Evaluation of Oxidative Stress Response Related Genetic Variants, Pro-oxidants, Antioxidants and Prostate Cancer

• Main Authors: Nicole Lavender, David W. Hein, Guy Brock, La Creis R. Kidd
• Format: Article
• Language: English
• Published: American Institute of Mathematical Sciences 2015-09-01
• Series: AIMS Medical Science
• Subjects: Prostate cancer; oxidative stress; multifactor dimensionality reduction; gene-gene interactions; gene-environment interactions; genome wide association study; Cancer Genetics Markers of Susceptibility
• Online Access: http://www.aimspress.com/medicalScience/article/421/fulltext.html

Background: Oxidative stress and detoxification mechanisms have been commonly studied in Prostate Cancer (PCa) due to their function in the detoxification of potentially damaging reactive oxygen species (ROS) and carcinogens. However, findings have been either inconsistent or inconclusive. These mixed findings may, in part, relate to failure to consider interactions among oxidative stress response related genetic variants along with pro- and antioxidant factors. Methods: We examined the effects of 33 genetic and 26 environmental oxidative stress and defense factors on PCa risk and disease aggressiveness among 2,286 men from the Cancer Genetic Markers of Susceptibility project (1,175 cases, 1,111 controls). Single and joint effects were analyzed using a comprehensive statistical approach involving logistic regression, multi-dimensionality reduction, and entropy graphs. Results: Inheritance of one <em>CYP2C8 rs7909236</em> T or two <em>SOD2 rs2758331</em> A alleles was linked to a 1.3- and 1.4-fold increase in risk of developing PCa, respectively (<em>p</em>-value = 0.006-0.013). Carriers of <em>CYP1B1 rs1800440GG</em>, <em>CYP2C8 rs1058932TC</em> and, <em>NAT2</em> (<em>rs1208GG, rs1390358CC, rs7832071TT</em>) genotypes were associated with a 1.3 to 2.2-fold increase in aggressive PCa [<em>p</em>-value = 0.04-0.001, FDR 0.088-0.939]. We observed a 23% reduction in aggressive disease linked to inheritance of one or more <em>NAT2 rs4646247</em> A alleles (<em>p</em> = 0.04, FDR = 0.405). Only three <em>NAT2</em> sequence variants remained significant after adjusting for multiple hypotheses testing, namely <em>NAT2 rs1208, rs1390358,</em> and <em>rs7832071.</em> Lastly, there were no significant gene-environment or gene-gene interactions associated with PCa outcomes. Conclusions: Variations in genes involved in oxidative stress and defense pathways may modify PCa. Our findings do not firmly support the role of oxidative stress genetic variants combined with lifestyle/environmental factors as modifiers of PCa and disease progression. However, additional multi-center studies poised to pool genetic and environmental data are needed to make strong conclusions.