Polymorphisms in Oxidative Stress–Related Genes Are Not Associated with Prostate Cancer Risk in Heavy Smokers Ji-Yeob Choi, 1 Marian L. Neuhouser, 2 Matt Barnett, 2 Matthew Hudson, 4 Alan R. Kristal, 3,5 Mark Thornquist, 2 Irena B. King, 2 Gary E. Goodman, 3,6 and Christine B. Ambrosone 1 1 Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Elm and Carlton Sts., Buffalo, New York; 2 Cancer Prevention Program and 3 Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington; 4 University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; 5 Department of Epidemiology, University of Washington, Seattle; and 6 Swedish Cancer Institute, Seattle, Washington Abstract Oxidative stress, associated with aging and inflammation, is likely to play a role in the etiology of prostate cancer. We evaluated potential associations between gene variants that result in reduced neutralization of reactive oxygen species (ROS; MnSOD Ala-16 Val, CAT 262 C>T, and GPX1 Pro200 Leu) and prostate cancer risk among 724 men with incident prostate cancer who participated in the Carotene and Retinol Efficacy Trial (CARET) cohort, a randomized trial for the prevention of lung cancer among men with a history of smoking and/or asbestos exposure. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by logistic regression. Nested case-control analyses included study participants with available DNA (n = 533 cases and 1,470 controls), matched for race, age, and length of follow- time. Overall, there were no associations between genotypes of MnSOD, CAT , and GPX1 and prostate cancer risk, although among men diagnosed before age 65, CAT TT genotype was associated with increased risk (OR, 2.0; 95% CI, 0.97 -3.95). Further analyses stratified by factors related to environmental oxidative stress exposures did not modify associations. When calculating the number of risk alleles of MnSOD, CAT , and GPX1 hypothetically related to reduced protection against ROS, there was a nonsignificant relation- ship between prostate cancer and carriage of five or more risk alleles, in comparison to men with less than five risk alleles (OR, 2.0; 95% CI, 0.90-4.42 ). In conclusion, it does not seem that variants in MnSOD, CAT , or GPX1 have an influence on prostate cancer risk in this cohort of men who were smokers or exposed to asbestos, although it is possible that cumulative defects in protection from oxidative stress may result in increased risk of the disease. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1115 – 20) Introduction Although the absolute number of deaths from prostate cancer has been decreasing substantially over the past decade, it remains one of the most common cancers in the United States, representing approximately one-third of all cancers diagnosed among American men in 2006 (1). Understanding factors contributing to carcinogenesis in the prostate has been, and continues to be, a crucial element in improving methods of cancer prevention as a whole. Given that prostate cancer incidence is highly dependent upon age, correlations between aging and tumorigenesis demand greater attention, particularly the role played by oxidative damage in both processes (2-5). The enzymes that are generally considered to be the front- line defense against reactive oxygen species (ROS) are the mitochondrial manganese superoxide dismutase (MnSOD), catalase (CAT), and glutathione peroxidase (GPX1). MnSOD catalyzes the conversion of superoxide radicals to hydrogen peroxide, whereas CAT and GPX1 facilitate the further reduction of hydrogen peroxide to water and oxygen. By this chain of enzymatic events, most of the ROS in the cell are eliminated, and potential damage is limited. A valine (Val)-to-alanine (Ala) substitution at amino acid 16 (T to C) occurs in the mitochondrial targeting sequence of the MnSOD gene (rs4880), which may affect the localization and transport of the enzyme into the mitochondria by altering the secondary structure of the protein (6). Sutton et al. (7) reported that MnSOD C alleles resulted in 30% to 40% greater efficiency in localizing the enzyme to the mitochondrial matrix, compared with MnSOD T alleles. Two studies, to date, have examined the influence of this polymorphism on the risk of prostate cancer (8, 9); one study observed a moderate elevation in risk, particularly among men with high-grade tumors (8). The other study found no overall association with risk, but the polymorphism significantly increased the risk of prostate cancer among men with lower prediagnostic levels of plasma antioxidants (9). To our knowledge, there have been no investigations of associations between prostate cancer risk and CAT and GPX1 polymorphisms. These variants have been linked to breast cancer and other disease conditions related to oxidative stress. A common 262 C to T (rs1001179) polymorphism has been identified in the promoter region of the human catalase gene (CAT ), and individuals with variant CT or TT genotypes have significantly lower activity than those with CC genotypes in Caucasians (10). A Pro-to-Leu allele polymorphism (rs1050450) of selenium-dependent GPX1 exists at codon 200 (C>T), with the variant Leu allele being less responsive than the common Pro allele to the stimulation of enzyme activity during selenium supplementation. It is likely that the balance of oxidants and antioxidants is affected by numerous genetic variants, as well as endogenous and exogenous exposures. Because ultimate levels of ROS are likely dependent not only on the generation of hydrogen peroxide by MnSOD, but also on the neutralization of H 2 O 2 by catalase and glutathione peroxidase, we evaluated potential associations between risk and variants in these enzymes, as well as potential interactions with ROS-related exposures, in a nested case-control study conducted in the h-Carotene and Retinol Efficacy Trial (CARET) study. 1115 Cancer Epidemiol Biomarkers Prev 2007;16(6). June 2007 Received 1/12/07; revised 2/9/07; accepted 3/26/07. Grant support: Grant U01 CA63673 and R01 CA096789-01 A1 from the National Cancer Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Ji-Yeob Choi, Roswell Park Cancer Institute, Elm and Carlton Sts., Buffalo, NY 14263. Phone: 716-845-1220. E-mail: ji-yeob.choi@roswellpark.org Copyright D 2007 American Association for Cancer Research. doi:10.1158/1055-9965.EPI-07-0040 on June 1, 2020. © 2007 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from