Carcinogenesis Advance Access published online on January 23, 2009
Carcinogenesis, doi:10.1093/carcin/bgp028
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Nitric oxide synthase gene polymorphisms and prostate cancer risk
1 Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
2 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
3 Marshfield Clinic Research Foundation, Marshfield, WI
4 Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
5 Section on Genomic Variation, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Gaithersburg, MD
Correspondence to Kyoung-Mu Lee, M.P.H., Ph.D. Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, 6120 Executive Blvd. EPS 8118, Bethesda, MD 20892-7240, Tel: 301-594-7485/ Fax: 301-402-1819, E-mail: leekyou{at}mail.nih.gov
Nitric oxide (NO) induces cytotoxicity and angiogenesis, and may play a role in prostate carcinogenesis, potentially modulated by environmental exposures. We evaluated the association of prostate cancer with genetic polymorphisms in two genes related to intracellular NO: NOS2A [i-NOS; -2892T>C, Ex16+14C>T (S608L), IVS16+88T>G, and IVS20+524G>A] and NOS3 [e-NOS; IVS1-762C>T, Ex7-43C>T (D258D), IVS7-26A>G, Ex8-63G>T (E298D), and IVS15-62G>T]. Prostate cancer cases (n=1,320) from the screening arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial were frequency-matched to controls (n=1,842), by age, race, time since initial screening, and year of blood draw. An antioxidant score (range 3-12; low [3-7] vs. high [8-12]) was created by summing the quartile levels of vitamin E, β-carotene, and lycopene, which were coded from 1 to 4, respectively. The global tests for all 8 SNPs (excluding NOS2 -2892T>C, with low minor allele frequency) were statistically significant for prostate cancer (P=0.005), especially for aggressive cancer (Stage III-IV or Gleason score
7) (P=0.01). The NOS2A IVS16+88 GT/TT was associated with increased prostate caner risk (OR=1.24, 95% CI=1.00-1.54), whereas the IVS20+524 AG/GG was associated with decreased risk (0.77, 0.66-0.90). The NOS3 IVS7-26 GG was associated with increased prostate caner risk (1.33, 1.07-1.64). All these SNPs showed significant associations with aggressive cancer and not for non-aggressive cancer. In the evaluation of effect modification, the effect of the NOS2A IVS16+88 GT/TT on aggressive cancer was stronger among subjects with higher antioxidant intake (1.61, 1.18-2.19; Pinteraction=0.01). Our results suggest that NOS gene polymorphisms are genetic susceptibility factors for aggressive prostate cancer.
Key Words: NOS2A • NOS3 • prostate cancer • polymorphism • antioxidant vitamin
Received October 30, 2008; revised January 8, 2009; accepted January 17, 2009.