Single-nucleotide polymorphisms within the antioxidant defence system and associations with aggressive prostate cancer

Prior studies have identified potential interaction effects between antioxidant nutrients and germline gene variants with regards to prostate cancer risk. In particular, the rs4880 gene variant in SOD2 (or MnSOD) has been linked to several cancers, including prostate, and appears to interact with antioxidant status and cancer risk. We identified additional variants in SOD2 and SOD1 that may affect risk of prostate cancer, or interact with selenium status to affect prostate cancer risk. OBJECTIVE To study the effects of oxidative stress on prostate cancer development as the exact biological mechanisms behind the relationship remain uncertain. We previously reported a statistically significant interaction between circulating selenium levels, variants in the superoxide dismutase 2 gene (SOD2; rs4880), and risk of developing prostate cancer and presenting with aggressive prostate cancer. PATIENTS AND METHODS We genotyped men with localized/regional prostate cancer for 26 loci across eight genes that are central to cellular antioxidant defence: glutathione peroxidase (GPX1, GPX4), peroxisome proliferator-activated receptor gamma coactivator (PPARGC1A, PPARGC1B), SOD1, SOD2, and SOD3, and 'X-ray repair complementing defective repair in Chinese hamster cell 1' (XRCC1). Among 489 men, we examined the relationships between genotypes, circulating selenium levels, and risk of presenting with aggressive prostate cancer at diagnosis, as defined by stage, grade and prostate-specific antigen (PSA) level (213 aggressive cases). RESULTS Two variants in SOD2 were significantly associated with the risk of aggressive prostate cancer (rs17884057, odds ratio 0.83, 95% confidence interval 0.70-0.99; and rs4816407, 1.27, 1.02-1.57); men with A alleles at rs2842958 in SOD2 had lower plasma selenium levels (median 116 vs 121.8 mu g/L, P = 0.03); and the association between plasma selenium levels and risk of aggressive prostate cancer was modified by SOD1 (rs10432782) and SOD2 (rs2758330). CONCLUSION While this study was cross-sectional and these associations might be due to chance, further research is warranted on the potential important role of antioxidant defence in prostate cancer.