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Cancer Epidemiology Biomarkers & Prevention 16, 1581, August 1, 2007. Published Online First July 23, 2007;
doi: 10.1158/1055-9965.EPI-07-0160
© 2007 American Association for Cancer Research
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Functional Variant of Manganese Superoxide Dismutase (SOD2 V16A) Polymorphism Is Associated with Prostate Cancer Risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Study

Daehee Kang1,2, Kyoung-Mu Lee2, Sue Kyung Park1, Sonja I. Berndt2, Ulrike Peters6, Douglas Reding7, Nilanjan Chatterjee3, Robert Welch4,8, Stephen Chanock5, Wen-Yi Huang1 and Richard B. Hayes2

1 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea; 2 Occupational and Environmental Epidemiology Branch, 3 Biostatistics Branch, and 4 Core Genotyping Facility, Division of Cancer Epidemiology and Genetics, National Cancer Institute; 5 Section on Genomic Variation, Pediatric Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland; 6 Fred Hutchinson Cancer Research Center, Seattle, Washington; 7 Marshfield Clinic Research Foundation, Marshfield, Wisconsin; and 8 Advanced Technology Program, SAIC Frederick, Inc., NCI-Frederick, Frederick, Maryland

Requests for reprints: Daehee Kang, Department of Preventive Medicine, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul 110-799, Korea. Phone: 82-2-740-8326; Fax: 82-2-747-4830. E-mail: dhkang{at}snu.ac.kr


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Superoxide dismutase (SOD) plays a key role in the detoxification of superoxide free radicals. We evaluated the association of prostate cancer with genetic polymorphisms in SOD1 (CuZn-SOD; IVS3-251A>G), SOD2 [MnSOD; Ex2+24T>C (V16A)], and SOD3 (EC-SOD; IVS1+186C>T, Ex3-631C>G, Ex3-516C>T, and Ex3-489C>T), the three main isoforms of SOD. Prostate cancer cases (n = 1,320) from the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial were frequency matched to nondiseased controls (n = 1,842) by age, race, time since initial screening, and year of blood draw. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI); stratified analysis by the level of antioxidative vitamins was also conducted. The higher activity Ala variant at SOD2 Ex2+24T>C (V16A), which has been hypothesized to suppress prostate carcinogenesis, was associated with elevation of prostate cancer risk in Caucasians (Val/Ala versus Val/Val: OR, 1.17; 95% CI, 0.97-1.42; Ala/Ala versus Val/Val: OR, 1.28; 95% CI, 1.03-1.60; Ptrend = 0.03). Stratification by quartiles of dietary and supplemental vitamin E intake (IU/d) showed risks of prostate cancer tended to be increased among SOD2 Ala allele carriers, except at the highest quartile of vitamin E intake (>222; Pinteraction = 0.06, Q1-Q3 versus Q4). The association between Ala allele and prostate cancer risk among those with lower intake of vitamin E (≤222) was stronger for smokers (OR, 1.44; 95% CI, 1.10-1.90). No significant association with prostate cancer was observed for polymorphic variants in SOD3 or SOD1. These results suggest that the Ala variant of SOD2 is associated with moderately increased risk of prostate cancer, particularly among men with lower intakes of dietary and supplemental vitamin E. (Cancer Epidemiol Biomarkers Prev 2007;16(8):1581–6)


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Superoxide dismutases (SODs) are a family of enzymes responsible for the detoxification of superoxide free radicals. Reactive oxygen species produced during chronic inflammation and other mechanisms involving oxidative stress may play an important role in prostate carcinogenesis. SODs are expressed in many human organs, including the prostate (1, 2). Thus, SOD genes are good candidates to evaluate genetic susceptibility for prostate cancer.

Among the three isoforms of SOD (SOD1, CuZn-SOD; SOD2, MnSOD; and SOD3, EC-SOD), SOD2 plays an important role as a primary mitochondria antioxidant enzyme and suppresses the growth of prostate cancer cells (1, 3-5). In this gene, several polymorphisms have been found, including Ex2+24T>C (V16A), which has been widely evaluated for association with various cancers, including prostate cancer (6-13).

