Sonja Berndt

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NCI, DCEG, OEEB

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PLCO (Learn more about this study)

2007-0012

May 22, 2007

Polymorphisms in DNA repair genes and the risk of colorectal cancer

In the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Study, smokers who used higher doses of supplemental vitamin E had reduced risks of advanced prostate cancer, complementing findings from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study and several other epidemiologic studies. In contrast, vitamin E supplementation was not associated with lower risks of advanced prostate cancer in nonsmokers. Given these findings, we propose to investigate the biological mechanisms that may underlie the apparent interaction between smoking and vitamin E supplementation in prostate carcinogenesis. Cigarette smoking has been associated with advanced and fatal prostate cancer in several epidemiologic studies, and may accelerate the progression of latent disease to aggressive cancer directly, or through its effects on oxidative stress, steroid hormones, protein kinase C activity and mitogenesis, or angiogenesis. Vitamin E exhibits several anticarcinogenic functions that could potentially interfere with the promotional effects of smoking, including antioxidant activity, interference with sex steroid hormone signaling, and inhibition of protein kinase C activity, cell proliferation, and vascular endothelial growth factor expression. The current proposal is to conduct a molecular epidemiologic study of several key biomarkers that potentially account for the biologic activity of vitamin E in preventing prostate cancer in smokers. Data for this investigation will come from 300male controls from the PLCO sample included in the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium, all of whom were free of cancer at study entry, provided a complete baseline risk factor and dietary questionnaire that included information on tobacco consumption and vitamin supplement use, and a blood sample. Serum levels of a-tocopherol, g-tocopherol, sex steroid hormones (sex hormone-binding globulin, androstanediol glucuronide, testosterone, estrone, and estradiol), and growth factors (insulin-like growth factor 1 and insulin-like growth factor binding protein 3) are being measured in these controls for the NCI Cohort Consortium, and will be available for analysis in the proposed biomarker investigation. We will additionally measure serum cotinine (a biochemical measure of tobacco smoke exposure), 8-hydroxydeoxyguanosine and 8-iso-prostaglandin F2a (measures of overall oxidative DNA damage and oxidative stress due to lipid peroxidation, respectively), vascular endothelial growth factor (the primary mediator of angiogenesis), and protein kinase C activity (involved in cell proliferation and growth). We will cross-sectionally examine whether concentrations of these biomarkers vary according to dose and duration of vitamin E supplement use (as well as by serum a- and g-tocopherol levels), overall and separately in nonsmokers and current / recent smokers. Multivariate linear regression will be utilized to control for confounding factors. Biomarkers that demonstrate significant differences across vitamin E categories and that show differential variation in smokers versus nonsmokers will be selected for inclusion in a second phase study, in which we will test the main effects of selected biomarkers on prostate cancer risk using a nested case-control design (a separate proposal for this will be submitted to PLCO EEMS after the present investigation has been completed and relevant biomarkers identified). Results obtained from this research should ultimately lead to a better understanding of the nature of the interaction between vitamin E supplementation and smoking in prostate carcinogenesis, and inform future research directed at identifying biological pathways that are important in the etiology of this common disease.