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Manganese Superoxide Dismutase Polymorphism, Prediagnostic Antioxidant Status, and Risk of Clinical Significant Prostate Cancer

¹ Channing Laboratory, Department of Medicine and ² Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School; ³ Lank Center for Genitourinary Oncology, Division of Solid Tumor Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute; ⁴ Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Massachusetts; ⁵ Massachusetts Veterans Epidemiology Research and Information Center, Veterans Administration Boston Healthcare System; and⁶ Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, U.S. Department of Health and Human Services, Bethesda, Maryland

Requests for reprints: Haojie Li, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Room 452, 181 Longwood Avenue, Boston, MA 02115. Phone: 617-525-2093; Fax: 617-525-2008; E-mail: haojie.li{at}channing.harvard.edu..

Oxidative stress may enhance prostatic carcinogenesis. A polymorphism [valine (V) alanine (A)] of manganese superoxide dismutase (MnSOD), the primary antioxidant enzyme in mitochondria, has been recently associated with prostate cancer. We examined the relationship between prostate cancer and the MnSOD polymorphism and its interactions with baseline plasma antioxidant levels (selenium, lycopene, and -tocopherol) and ß-carotene treatment among 567 cases and 764 controls nested in the prospective Physicians' Health Study. We found little overall association between MnSOD polymorphism and prostate cancer risk; however, this polymorphism significantly modified risk of prostate cancer associated with prediagnostic plasma antioxidants (P_interaction 0.05). Among men with the AA genotype, high selenium level (4th versus 1st quartile) was associated with a relative risk (RR) of 0.3 [95% confidence interval (CI), 0.2-0.7] for total prostate cancer; for clinically aggressive prostate cancer, the RR was 0.2 (95% CI, 0.1-0.5). In contrast, among men with the VV/VA genotype, the RRs were 0.6 (0.4-1.0) and 0.7 (0.4-1.2) for total and clinically aggressive prostate cancer. These patterns were similar for lycopene and -tocopherol and were particularly strong when these antioxidants and selenium were combined; men with the AA genotype had a 10-fold gradient in risk for aggressive prostate cancer across quartiles of antioxidant status. Men with AA genotype who were randomly assigned to ß-carotene treatment (versus placebo) had a RR of 0.6 (95% CI, 0.2-0.9; P_interaction = 0.03) for fatal prostate cancer, but no significant association was observed in men with the VV/VA genotype. Both endogenous and exogenous antioxidants play an important and interdependent role in preventing clinically significant prostate cancer.

Key Words: manganese superoxide dismutase • antioxidant • prostate cancer • risk • progression

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