The Ala variant at a mitochondrial targeting sequence of SOD2 allows more efficient SOD2 uptake into the mitochondrial matrix and generates more active SOD2 compared with the Val variant, suggesting that Ala/Ala homozygous subjects may have higher SOD2 activity (14-16). Contrary to this, two small epidemiologic studies on the association between SOD2 polymorphism and prostate cancer showed the Ala variant associated with increased risk of prostate cancer in poorly differentiated prostate cancer cases (17) or men with lower antioxidant intakes (18).

Two other isoforms of SOD with Cu and Zn in their catalytic center (CuZn SODs) are localized in intracellular cytoplasmic compartments (SOD1) and extracellular elements (SOD3), respectively. SOD1 polymorphisms have not been found to be associated with breast cancer risk (9, 10). SOD3 Ex3-631G (231G) allele has been reported to increase the serum level of SOD3 (19, 20); however, it has not been evaluated for the association with cancer risk.

We evaluated the association of prostate cancer with genetic polymorphisms in the three main isoforms of SOD, and explored potential risk modification by intake of antioxidants, in a large case-control study nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Setting
This nested case-control study was conducted within the screening arm of the PLCO Trial, which was designed to evaluate the effectiveness of screening intervention for prostate, lung, colorectal, and ovarian cancer and to investigate etiologic factors and early markers of cancer (21, 22). Participants in the PLCO Trial, ages 55 to 74 years, were recruited at 10 centers in the United States (Birmingham, Alabama; Denver, Colorado; Detroit, Michigan; Honolulu, Hawaii; Marshfield, Wisconsin; Minneapolis, Minnesota; Pittsburgh, Pennsylvania; Salt Lake City, Utah; St. Louis, Missouri; and Washington, District of Columbia) between September 1993 and June 2001.

Men randomized to the screening arm of the trial were offered prostate cancer screening by serum prostate-specific antigen, at entry and annually for 5 years, and digital rectal examination, at entry and annually for 3 years. If the prostate-specific antigen test result was ≥4 ng/mL or digital rectal examination was suspicious for prostate cancer, men were referred to their medical care providers for prostate cancer diagnostic evaluation. In addition, annual follow-up for recent diagnosis of cancer was carried out by mailed questionnaires and through periodic search of the National Death Index. All medical and pathologic records related to diagnosis were obtained for those who might be prostate cancer case. Furthermore, death certificates and supporting medical/pathologic records were collected. All data related to diagnosis of cancer and death were abstracted by trained medical record specialists. Blood samples were drawn from screening arm participants at each of the screening visits. Participants provided written informed consent. The trial was approved by the institutional review boards of the U.S. National Cancer Institute and the 10 study centers.

Study Population
Men randomized to the screening arm were eligible for this nested case-control study if they had at least one valid screening for prostate cancer (prostate-specific antigen and/or digital rectal examination) before October 1, 2001 (the censor date for this analysis), completed the baseline risk factor questionnaire, provided a blood sample, and signed the informed consent for studies on cancer (n = 26,975). All men were followed from their initial valid prostate cancer screen (prostate-specific antigen and/or digital rectal examination) to first occurrence of prostate cancer, loss to follow-up, death, or October 1, 2001, whichever came first. Cases were defined as men diagnosed with adenocarcinoma of the prostate. We excluded all cases that were diagnosed within the first year after the initial prostate cancer screen (prostate-specific antigen and/or digital rectal examination). Staging procedures corresponded to the tumor-node-metastasis stage of disease classification. Cases were classified as clinically significant (n = 562) if they were stages III or IV or Gleason score ≥7. The eligible group included 1,320 prostate cancer cases (1,213 non-Hispanic Caucasians and 107 African-Americans). For comparison, we selected 1,842 controls (1,433 non-Hispanic Caucasians and 409 African-Americans) using risk-set sampling frequency matched to cases by age (55-59, 60-64, 65-69, and 70-74), ethnicity (case-control ratio of 1.2:1 for Caucasians and 4:1 for African-Americans), time since initial screening (1-year time windows), and year of blood draw (1-year calendar periods; ref. 23).

