Oxidative stress may be involved in prostatic carcinogenesis. Low intakes of antioxidants (e.g., lycopene, vitamin E, and selenium) are associated with increased prostate cancer (CaP) risk. Within mitochondria, manganese superoxide dismutase (MnSOD) plays a key role in protecting cells from oxidative damage. A polymorphism, incorporating either a Valine (V) or Alanine (A), in the mitochondrial targeting sequence of the MnSOD gene has recently been associated with risk of CaP. We prospectively assessed the association of MnSOD polymorphisms with CaP risk among 569 cases and 755 controls in a case-control study nested within the Physicians’ Health Study cohort. We also evaluated the potential interaction between MnSOD polymorphisms and baseline plasma antioxidant levels. An antioxidant score, ranging from 3 to12 (low to high), was estimated for each man based on prediagnostic quartile levels of plasma lycopene, α-tocopherol, and selenium among controls. Overall, MnSOD genotype with one or two A alleles was not associated with risk of total CaP (VA vs. VV, odds ratio, OR = 1.11, 95% confidence interval, CI = 0.85-1.46; AA vs. VV, OR = 1.12, 95% CI = 0.82-1.53) or when limited to advanced CaP. However, the associations between MnSOD polymorphisms and CaP risk were significantly modified by baseline plasma antioxidant level (P for interaction ≤0.05). Among men with the AA genotype, greater plasma antioxidant levels were associated with reduced risk of total and advanced CaP (P for trend ≤0.01); whereas no such patterns were found for men with the VV or VA genotype. Using men with low plasma antioxidant levels (antioxidant score = 3-5) who had one or two V alleles as the common reference group, men with low plasma antioxidant levels who were homozygous for the A allele had significant increased risks of total (OR = 2.92, 95% CI = 1.39-6.12) and advanced (OR = 3.78, 95% CI = 1.55-9.20) CaP. These data suggest that men with the MnSOD AA genotype and low antioxidant levels are at especially increased risk of CaP; thus, antioxidants such as lycopene, α-tocopherol, and selenium may be particularly beneficial in reducing CaP risk for these men.
[Proc Amer Assoc Cancer Res, Volume 45, 2004]