Associations Between Polymorphisms in Genes Related to Oxidative Stress and DNA Repair, Interactions With Serum Antioxidants, and Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial.

Zhihong Gong,Marian L Neuhouser,Mary E Platek,Ian M Thompson,Regina M Santella,Christine B Ambrosone,Elizabeth A Platz,Phyllis J Goodman,Catherine M Tangen,Cathee Till

doi:10.3389/fonc.2021.808715

Abstract

Study of polymorphisms in genes related to the generation and removal of oxidative stress and repair of oxidative DNA damage will lead to new insights into the genetic basis of prostate cancer. In the Prostate Cancer Prevention Trial (PCPT), a double-blind, randomized controlled trial testing finasteride versus placebo for prostate cancer prevention, we intend to investigate the role of oxidative stress/DNA repair mechanisms in prostate cancer etiology and whether these polymorphisms modify prostate cancer risk by interacting with antioxidant status in both placebo and finasteride arms. We evaluated associations of selected candidate polymorphisms in genes in these pathways, and interactions with pre-diagnostic serum antioxidants, and the risk of prostate cancer among 1,598 cases and 1,706 frequency-matched controls enrolled in the PCPT. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable-adjusted logistic regression models. While there were no statistically significant associations observed in the placebo arm, several SNPs were associated with prostate cancer in the finasteride arm. Specifically, APEX1-rs1760944 was associated with increased risk of total prostate cancer (per minor allele: p-trend=0.04). OGG1-rs1052133 was positively (CG/GG vs. CC: OR=1.32, 95% CI: 1.01-1.73) and NOS3-rs1799983 was inversely (per minor allele: p-trend=0.04) associated with risk of low-grade prostate cancer. LIG3-rs1052536 and XRCC1-rs25489 were suggestively associated with reduced risk of high-grade prostate cancer (per minor allele: both p-trend=0.04). In the placebo arm, significant associations were observed among men with higher serum lycopene for APEX1-rs1760944 and NQO1-rs1800566, or higher serum β-cryptoxanthin for ERCC4-rs1800067. In the finasteride arm, stronger associations were observed among men with lower serum lycopene for NOS3-rs1799983, higher serum α-carotene, β-carotene, and β-cryptoxanthin for LIG3-rs1052536, or lower serum retinol for SOD2-rs1799725. These results suggest that germline variations in oxidative stress and DNA repair pathways may contribute to prostate carcinogenesis and that these associations may differ by intraprostatic sex steroid hormone status and be further modified by antioxidant status. Findings provide insights into the complex role of gene, gene-antioxidant and -finasteride interactions in prostate cancer etiology, and thus may lead to the development of preventative strategies.

Highlights

Prostate cancer remains the most commonly diagnosed cancer and the second leading cause of cancer death in men among the majority of countries, including the United States (U.S.) [1, 2]
Observed among men with higher levels of lycopene, lower levels of a-carotene (p-trend=0.02) and retinol (p-trend=0.006), with a p-interaction of 0.32, 0.25, and 0.07, respectively. In this nested case-control study of 1,598 cases and 1,706 controls enrolled in the Prostate Cancer Prevention Trial (PCPT), we conducted an analysis of a panel of candidate genetic polymorphisms involved in the oxidative stress and DNA repair pathways with risk of prostate cancer in both placebo and finasteride arms
There were no significant associations observed in the placebo arm, in the finasteride arm, several single nucleotide polymorphisms (SNPs) in APEX1, OGG1, NOS3, LIG3 and XRCC1 were associated with risk of total, low- or high-grade prostate cancer

Summary

Introduction

Prostate cancer remains the most commonly diagnosed cancer and the second leading cause of cancer death in men among the majority of countries, including the United States (U.S.) [1, 2]. Many of the known and suspected risk factors for prostate cancer such as age are associated with higher levels of reactive oxygen species (ROS) and/or decreased antioxidant capabilities [7, 8]. An imbalance between ROS and antioxidant capacity, leads to damaged DNA and mutations. Various DNA repair systems can remedy this situation before cell replication and mutation fixation, but inherent variation can lead to diminished DNA repair capacity [10, 11]. Oxidative stress and DNA repair capacity might interact with serum levels of antioxidants, resulting in an increased or reduced antioxidant/DNA repair capacity, which, in turn, influence prostate cancer risk

Methods

Results

Conclusion