Assessment of Questionnaire-Based Covariates
At enrollment, all participants were asked to complete a questionnaire, including age, ethnicity, education, occupation, current and past smoking behavior, history of cancer and other diseases, use of selected drugs, recent history of screening exams, and prostate-related health factors. Usual dietary intake over the 12 months before enrollment was assessed with a 137-item food frequency questionnaire, including an additional 14 questions about intake of vitamin and mineral supplements and 10 questions on meat cooking practice (PLCO Cancer Screening Trial).8 Daily dietary nutrient intake was calculated by multiplying the daily frequency of each consumed food item by the nutrient value of the sex-specific portion size (24) using the nutrient database from the U.S. Department of Agriculture (25). Total vitamin and mineral intake was calculated by adding dietary and supplemental intake.

Serum Selenium Analysis
Serum selenium concentrations were determined using an inductively coupled plasma mass spectrometry method (26). Serum for selenium analysis was available for 724 (92.6%) cases and 879 (94.7%) controls. Cases and their matched controls were analyzed in the same batch. Quality control samples were monitored throughout the analysis. The coefficient of variation estimated from 181 duplicates was 9.4%.

SOD1/SOD2/SOD3 Genotyping
Genotype analysis was done at the National Cancer Institute Core Genotyping Facility.9 All Taqman assays (Applied Biosystems, Inc.) were optimized on the ABI 7900 HT detection system with 100% concordance with sequence analysis of 102 individuals listed on the SNP500Cancer Web site (27).10 Six SNPs in three genes were genotyped: SOD1 IVS3-251A>G (rs2070424), SOD2 Ex2+24T>C (V16A; rs1799725), and SOD3 IVS1+186C>T (rs699473), Ex3-631C>G (R231G; rs1799895), Ex3-516C>T (rs2853796), and Ex3-489C>T (rs2855262). These SNPs were selected based on functional significance, the results of previous association studies with cancer, and minor allele frequency criteria (>5%; refs. 6-8, 11, 12, 14-16, 19, 20, 27).

The Hardy-Weinberg equilibrium for each SNP was tested with Pearson {chi}2 or exact test if any of the cell counts was small. The genotype distributions of SOD3 Ex3-516C>T and Ex3-489C>T diverted from Hardy-Weinberg equilibrium in African-American controls (P = 0.02 and 0.003, respectively). However, no deviations from Hardy-Weinberg equilibrium were observed in the Caucasian controls (P > 0.05), and the concordance rates for quality control samples (n = 253), which were replicates from 48 study subjects interspersed throughout study samples, were >99% for the two assays.

Statistical Analysis
We used conditional logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (95% CI) of prostate cancer. All P values are two sided. The analyses were conditioned on the matching factors (age, time since initial screening, and year of blood draw). Genotype data were analyzed with the homozygote of the common allele as the reference group. Variants of homozygotes and heterozygotes were combined to evaluate the dominant effect. For each SNP, trend tests were conducted by assigning the ordinal values 1, 2, and 3 to homozygous wild-type, heterozygous, and homozygous variant genotypes, respectively, and by adding these scores as a continuous variable in logistic regression model.

To explore potential effect modification by antioxidants intake, we did stratified analyses and evaluated multiplicative interaction by creating product terms. Statistical significance of multiplicative interactions was evaluated by comparison of the log likelihood statistics between the main effect model and the joint effects model.

