LaVerne A. Mooney

Sulfotransferase 1A1 (SULT1A1) Polymorphism, PAH-DNA Adduct Levels in Breast Tissue and Breast Cancer Risk in a Case-Control Study

Gene–environment interactions are hypothesized to be major contributors to susceptibility to environmental carcinogens and interindividual variability in cancer risk. We present findings on associations between genetic susceptibility due to inherited polymorphisms of the Phase II detoxification enzyme sulfotransferase 1A1 (SULT1A1), breast cancer risk, and polycyclic aromatic hydrocarbon (PAH)-DNA adducts. A hospital based case-control study was conducted at the New York-Presbyterian Medical Center (NYPMC). The study utilized two control groups: one comprised of women with benign breast disease (BBD) and the other comprised of women visiting NYPMC for routine gynecologic checkups (healthy controls). Blood samples were collected from cases and controls; and breast tissue from pathology blocks was collected from cases (tumor and non-tumor tissue) and BBD controls (benign tissue). PAH-DNA adduct levels were measured by immunohistochemistry in breast tissue samples, and the SULT1A1 (Arg/His) polymorphism at codon 213 was determined by PCR RFLP analyses using DNA from white blood cells. Increasing number of His alleles was modestly associated with breast cancer case-control status, when cases were compared to healthy controls (p for trend = 0.08), when cases were compared to BBD controls (p for trend = 0.08) and when cases were compared to both control groups combined (p for trend = 0.07). Contrary to our hypothesis PAH-DNA adduct levels in breast tissue were not associated with SULT1A1 genotype. Our findings are consistent with a prior report that the Arg/His polymorphism in SULT1A1 is associated with breast cancer risk.

MOLECULAR EPIDEMIOLOGY IN ENVIRONMENTAL CARCINOGENESIS

Environmental factors such as smoking, diet, and pollutants act in concert with individual susceptibility to cause most human cancers. This article briefly reviews molecular evidence that two types of susceptibility factors--common predisposing genetic traits and young age at exposure--convey heightened risk from certain exposures. Examples are drawn from molecular epidemiologic studies of common environmental carcinogens such as polycyclic aromatic hydrocarbons (PAH) and aromatic amines. Understanding of both genetic and acquired susceptibility in the population will be instrumental in developing health and regulatory policies that adequately protect of the more susceptible groups from risks of environmental carcinogens.

The association between benzo[a]pyrene-DNA adducts and body mass index, calorie intake and physical activity

Abstract Prior work suggests that body size and fat content may influence carcinogen-DNA adduct levels measured in white blood cells. Here we consider energy balance more broadly by assessing the impact of body mass index (BMI), physical activity and calorie intake on the presence of benzo[a]pyrene-DNA (BP-DNA) adducts in white blood cell DNA. Our cross-sectional study employed subjects from a separately conducted intervention trial. Physical activity and food intake data were collected at 12 and 15 months of follow-up, respectively. BP-DNA adducts were measured by high-performance liquid chromatography (HPLC) in white blood cell samples collected at 12 months of follow-up. Complete data on all variables were available from 143 subjects. Logistic regression showed that BMI was inversely associated with the presence of detectable adducts (OR = 0.90, p=0.02), and that hours of moderate-intensity physical activity were positively associated with the presence of detectable adducts (OR = 1.04, p=0.04). These results provide further evidence that body fat content influences carcinogen-DNA adduct levels, probably by altering the distribution of the lipophilic parent compound.

Preliminary studies on the effect of moderate physical activity on blood levels of glutathione.

Abstract Molecular epidemiological approaches are being used to study how physical activity may protect against cancer. Prior epidemiological data suggest that physical activity protects against lung cancer; however, interpretation of these data is complicated by potential confounding by smoking. Glutathione (GSH) detoxifies cigarette smoke carcinogens and the paper tests whether physical activity levels are associated with blood GSH levels. Study subjects were enrolled in a chemoprevention trial testing whether antioxidant micronutrient supplementation reduces genetic damage from cigarette smoking. Physical activity data were collected by questionnaire from 178 subjects at 12 months of follow-up in the trial. Total GSH (tGSH), which is the sum of free and protein-bound GSH and glutathione disulfide levels, was measured using the 5,5′-dithiobis-(2-nitrobenzenoic acid) colormetric assay with red blood cell samples collected at the 12-month time point. In multivariate linear regression analyses that controlled for gender and cigarettes smoked per day, tGSH was positively associated with hours per week of moderate intensity activity (β=0.005, p=0.02). Hours per week of vigorous intensity activity were unassociated with tGSH and the effect of moderate activity remained after control for vigorous activity. The results are consistent with prior research showing differential effects of moderate and vigorous activity and suggest a mechanism through which physical activity may influence lung cancer risk.

Application of molecular epidemiology to lung cancer chemoprevention

Molecular epidemiology has made great progress in detecting and documenting carcinogenic exposures and host susceptibility factors, in an effort to explain interindividual variation in disease. Interindividual differences in cancer risk have been hypothesized to result from an array of both genetic and acquired factors including nutritional status. Elevated risk of lung cancer has been associated with polymorphisms of metabolic genes such as CYP1A1 and GSTM1. On the other hand, numerous studies have demonstrated that diets rich in fruits and vegetables are protective against cancer, and have correlated high levels of antioxidants in the blood with decreased risk.