Date on Master's Thesis/Doctoral Dissertation
Pharmacology and Toxicology
Kidd, La Creis Renee
Prostate cancer epidemiology; Oxidative stress response; Apoptosis; Gene-gene interactions
Prostate--Cancer--Genetic aspects; Oxidative stress
Prostate cancer (PCA) development may be influenced by genetic variations within oxidative stress response (OSR) related mechanisms, such as antioxidation (e.g., carcinogen metabolism/detoxification), DNA repair, and apoptotic regulation. Excessive oxidative stress can produce DNA base changes, damage tumor suppressors, enhance proto-oncogene expression, and induce malignant transformation of cells. Persistent oxidative stress may even trigger apoptosis. Environmental reactive oxygen species (ROS) exposure attributable to lifestyle factors may exacerbate this situation by increasing oxidative stress. Therefore, it is likely that genetic variation resulting in compromised ROS capacity combined with increased environmental ROS exposure may increase PCA risk and disease aggressiveness. Consequently, this research evaluated the individual and joint modifying effects of OSR 242 genetic and 27 environmental factors in relation to PCA development among men of European and African descents. This analysis utilized a combination of traditional and innovative advanced mathematical methodologies that provided an opportunity to visualize, verify, and evaluate the predictive accuracy of higher-order interactions as indicators of disease risk and aggressiveness. Our analysis identified several OSR sequence variants to individually associated PCA risk among MED. In addition, antioxidative- and apoptotic-related SNPs were linked to increased disease risk in MAD. Higher order interaction analyses for across both populations detected gene-gene combinations among antioxidative- and apoptoticrelated sequence targets associated with increased risk. The potential functional consequences of these polymorph isms suggest that compromised detoxification and apoptotic induction may cause increased risk for PCA and more aggressive disease. Our results also indicate that environmental factors related to meat consumption and cooking methods may contribute to PCA mechanisms. Unfortunately, we were not able to characterize environmental factors alone or combined with gene variants that are involved in PCA. This may be attributed to MDR data filtering, small MAD sample size, or limitations in some study variables (e.g., meat-derived carcinogen exposure). However, future analysis within larger study populations, more accurate exposure variables, and improved computational power may allow us to identify and validate environmental factors relevant to PCA development.
Lavender, Nicole A., "The role of genetic and environmental oxidative stress factors in prostate cancer." (2010). Electronic Theses and Dissertations. Paper 797.