Haplotype analyses for SOD3 were conducted using the haplo.stats package11 in the R program (version 2.2.1),12 which uses an expectation-maximization algorithm to estimate haplotypes from genotype data (28). The Ex3-631C>G (R231G) polymorphism was excluded because of low variant allele frequency (G: <1.5%). Haplotypes were estimated separately for Caucasians and African-Americans excluding subjects missing all the genotype data. Haplotypes were estimated for persons missing one to two genotypes using an extension of the expectation-maximization algorithm. Each haplotype pair was weighted by its probability, rather than assigning a most likely haplotype to an individual, and the generalized linear model implemented in haplo.stats was used to estimate the effect of individual haplotypes by fitting an additive model, adjusting for age, time to diagnosis, and year of blood draw. The overall difference in haplotype frequencies between cases and controls was assessed by race using a global score test, adjusting for age, time to diagnosis, and year of blood draw.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The characteristics of 1,320 cases and 1,842 controls are shown in Table 1 . Briefly, age distribution was similar between cases and controls: mean age was 64.8 (±5.0) for cases and 64.5 (±5.0) for controls. The proportion of African-Americans was higher in controls than in cases due to oversampling (4:1) of African-American controls. Mean body mass index was marginally different and percentages with family history of prostate cancer were significantly different (P < 0.001) between cases and controls; smoking and alcohol consumption were not associated with case-control status.


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  		Table 1. Selected characteristics for 1,320 cases and 1,842 controls

 
The Ala variant of SOD2 Ex2+24T>C (V16A) was associated with increased risk of prostate cancer in Caucasians (Val/Ala versus Val/Val: OR, 1.17; 95% CI, 0.97-1.42; Ala/Ala versus Val/Val: OR, 1.28; 95% CI, 1.03-1.60; Ptrend = 0.03); number of African-American carriers with the Ala/Ala genotype was small, making inferences difficult. No other significant associations were noted in Caucasians or African-Americans (Table 2 ). When stratified by the level of dietary and supplemental intake, significant trends were noted in men with dietary and supplemental intake of vitamin E below the median (31.2 IU/d; Val/Ala versus Val/Val: OR, 1.58; 95% CI, 1.17-2.12; Ala/Ala versus Val/Val: OR, 1.56; 95% CI, 1.11-2.20; Ptrend = 0.01; Table 3 ). Further stratification by quartiles of dietary and supplemental vitamin E intake (Q1 = 13.3 IU/d, Q2 = 31.2 IU/d, and Q3 = 222 IU/d) showed risks of prostate cancer tended to be increased among SOD2 Ala allele carriers, except at the highest quartile of vitamin E intake (>222 IU/d; Pinteraction = 0.06, Q1-Q3 versus Q4; Fig. 1 ). Risks tended also to follow this pattern for clinically significant disease (stages III/IV or Gleason score ≥7; Pinteraction = 0.02); similar results were observed when advanced stage and Gleason score were evaluated separately. Among those with lower intake of vitamin E (Q1-Q3: <222 IU/d), the association between Ala-containing genotypes and prostate cancer was stronger for smokers (OR, 1.44; 95% CI, 1.10-1.90) compared with nonsmokers (OR, 1.17; 95% CI, 0.78-1.75; Table 4 ). Interaction test result for SOD2 genotype and vitamin E was marginally significant among smokers (Pinteraction = 0.08) and not significant among nonsmokers (Pinteraction = 0.44). SOD2 Ala–associated risks did not vary significantly with respect to dietary intake of ß-carotene or lycopene or serum selenium level.


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  		Table 2. The distributions of SOD1, SOD2, and SOD3 genotypes and prostate cancer risk in the PLCO Trial

 

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  		Table 3. SOD2 genotypes [Ex2+24T>C (V16A)] and the risk of prostate cancer in Caucasian: stratified analysis by dietary intake from questionnaire data (vitamin E, ß-carotene, and lycopene) and serum measurement (selenium)

 

Figure 1
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  		Figure 1. SOD2 genotypes [Ex2+24T>C (V16A)] and risk of prostate cancer in Caucasians by quartiles of vitamin E intake (IU/d). Stratification by quartiles of dietary and supplemental vitamin E intakes showed that increased risk of prostate cancer among SOD2 Ala allele carriers disappeared only at the highest quartile (>222 IU/d). A marginal significance was observed for product term [i.e., (Q1 + Q2 + Q3 versus Q4) x (Val/Ala + Ala/Ala versus Val/Val)], showing the interaction between SOD2 Ala allele and vitamin E intake on prostate cancer risk (Pinteraction = 0.06). The patterns of risk were similar for clinically significant disease (stages III/IV or Gleason score ≥7; Pinteraction = 0.02); similar results were observed when advanced stage and Gleason score were evaluated separately.

