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Modifying Effects of Variant Oxidative Stress Related Genes in Relation to Prostate Cancer Outcomes

Principal Investigator
Name
LaCreis Kidd
Institution
University of Louisville
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
2009-0244
Initial CDAS Request Approval
Jan 21, 2010
Title
Modifying Effects of Variant Oxidative Stress Related Genes in Relation to Prostate Cancer Outcomes
Summary
Unfortunately, complex interactions that may occur between genetic and environmental factors and their contribution in prostate carcinogenesis remain largely unknown.1-3 Essential to eliminating this shortcoming is the identification and validation of new genomic profiles in important biological pathways as effective predictors of prostate cancer (PCA) and clinical outcomes.1,4 Consequently, the proposed research will systematically identify and evaluate single- and joint-modifying effects of 101 single nucleotide polymorphisms (SNPs) within oxidative stress response (OSR) related genes [e.g., LIG1, LIG3, XRCC1, CAT, EPHX1, CASP (5 & 9), BAX, BCL2, NFKB1] and cigarette smoking on PCA risk and disease progression (see Table 1). We hypothesize that increased PCA risk and aggressive disease may be attributed to inheritance of two or more OSR sequence alleles linked with a decreased capacity to suppress ROS, induce oxidative DNA damage repair, or elicit cell death signaling pathways.5,6 In addition, inheritance of OSR genetic susceptibilities combined with increased exposure to oxidative species due to cigarette smoking may further contribute to poor PCA health outcomes. The influence of main effects as well as gene-gene and gene-environment interactions on PCA outcomes will be determined using genetic profile and cigarette smoking data from 2277 men of European-descent (1101 controls, 488 non-aggressive cases and 688 aggressive cases) available through the Cancer Genetic Markers of Susceptibility (CGEMS) project. Evaluation of complex interactions will involve conventional logistic regression (LR) and Multifactor Dimensionality Reduction (MDR) modeling. Validation of promising epistasis models will involve additional advanced tools including: Symbolic Modeling (SyMod), Set Association (SA), Classification and Regression Tree Approaches (CART), and Random Forest (RF). This analysis will be used to generate a unique panel of polymorphic OSR related genes that we will subsequently validate and characterize within future independent population-based study sets.
Aims

Aim 1: Determine the single- and joint-modifying effects of variations within oxidative stress response (OSR)-related genes and smoking status in relation to PCA risk using a highly integrative genomic and bioinformatic approach. Individuals with two or more alleles associated with decreased antioxidation, compromised base excision repair, and reduced apoptosis are hypothesized to have increased PCA vulnerability relative to those with low-risk genotypes. We anticipate that increased cancer risk may also be attributed antioxidation or base excision repair sequence variants linked with a decreased capacity to suppress ROS and repair oxidative stress induced DNA damage, respectively. Furthermore, cell survival alleles linked with reduced apoptotic potential will increase the risk of developing PCA (i.e., transformed cells that escape apoptosis). Increased risk is presumably attributed to reduced cell death, increased accumulation of damaged cells and instability, cell proliferation, tumor growth, and metastasis. Lastly, environmental factors (e.g., cigarette smoke) that increase the amount of exposure to oxidative species, combined with a decreased capacity to remove them and/or damaged cells will presumably further modify PCA risk. Specific Aim 2: Assess the individual and combined effects of "cell survival" loci (favoring reduced apoptosis) in relation to prostate cancer disease progression. We hypothesize "cell survival" alleles linked with reduced apoptotic potential will increase the risk of developing aggressive/advanced PCA (i.e., transformed cells that escape apoptosis). Genetic variations that disrupt cell death and cell cycle regulation pathways may result in more aggressive phenotypes in prostatic tumors. Regulation of the cell death is critical to maintain cellular homeostasis, proliferation, and differentiation by facilitating repair or induction of cell death. This process involves multiple pathways and a balance between pro- and anti-apoptotic genes that function to activate or block apoptosis. A decrease or loss of apoptotic induction can permit escape of transformed cells from programmed cell death, increase the accumulation of damaged cells, and lead to tumor formation and progression.7,8

Collaborators

Marnita Benford (Univeristy of Louisville)
Nicole Lavender (University of Louisville)
Tiva VanCleave (University of Louisville)