Manganese superoxide dismutase (MnSOD) gene polymorphism, interactions with carotenoid levels and prostate cancer risk

Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
Carcinogenesis (Impact Factor: 5.33). 10/2008; 29(12):2335-40. DOI: 10.1093/carcin/bgn212
Source: PubMed


The manganese superoxide dismutase (MnSOD) gene encodes an antioxidant enzyme (SOD2) that may protect cells from oxidative damage. The MnSOD allele with Val as amino acid 16 encodes a protein that has 30-40% lower activity compared with the MnSOD Ala variant, hence possibly increasing susceptibility to oxidative stress. On the other hand, some epidemiologic studies suggest that the Ala allele is associated with a higher risk of cancer, including prostate cancer.
We conducted a nested case-control study in the Health Professionals Follow-up Study with 612 incident prostate cancer cases and 612 matched controls to investigate the role of the MnSOD gene Ala16Val polymorphism and its joint association with plasma carotenoid concentrations in relation to risk of total prostate cancer and aggressive prostate cancer (advanced stage or Gleason sum > or =7).
The allele frequencies in the controls were 49.8% for Ala and 50.2% for Val. No association was found between the MnSOD genotype and risk of total and aggressive prostate cancer. Furthermore, no statistically significant interaction was observed between the MnSOD genotype and any of the plasma carotenoids in relation to risk of total and aggressive prostate cancer. In analyses in which we combined data from plasma and dietary carotenoids and created a quintile score to reflect long-term carotenoid status, a 3-fold [95% confidence interval: 1.37-7.02] increased risk of aggressive prostate cancer was observed among men with the Ala/Ala genotype in the presence of low long-term lycopene status (P-value, test for interaction = 0.02) as compared with men with the Ala/Val+Val/Val genotypes with low long-term lycopene status.
In this cohort of mainly white men, the MnSOD gene Ala16Val polymorphism was not associated with total or aggressive prostate cancer risk. However, men with the MnSOD Ala/Ala genotype who had low long-term lycopene status had a higher risk of aggressive prostate cancer compared with individuals with the other genotypes. These results are consistent with findings from earlier studies that reported when antioxidant status is low, the MnSOD Ala/Ala genotype may be associated with an increased risk of aggressive prostate cancer.

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    • "The association of Ala/Ala genotype and aggressive behavior of tumor has also been studied previously. Mikhak et al. reported that Ala/Ala allele was significantly associated with more aggressive form of prostate cancer in men with low lycopene status [40]. Similarly, Woodson et al. also noted that Ala/Ala genotype was associated with high grade tumor in prostate cancer patients [41]. "
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    ABSTRACT: Objectives . The aim of this study was to investigate the association of RCC and Ala16Val polymorphism in Turkish patients with RCC. Materials and Methods . A total of 41 patients with RCC who underwent radical or partial nephrectomy in our clinic and 50 healthy volunteers living in the same geographic area were included in this study. DNA samples from serum of RCC patients and controls were genotyped for MnSOD polymorphism analysis. Genotype ratios and allele frequencies were compared between two groups and odd ratios with 95% confidence intervals were calculated statistically. A P value of
    Advances in Urology 01/2014; 2014(1):932481. DOI:10.1155/2014/932481
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    • "P = 0.02, confidence interval: 1.37–7.02) (Mikhak et al., 2008 "
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    ABSTRACT: Reactive oxygen species (ROS) are generated during mitochondrial oxidative metabolism. Accumulation of ROS without an effective antioxidant response can lead to oxidative stress, resulting in macromolecular damage that is implicated in the etiology of various diseases including cancer. ROS detoxification is regulated by various antioxidant proteins, specifically manganese superoxide dismutase (MnSOD), which catalyzes the conversion of superoxide into H2O2, and the subsequent conversion of H2O2 into water is catalyzed by glutathione peroxidase 1 (GPx-1). In vitro and in vivo evidence supports a conflicting role of MnSOD in tumor biology and indicates that an interaction between MnSOD and GPx-1 can modulate the impact of MnSOD on carcinogenesis. Additional support for this idea is provided by epidemiological data indicating that an association exists between polymorphisms in the MnSOD and GPx-1 genes and cancer risk, such that individuals who carry both at-risk polymorphisms are at a higher risk of several types of cancer. Future studies examining the impact of these 2 antioxidants on tumor biology need to consider the interplay between the 2 genes.
    Turkish Journal of Biology 01/2014; 38(6):748-753. DOI:10.3906/biy-1406-55 · 1.34 Impact Factor
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    • "In this meta-analysis, we have identified 22 eligible studies from 2003 to 2009, including 8,181 cancer cases and 11,844 controls using our inclusion and exclusion criteria. Briefly, of the 22 studies (Wang et al., 2001; Woodson et al., 2001; Lin et al., 2003; Liu et al., 2004; Wang et al., 2004; Li et al., 2005; Taufer et al., 2005; Ho et al., 2006; Choi et al., 2007; di Martino et al., 2007; Ergen et al., 2007; Kang et al., 2007; Arsova-Sarafinovska et al., 2008; Iguchi et al., 2008; Mikhak et al., 2008; Bica et al., 2009; Cheng et al., 2009; Iguchi et al., 2009; Sun et al., 2009; Zejnilovic etal., 2009), the sample size ranged between 100 and 3,030, and there were twelve studies on prostate cancer, four studies on esophageal cancer, and six studies on lung cancer. All studies, except for five of them (Taufer et al., 2005; Bica et al., 2009; Sun et al., 2009; Zejnilovic et al., 2009), indicated that the distribution of genotypes in the controls was consistent with Hardy- Weinberg equilibrium, while only one study conducted by Lin et al. (2003) contained no data for Hardy-Weinberg equilibrium. "
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    ABSTRACT: Altered expression or function of manganese superoxide dismutase (MnSOD) has been shown to be associated with cancer risk but assessment of gene polymorphisms has resulted in inconclusive data. Here a search of published data was made and 22 studies were recruited, covering 20,025 case and control subjects, for meta- analyses of the association of MnSOD polymorphisms with the risk of prostate, esophageal, and lung cancers. The data on 12 studies of prostate cancer (including 4,182 cases and 6,885 controls) showed a statistically significant association with the risk of development in co-dominant models and dominant models, but not in the recessive model. Subgroup analysis showed there was no statistically significant association of MnSOD polymorphisms with aggressive or nonaggressive prostate cancer in different genetic models. In addition, the data on four studies of esophageal cancer containing 620 cases and 909 controls showed a statistically significant association between MnSOD polymorphisms and risk in all comparison models. In contrast, the data on six studies of lung cancer with 3,375 cases and 4,050 controls showed that MnSOD polymorphisms were significantly associated with the decreased risk of lung cancer in the homozygote and dominant models, but not the heterozygote model. A subgroup analysis of the combination of MnSOD polymorphisms with tobacco smokers did not show any significant association with lung cancer risk, histological type, or clinical stage of lung cancer. The data from the current study indicated that the Ala allele MnSOD polymorphism is associated with increased risk of prostate and esophageal cancers, but with decreased risk of lung cancer. The underlying molecular mechanisms warrant further investigation.
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