 

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  		Table 4. Smoking status and interactive effect between SOD2 genotype [Ex2+24T>C (V16A)] and vitamin E intake (IU/d) on the prostate cancer risk

 
No significant associations with prostate cancer were observed for polymorphic variants in SOD3 or SOD1 (Table 2). Haplotype frequencies of SOD3 were also not significantly different between cases and controls in either Caucasians or African-Americans (Pomnibus = 0.60 and 0.20, respectively; data not shown).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our results suggest that the Ala variant of SOD2 Ex2+24T>C (V16A) was associated with a moderately increased risk of prostate cancer in Caucasians, particularly among men with lower intake of dietary and supplemental vitamin E. No significant associations with prostate cancer were observed for polymorphic variants in SOD3 or SOD1. Similar to our study, men homozygous for the SOD2 Ala allele had a 70% increase in risk over men homozygous for the Val allele in Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study conducted for 197 cases and 190 controls (17), whereas no overall association was found in the Physician's Health Study conducted for 567 cases and 764 controls (18).

In our study, the elevation of prostate cancer risk associated with the SOD2 Ala allele was observed particularly for smokers with lower vitamin E intake. We previously reported, in the PLCO Trial, that greater vitamin E intake was associated with lower prostate cancer risk, only in smokers (29), as also reported by several other groups (30, 31). The current report suggests that SOD2 may be involved in this relationship. Similar to our findings, others reported the homozygous Ala genotype associated with a 2.5-fold increased risk for prostate cancer among men with low antioxidant status (18) and with premenopausal breast cancer in women with low dietary antioxidant intake (6, 8).

SOD2 plays a pivotal role in protecting cells from reactive oxygen species–induced oxidative damage and is a known tumor suppressor in prostate cancer cells (1, 3-5). The Ala variant of SOD2 allows more efficient SOD2 import into the mitochondrial matrix and generates more active SOD2 compared with the Val variant (14-16). Thus, it is hypothesized that the higher activity (Ala) variant suppresses prostate carcinogenesis; however, our results and previous association studies on prostate cancer contradict this hypothesis (17, 18).

Alternatively, increased levels of hydrogen peroxide (H2O2) are found in prostate cancer cells (32) and have been related to overexpression of SOD2 (33). H2O2 is a major intracellular oxidant involved in H2O2-induced DNA damage in prostate cancer (34) and in induction of genes for prostate carcinogenesis (33, 35). Thus, the SOD2 Ala allele might increase the risk of prostate cancer by producing excessive H2O2.

Our study was limited in that only one SNP was evaluated in SOD1 or SOD2 and the haplotype analysis for SOD3 was not comprehensive. However, SOD1 is a small gene and alleles in SOD1 show strong linkage disequilibrium in Caucasians (9). In addition, SOD2 Ex2+24T>C (V16A) itself is located in mitochondrial targeting sequence and has experimental evidences of functional significance in vivo (16) as well and in vitro (14, 15). Another limitation is insufficient statistical power in subgroup analysis for African-Americans. Although we presented data for African-Americans, sample size was small and conclusions for this group are limited.

Our study, the largest to evaluate the role of genetic polymorphisms in SOD genes and prostate cancer risk, indicates that the Ala variant of SOD2 Ex2+24T>C (V16A) is associated with increased risk for prostate cancer, particularly among smokers and men with lower intake of dietary and supplemental vitamin E.


