Carcinogenesis Advance Access originally published online on January 23, 2009
Carcinogenesis 2009 30(4):621-625; doi:10.1093/carcin/bgp028
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Nitric oxide synthase gene polymorphisms and prostate cancer risk
Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Boulevard, EPS 8118, Bethesda, MD, USA
1 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
2 Marshfield Clinic Research Foundation, Marshfield, WI, USA
3 Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
4 Section on Genomic Variation, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Gaithersburg, MD, USA
* To whom correspondence should be addressed. Tel: +1 301 594 7485; Fax: +1 301 402 1819; Email: 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 [inducible nitric oxide synthase (NOS); –2892T>C, Ex16 + 14C>T (S608L), IVS16 + 88T>G and IVS20 + 524G>A] and NOS3 [endothelial NOS; IVS1 – 762C>T, Ex7 – 43C>T (D258D), IVS7 – 26A>G, Ex8 – 63G>T (E298D) and IVS15 – 62G>T]. Prostate cancer cases (n = 1320) from the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial were frequency matched to controls (n = 1842), by age, race, time since initial screening and year of blood draw. An antioxidant score [range 3–12; low (3–7) versus 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 eight single-nucleotide polymorphisms (SNPs) (excluding NOS2A –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 (odds ratio = 1.24, 95% confidence interval = 1.00–1.54), whereas the IVS20 + 524 AG/GG was associated with decreased risk (0.77, 0.66–0.90). The NOS3 IVS7 – 26GG 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.
Abbreviations: CGEMS, Cancer Genetic Markers of Susceptibility; CI, confidence interval; NO, nitric oxide; NOS, nitric oxide synthase; OR, odds ratio; ROS, reactive oxygen species; SNP, single-nucleotide polymorphism
Received October 30, 2008; revised January 8, 2009; accepted January 17, 2009.