Metabolism of NNK Among African Americans
Condition: Lung Cancer
MeSH terms: Lung Neoplasms
Study type: Observational

Summary: 
      Metabolism and DNA adduct formation are critical in cancer induction by NNK. The
      investigators goal is to understand whether the observed ethnic/racial differences in lung
      cancer incidence are due to variations in NNK metabolism. The investigators overall
      hypothesis is that cancer susceptibility relates to carcinogen dose and to the balance
      between carcinogen metabolic activation and detoxification. The investigators propose to test
      this hypothesis via investigation of potential differences in NNK metabolic activation and
      detoxification in African American and European American smokers.
    

Detailed description: 
      Lung cancer is the most common cause of cancer death in the United States, with the annual
      number of cases estimated at 162,460 deaths per year. It is more prevalent in African
      Americans as compared to European Americans. Cigarette smoking causes up to 90% of lung
      cancer, being the major risk factor in both African Americans and European Americans.

      Tobacco-specific nitrosamines (TSNA) are among the most significant carcinogens in tobacco
      products. Multiple international studies clearly document the occurrence of substantial
      amounts of these carcinogens in both unburned tobacco and tobacco smoke. One of the most
      prevalent of these compounds, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is
      present in both unburned tobacco and cigarette smoke, and is a remarkably effective lung
      carcinogen in laboratory animals, inducing lung tumors in rodents independent of the route of
      administration. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a metabolite of NNK, is
      also a pulmonary carcinogen. NNK has been classified by the International Agency for Research
      on Cancer as a Group 1 carcinogen (carcinogenic to humans). Consistent with this, 2 recent
      studies by our group have demonstrated that levels of NNAL in serum or urine are related to
      lung cancer in smokers.

      Our primary aim is to conduct a comprehensive analysis of urinary biomarkers of NNK metabolic
      activation and detoxification in African American and European American smokers. We
      hypothesize that, after adjustment for smoking level, the relative contribution of the
      biomarkers of NNK metabolic activation to the total amount of NNK metabolites will be higher
      in African Americans as compared to European Americans. Our secondary aim is to measure in
      exfoliated oral mucosa cells of African American and European American smokers DNA adducts
      formed as a result of NNK metabolic activation. The results of these measurements will offer
      a direct measure of NNK-induced DNA damage in smokers, and will be critical to an
      understanding of the balance between the urinary excretion of NNK metabolites and the extent
      of NNK DNA binding. We hypothesize that African Americans will have in the DNA of their oral
      mucosa cells higher levels of NNK-derived DNA adducts as compared to European Americans.
      Finally, we will investigate the relationship between levels of NNK-derived DNA adducts
      measured in oral mucosa cells and the rates of repair of these adducts in cultured
      lymphocytes from our subjects. These measurements will allow us to evaluate more fully the
      role of variations in NNK metabolism in the observed differences in lung cancer risk between
      European American and African American smokers. We expect that that African Americans will
      have lower capacity to repair NNK-induced DNA damage as compared to European Americans, and
      this will correlate with higher levels of NNK-derived buccal DNA adducts.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Subjects will be classified as African American if they report themselves, biological
        parents and both sets of biological grandparents as African American or African descent.
        Similar criteria will be applied to European Americans (e.g., self, both parents and four
        grandparents of European American or European descent). Subjects will be evenly divided by
        gender.
      
Biospecimen description: 
      Venous blood sample (approximately 40 ml) will be drawn from each study participant at the
      baseline visit. Approximately 33 ml will be used immediately for the study, and the remaining
      two 3-ml volumes will be reserved for future use. The various components of the blood
      including buffy coat (white blood cells), red blood cells, plasma, and serum will be
      separated immediately after their collection, labelled using a unique subject number, and
      stored in a -80C freezer. Urine samples and oral cells will be collected from study subjects
      at various time points. All these samples will be labelled using a unique subject number, and
      stored at a -80C freezer.
    
Keywords: smoking; lung cancer; ethnic racial differences; tobacco specific nitrosamines; metabolism of carcinogens