Abstract A80: Polymorphisms in oxidative stress regulatory enzymes modify the association of serum α- and γ-tocopherols with aggressive prostate cancer risk in the Carotene and Retinol Efficacy Trial (CARET)

Abstract

Abstract Objective: The antioxidant potential of vitamin E or tocopherols has been thought to play an important role in prostate cancer prevention, but the null results from the SELECT and PHS II trials testing the effect of α-tocopherol supplements shed doubt on prior beliefs. Therefore, to further understand the function of tocopherols and antioxidative stress pathways on prostate cancer etiology, we investigated associations of serum α- and γ-tocopherols with prostate cancer and whether these associations differed by polymorphisms of oxidative stress regulatory enzymes. Methods: In a nested case-control study in the Carotene and Retinol Efficacy Trial (CARET), cases were 628 men with incident prostate cancer and controls were 1,328 men without prostate cancer. Baseline serum α- and γ-tocopherol were measured by HPLC and genotyping for manganese superoxide dismutase (MnSOD) Ala-16Val, glutathione peroxidase 1 (GPX1) Pro200Leu, catalase (CAT) −262 C>T, and myeloperoxidase (MPO) G463A was completed using Sequonom's MALDI-TOF. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by multivariate logistic regression adjusted for age at enrollment, race, family history of prostate cancer, smoking, body mass index, serum cholesterol, total energy intake, alcohol consumption, and vitamin C intakes. Models for γ-tocopherol were additionally adjusted for α-tocopherol concentrations. Results: Current smokers in the 4th vs. 1st quartile of α-tocopherol (≥16 µg/mL) had a 40% lower risk of prostate cancer (OR=0.60, 95% CI=0.38-0.96). Men with γ-tocopherol in quartile 2 or above (≥1.8 µg/mL) had significant 34-41% lower risks of aggressive (stage III/IV or Gleason score ≥7) prostate cancer, compared to those in the first quartile. Analyses to test effect modification by the polymorphisms were restricted to current smokers and aggressive disease. When comparing α- and γ-tocopherol concentrations above vs. below the median, no effect modification between α- and γ-tocopherol and polymorphisms of MnSOD or GPX1 in relation to prostate cancer risk was observed. However, there was suggestive evidence that CAT and MPO modify the risk. The effect sizes for α-tocopherol associations were stronger among men with CAT C/C genotypes, associated with higher antioxidant activity (OR=0.25, 95% CI=0.12-0.52) than those with CAT C/T+T/T (OR=0.63, 95% CI=0.24-1.65). Similarly, γ-tocopherol concentrations above the median were also associated with 50% lower risk in men with CAT C/C (OR=0.50, 95% CI=0.27-0.92) but not in those with C/T+T/T genotypes (OR=1.11, 95% CI=0.45-2.73). Further, a significant statistical interaction was observed for -tocopherol associations between men with MPO G/A+A/A (OR=0.15, 95% CI=0.05-0.40) and those with MPO G/G genotypes, which result in higher oxidative stress (OR=0.65, 95% CI=0.33-1.26; p for interaction=0.006). Conclusion: Both elevated serum α- and γ-tocopherol concentrations are associated with reduced prostate cancer risk, particularly for aggressive disease in current smokers. The associations may be modified by polymorphisms in CAT and MPO, two important oxidative stress regulatory enzymes. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A80.