Plasma antioxidants, genetic variation in SOD2, CAT, GPX1, GPX4, and prostate cancer survival.

BACKGROUND Antioxidants may reduce risk of aggressive prostate cancer, and single-nucleotide polymorphisms (SNP) in antioxidant genes may modify this association. METHODS We used Cox proportional hazards regression to examine circulating prediagnostic α-tocopherol, γ-tocopherol, and lycopene; SNPs in SOD2 (n = 5), CAT (n = 6), GPX1 (n = 2), GPX4, (n = 3); and their interactions and risk of lethal prostate cancer among 2,439 men with nonmetastatic prostate cancer in the Health Professionals Follow-up Study and Physicians' Health Study. RESULTS We observed 223 events over a median follow-up of 10 years. Higher α-tocopherol levels were associated with lower risk of lethal prostate cancer [HR 3rd versus 1st quartile (Q): 0.51; 95% confidence interval (CI), 0.30-0.89; HR 4th versus 1st Q: 0.68; 95% CI, 0.41-1.13; P trend: 0.02]. Men homozygous for the less common allele (G) at rs3746165 in GPX4 had a 35% lower risk of lethal prostate cancer compared with men homozygous for the more common allele (A; HR, 0.65; 95% CI, 0.43-0.99). Among men homozygous for the less common allele in rs3746165, high γ-tocopherol levels were associated with a 3.5-fold increased risk of lethal prostate cancer (95% CI, 1.27-9.72; P value, 0.02; interaction P value, 0.01). CONCLUSIONS Among men with nonmetastatic prostate cancer, higher circulating prediagnostic α-tocopherol may be associated with lower risk of developing lethal disease. Variants in GPX4 may be associated with risk of lethal prostate cancer, and may modify the relation between γ-tocopherol and prostate cancer survival. IMPACT Circulating tocopherol levels and variants in GPX4 may affect prostate cancer progression. Cancer Epidemiol Biomarkers Prev; 23(6); 1037-46. ©2014 AACR.