   Acknowledgments
 
We thank Drs. Christine Berg and Philip Prorok (Division of Cancer Prevention, National Cancer Institute), the Screening Center investigators and staff of the PLCO Cancer Screening Trial, Tom Riley and staff (Information Management Services, Inc.), Barbara O'Brien and staff (Westat, Inc.), and Drs. Bill Kopp and Wen Shao and staff (Science Applications International Corporation-Frederick) for their contributions to making this study possible.


   Footnotes
 
Grant support: National Cancer Institute, NIH, contract N01-CO-12400.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does not mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

8 Available at http://www.parplco.org (access can be requested by contacting parplcohelpdesk{at}westat.com). Back

9 http://cgf.nci.nih.gov Back

10 http://snp500cancer.nci.nih.gov Back

11 http://mayoresearch.mayo.edu/mayo/research/biostat/schaid.cfm Back

12 http://www.r-project.org Back

Received 2/20/07; revised 5/ 2/07; accepted 6/ 1/07.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Li N, Oberley TD, Oberley LW, Zhong W. Overexpression of manganese superoxide dismutase in DU145 human prostate carcinoma cells has multiple effects on cell phenotype. Prostate 1998;35:221–33.[CrossRef][Medline]
  2. Bostwick DG, Alexander EE, Singh R, et al. Antioxidant enzyme expression and reactive oxygen species damage in prostatic intraepithelial neoplasia and cancer. Cancer 2000;89:123–34.[CrossRef][Medline]
  3. Plymate SR, Haugk KH, Sprenger CC, et al. Increased manganese superoxide dismutase (SOD-2) is part of the mechanism for prostate tumor suppression by Mac25/insulin-like growth factor binding-protein-related protein-1. Oncogene 2003;22:1024–34.[CrossRef][Medline]
  4. Duan H, Zhang HJ, Yang JQ, Oberley LW, Futscher BW, Domann FE. MnSOD up-regulates maspin tumor suppressor gene expression in human breast and prostate cancer cells. Antioxid Redox Signal 2003;5:677–88.[CrossRef][Medline]
  5. Venkataraman S, Jiang X, Weydert C, et al. Manganese superoxide dismutase overexpression inhibits the growth of androgen-independent prostate cancer cells. Oncogene 2005;24:77–89.[CrossRef][Medline]
  6. Ambrosone CB, Freudenheim JL, Thompson PA, et al. Manganese superoxide dismutase (MnSOD) genetic polymorphisms, dietary antioxidants, and risk of breast cancer. Cancer Res 1999;59:602–6.[Abstract/Free Full Text]
  7. Mitrunen K, Sillanpaa P, Kataja V, et al. Association between manganese superoxide dismutase (MnSOD) gene polymorphism and breast cancer risk. Carcinogenesis 2001;22:827–9.[Abstract/Free Full Text]
  8. Cai Q, Shu XO, Wen W, et al. Genetic polymorphism in the manganese superoxide dismutate gene, antioxidant intake, and breast cancer risk: results from the Shanghai Breast Cancer Study. Breast Cancer Res 2004;6:R647–55.[CrossRef][Medline]
  9. Cebrian A, Pharoah PD, Ahmed S, et al. Tagging single-nucleotide polymorphisms in antioxidant defense enzymes and susceptibility to breast cancer. Cancer Res 2006;66:1225–33.[Abstract/Free Full Text]
  10. Oestergaard MZ, Tyrer J, Cebrian A, et al. Interactions between genes involved in the antioxidant defence system and breast cancer risk. Br J Cancer 2006;95:525–31.[Medline]
  11. Hung RJ, Boffetta P, Brennan P, et al. Genetic polymorphisms of MPO, COMT, MnSOD, NQO1, interactions with environmental exposures and bladder cancer risk. Carcinogenesis 2004;25:973–8.[Abstract/Free Full Text]
  12. Martin RC, Lan Q, Hughes K, et al. No apparent association between genetic polymorphisms (–102 C>T) and (–9 T>C) in the human manganese superoxide dismutase gene and gastric cancer. J Surg Res 2005;124:92–7.[CrossRef][Medline]
  13. Koistinen P, Ruuska S, Saily M, et al. An association between manganese superoxide dismutase polymorphism and outcome of chemotherapy in acute myeloid leukemia. Haematologica 2006;91:829–32.[Abstract/Free Full Text]
  14. Hiroi S, Harada H, Nishi H, Satoh M, Nagai R, Kimura A. Polymorphisms in the SDO2 and HLA-DRB1 genes are associated with nonfamilial idiopathic dilated cardiomyopathy in Japanese. Biochem Biophys Res Commun 1999;261:332–9.[CrossRef][Medline]
  15. Sutton A, Khoury H, Prip-Buus C, Cepanec C, Pessayre D, Degoul F. The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria. Pharmacogenetics 2003;13:145–57.[CrossRef][Medline]
