Oxidative Damage and DNA Repair in the PCPT

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DESCRIPTION (provided by applicant): The Prostate Cancer Prevention Trial (PCPT) of finasteride resulted in reduced cancers among the intervention group; however, among the men diagnosed with prostate cancer, the absolute number of tumors with high Gleason score was greater in the finasteride arm than in the placebo arm. Many of the known and suspected risk factors for prostate cancer are associated with higher levels of reactive oxygen species (ROS) or decreased antioxidant capabilities. Oxidative stress results from an imbalance between ROS and antioxidant capacities, which can cause direct DNA damage and mutations. There are extensive DNA repair systems that can correct damaged DNA before cell replication and mutation fixation, although inherent variability can result in diminished DNA repair capabilities. Additional data presented in this revised application on DNA repair and oxidative stress in prostate cancer further strengthen the hypothesis that these two pathways are involved in risk. Using biospecimens and data collected in PCPT and in the other projects of this P01, we intend to: 1) evaluate potential risk factors for prostate cancer that are linked to an oxidative stress/DNA repair mechanism; and 2) investigate mechanisms whereby finasteride could be associated with high grade tumors. We will determine whether polymorphisms in genes encoding enzymes that generate ROS, neutralize ROS, and repair DNA damage are associated with risk of prostate cancer and high grade cancer. We will also measure serum levels of oxidized proteins, a biomarker of oxidative damage, to determine if baseline levels of oxidative stress are elevated in those who go on to develop cancer and whether finasteride influences its level. In cross-project interactive aims, we will collaborate with investigators in other projects in this P01 to better understand the role of oxidative stress and DNA repair in prostate cancer risk. With Project 2, we will determine whether associations of dietary factors with prostate cancer differ by oxidative stress genotype and with Project 4 whether genotype for oxidative stress and DNA repair genes are associated with prevalence and extent of atrophy and inflammation.