Apr 21, 2006
Title
Measuring carcinogen metabolite levels in long-term smokers and estimating the risk of lung cancer
Summary
Identifying mechanisms of harm and susceptibility in individual tobacco users can assist in reducing disease from tobacco. To do harm, the carcinogens in tobacco smoke must be absorbed and activated by the body. Biomarkers in blood for specific tobacco carcinogens can measure the effective dose; other biomarkers measure the degree to which those carcinogens have become capable of damaging DNA and so indicate the individual phenotypic susceptibility. This proposed study would estimate in smokers the association of biomarkers of tobacco carcinogen exposure and metabolic activation to their risk of developing lung cancer. The study would be nested in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), selecting from the nearly 7,000 subjects who smoked at baseline. The PLCO is ideal for this study, because it provides a well characterized smoking population with rigorously collected data, has an associated, extensive biorepository of blood samples collected at screening visits, and eliminates bias found in partially screened populations. From PLCO bio-repository participants who reported smoking on their baseline questionnaire, a sample of 100 incident lung cancer cases and 100 controls will be drawn and their demographic and baseline data obtained. Each biological sample will be analyzed to measure the specific exposure and activation metabolites. The biomarker levels in lung cancer cases will be compared to those in controls and regression estimates will be made of the odds ratios for lung cancer associated with these biomarkers. In addition to these exposure and activation biomarkers, the study can examine polymorphisms in key genes that are related to detoxification pathways. If successful, these data will improve 1) understanding of lung cancer etiology and gentopic risk , and 2) predictive models for lung cancer. We project that carcinogen metabolite phenotyping will enhance prevention, early detection, and risk reduction. Moreover, this will provide a platform for studying the relationship of genetic and other molecular markers to risk. The investigators are actively developing additional genotyping and phenotyping studies addressing detoxification and repair pathways; these studies will piggyback on the subjects and samples for this study to increase their scientific value in two ways.
Aims

The main hypothesis of this study is that higher levels of carcinogen biomarkers in smokers will be associated with increased risk for lung cancer. The goal is to determine whether, in a population of humans, the biomarkers are associated with lung cancer diagnosis when combined with other known, measured risk factors for lung cancer, such as age, sex, and smoking history. Specifically, the study will: In a nested case-control design, randomly select from the source cohort, consisting of all PLCO subjects who smoked at the time of study entry, 100 incident lung cancer cases and 100 controls (participants who have no diagnosis of lung cancer). Obtain demographic and baseline data from the PLCO database on the 100 cases and 100 controls. Obtain from the study biorepository samples of serum and red blood cells of these participants that, are adequate to measure the following biomarkers: a. Total cotinine (cotinine plus cotinine-glucuronide), major metabolites of nicotine, in serum; b. total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) [NNAL plus NNAL-glucuronides], metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in serum; c. r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (phenanthrene tetraol), a metabolite of phenanthrene, in serum; d. anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE)-hemoglobin adducts, from metabolic activation of benzo[a]pyrene (BaP); e. N-terminal N-(2-hydroxyethyl)valine, a hemoglobin adduct derived from the carcinogen ethylene oxide; f. N-terminal N-ethylvaline, a hemoglobin adduct derived from an ethylating agent in cigarette smoke. Analyze PLCO study samples for the above biomarkers and link the results to participant demographic data, smoking history, and lung cancer status to estimate the odds ratios of lung cancer and their confidence regions for these biomarkers, controlling for variables indicated by the presumed causal model, with appropriate sensitivity analyses. By combining these results with early PLCO results on chest x-ray screening, estimate the change in sensitivity and specificity of screening that incorporating these biomarkers could produce. Develop a study to examine the effect of genetic polypmorphisms in three detoxification pathway genes that would use the samples from these cases and controls.

Collaborators

Kristin Anderson (University of Minnesota)
Neil Caporaso (NCI, DCEG)
Stephen Hecht (University of Minnesota)
Timothy Church (University of Minnesota)

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