  16. Sutton A, Imbert A, Igoudjil A, et al. The manganese superoxide dismutase Ala16Val dimorphism modulates both mitochondrial import and mRNA stability. Pharmacogenetics 2005;15:311–9.
  17. Woodson K, Tangrea JA, Lehman TA, et al. Manganese superoxide dismutase (MnSOD) polymorphism, {alpha}-tocopherol supplementation and prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (Finland). Cancer Causes Control 2003;14:513–8.[CrossRef][Medline]
  18. Li H, Kantoff PW, Giovannucci E, et al. Manganese superoxide dismutase polymorphism, prediagnostic antioxidant status, and risk of clinical significant prostate cancer. Cancer Res 2005;65:2498–504.[Abstract/Free Full Text]
  19. Folz RJ, Peno-Green L, Crapo JD. Identification of a homozygous missense mutation (Arg to Gly) in the critical binding region of the human EC-SOD gene (SOD3) and its association with dramatically increased serum enzyme levels. Hum Mol Genet 1994;3:2251–4.[Free Full Text]
  20. Sandstrom J, Nilsson P, Karlsson K, Marklund SL. 10-fold increase in human plasma extracellular superoxide dismutase content caused by a mutation in heparin-binding domain. J Biol Chem 1994;269:19163–6.[Abstract/Free Full Text]
  21. Gohagan JK, Prorok PC, Hayes RB, Kramer BS. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial of the National Cancer Institute: history, organization, and status. Control Clin Trials 2000;21:251–72S.
  22. Hayes RB, Sigurdson A, Moore L, et al. Methods for etiologic and early marker investigations in the PLCO trial. Mutat Res 2005;592:147–54.[Medline]
  23. Rothman KJ, Greeenland S. Modern epidemiology. Philadelphia (PA): Lippincott Raven; 1998.
  24. Subar AF, Midthune D, Kulldorff M, et al. Evaluation of alternative approaches to assign nutrient values to food groups in food frequency questionnaires. Am J Epidemiol 2000;152:279–86.[Abstract/Free Full Text]
  25. Tippett KS, Cypel YS. Design and operation: the continuing survey of food intakes by individuals and the diet and health knowledge survey, 1994-96. In: Continuing survey of food intakes by individuals 1994-96, Nationwide Food Surveys Report No. 96-1. U.S. Department of Agriculture, Agricultural Research Service; 1997.
  26. Stürup S, Hayes RB, Peters U. Development and application of a simple routine method for the determination of selenium in serum by octopole reaction system ICPMS. Anal Bioanal Chem 2005;381:686–94.[CrossRef][Medline]
  27. Packer BR, Yeager M, Burdett L, et al. SNP500Cancer: a public resource for sequence validation, assay development, and frequency analysis for genetic variation in candidate genes. Nucleic Acids Res 2006;34:D617–21.[Abstract/Free Full Text]
  28. Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA. Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 2002;70:425–34.[CrossRef][Medline]
  29. Kirsh VA, Hayes RB, Mayne ST, et al. Supplemental and dietary vitamin E, ß-carotene, and vitamin C intakes and prostate cancer risk. J Natl Cancer Inst 2006;98:245–54.[Abstract/Free Full Text]
  30. Chan JM, Stampfer MJ, Ma J, Rimm EB, Willett WC, Giovannucci EL. Supplemental vitamin E intake and prostate cancer risk in a large cohort of men in the United States. Cancer Epidemiol Biomarkers Prev 1999;8:893–9.[Abstract/Free Full Text]
  31. Rodriguez C, Jacobs EJ, Mondul AM, Calle EE, McCullough ML, Thun MJ. Vitamin E supplements and risk of prostate cancer in U.S. men. Cancer Epidemiol Biomarkers Prev 2004;13:378–82.[Abstract/Free Full Text]
  32. Lim SD, Sun C, Lambeth JD, Marshall F, et al. Increased Nox1 and hydrogen peroxide in prostate cancer. Prostate 2005;62:2000–7.
  33. Wenk J, Brnneisen P, Wlaschek M, et al. Stable overexpression of manganese superoxide dismutase in mitochondria identifies hydrogen peroxide as a major oxidant in the AP-1-mediated induction of matrix-degrading metalloprotease-1. J Biol Chem 1999;274:25869–76.[Abstract/Free Full Text]
  34. Lockett KL, Hall MC, Clark PE, et al. DNA damage levels in prostate cancer cases and controls. Carcinogenesis 2006;27:1187–93.[Abstract/Free Full Text]
  35. Polytarchou C, Hatziapostolou M, Papadimitriou E. Hydrogen peroxide stimulates proliferation and migration of human prostate cancer cells through activation of activator protein-1 and up-regulation of the heparin affin regulatory peptide gene. J Biol Chem 2005;49:40428–35.



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Clin. Cancer Res., June 15, 2009; 15(12): 4165 - 4173.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
K.-M. Lee, D. Kang, S. K. Park, S. I. Berndt, D. Reding, N. Chatterjee, S. Chanock, W.-Y. Huang, and R. B. Hayes
Nitric oxide synthase gene polymorphisms and prostate cancer risk
Carcinogenesis, April 1, 2009; 30(4): 621 - 625.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
A. Bag and N. Bag
Target Sequence Polymorphism of Human Manganese Superoxide Dismutase Gene and Its Association with Cancer Risk: A Review
Cancer Epidemiol. Biomarkers Prev., December 1, 2008; 17(12): 3298 - 3305.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
B. Mikhak, D. J. Hunter, D. Spiegelman, E. A. Platz, K. Wu, J. W. Erdman Jr, and E. Giovannucci
Manganese superoxide dismutase (MnSOD) gene polymorphism, interactions with carotenoid levels and prostate cancer risk
Carcinogenesis, December 1, 2008; 29(12): 2335 - 2340.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
W.-Y. Huang, R. Hayes, R. Pfeiffer, R. P. Viscidi, F. K. Lee, Y. F. Wang, D. Reding, D. Whitby, J. R. Papp, and C. S. Rabkin
Sexually Transmissible Infections and Prostate Cancer Risk
Cancer Epidemiol. Biomarkers Prev., September 1, 2008; 17(9): 2374 - 2381.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
J.-Y. Choi, M. L. Neuhouser, M. J. Barnett, C.-C. Hong, A. R. Kristal, M. D. Thornquist, I. B. King, G. E. Goodman, and C. B. Ambrosone
Iron intake, oxidative stress-related genes (MnSOD and MPO) and prostate cancer risk in CARET cohort
Carcinogenesis, May 1, 2008; 29(5): 964 - 970.
[Abstract] [Full Text] [PDF]

Home page
 Neuro OncolHome page
P. Rajaraman, A. Hutchinson, N. Rothman, P. M. Black, H. A. Fine, J. S. Loeffler, R. G. Selker, W. R. Shapiro, M. S. Linet, and P. D. Inskip
Oxidative response gene polymorphisms and risk of adult brain tumors
Neuro-oncol, January 1, 2008; 10(5): 709 - 715.
[Abstract] [Full Text] [PDF]

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