Review Target Sequence Polymorphism of Human Manganese Superoxide Dismutase Gene and Its Association with Cancer Risk: A Review (original) (raw)
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In normal state of a cell, endogenous antioxidant enzyme system maintains the level of reactive oxygen species generated by mitochondrial respiratory chain. Mitochondrial superoxide dismutase [SOD; manganese SOD (MnSOD) or SOD2] neutralizes highly reactive superoxide radical (O.-2), the first member in the plethora of mitochondrial reactive oxygen species. A polymorphism in the target sequence of MnSOD enzyme, Val16Ala, is known to disrupt proper targeting of the enzyme from cytosol to mitochondrial matrix where it acts on O.-2 to dismutate it to hydrogen peroxide (H2O2). A change in the level of O.-2 and of H2O2 in mitochondria modulates the molecular mechanisms of apoptosis, cellular adhesion, and cell proliferation and thus play key role in cancer development. Previous studies investigating the association between MnSOD Val16Ala polymorphism and cancer risk have revealed inconsistent results. We conducted a meta-analysis on these studies. Our meta-analysis on total of 7,366 cancer cases and 9,102 controls from 13 published case-control studies showed no overall association of this polymorphism either with breast cancer risk or for cancer risk as such (for Ala homozygous odds ratio, 0.98; 95% confidence interval, 0.90-1.07 and odds ratio, 1.02; 95% confidence interval, 0.91-1.14, respectively). Also, there was no major effect in either recessive or dominant model for the MnSOD Val16Ala. However, a proper evaluation of this polymorphism with cancer link demands experiments involving large sample size, cross-tabulation of gene-gene, gene-environment interactions, and linkage studies, as cell biological experiments clearly correlate critical levels of mitochondrial O.-2 and H2O2 to carcinogenesis.
In normal state of a cell, endogenous antioxidant enzyme system maintains the level of reactive oxygen species generated by mitochondrial respiratory chain. Mitochondrial superoxide dismutase [SOD; manganese SOD (MnSOD) or SOD2] neutralizes highly reactive superoxide radical (O . -2 ), the first member in the plethora of mitochondrial reactive oxygen species. A polymorphism in the target sequence of MnSOD enzyme, Val 16 Ala, is known to disrupt proper targeting of the enzyme from cytosol to mitochondrial matrix where it acts on O . -2 to dismutate it to hydrogen peroxide (H 2 O 2 ). A change in the level of O . -2 and of H 2 O 2 in mitochondria modulates the molecular mechanisms of apoptosis, cellular adhesion, and cell proliferation and thus play key role in cancer development. Previous studies investigating the association between MnSOD Val 16 Ala polymorphism and cancer risk have revealed Cancer Epidemiol Biomarkers Prev
Genetic polymorphism of manganese superoxide dismutase (MnSOD) and breast cancer susceptibility
Cell Biochemistry and Function, 2004
Within mitochondria, manganese superoxide dismutase (MnSOD) provides a major defence against oxidative damage by reactive oxygen species (ROS). An alanine-9valine (Ala-9Val) polymorphism in the mitochondrial targeting sequence of MnSOD has been described and has recently been associated with risk of human breast cancer. Our present case-control study was performed to explore the association between MnSOD genetic polymorphism and individual susceptibility to breast cancer. Ala-9Val polymorphism in the signal sequence of the protein for MnSOD was determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in a study population. There was no significant difference in risk for breast cancer development between patients positive and negative for the MnSOD Ala allele with adjusted odds ratio (OR): 0.86 (95% confidence interval (CI) 0.43 to 1.72). When MnSOD Ala was combined with either cytochrome P450 1B1 CYP1B1*1 and catechol O-methyltransferase COMT-L (V158M) genotypes, the risk for developing breast cancer was significantly increased in patients with a body mass index (BMI) greater than 24 kg m À2 (OR: 1.42 (95%CI ¼ 1.04-1.93)).
Association between manganese superoxide dismutase polymorphism and risk of lung cancer
Cancer genetics and cytogenetics, 2009
A growing body of evidence suggests that reactive oxygen species (ROS) play an important role in human cancers. Manganese superoxide dismutase (MnSOD) is the major antioxidant in the mitochondria, catalysing the dismutation of superoxide radicals to form hydrogen peroxide. Since the identification of a well-characterised functional polymorphism, Val-9Ala of MnSOD, a number of molecular epidemiological studies have evaluated the association between Val-9Ala and cancer risk. However, the results remain conflicting rather than conclusive. This meta-analysis on 15,320 cancer cases and 19,534 controls from 34 published case-control studies shows no significant overall main effect of MnSOD Val-9Ala on cancer risk. However, we found that the MnSOD 9Ala allele was associated with an increased prostate cancer risk (Val/Ala versus Val/Val: odds ratio (OR) = 1.1; 95% confidence intervals (CI): 1.0-1.3; Ala/Ala versus Val/Val: OR = 1.3; 95% CI: 1.0-1.6; Val/Ala + Ala/Ala versus Val/Val: OR = 1.2; 95% CI, 1.0-1.3). In addition, we found that the MnSOD Ala-9Ala genotype contributed to an increased breast cancer risk in premenopausal women who had low consumption of antioxidants (Ala/Ala versus Val/Ala + Val/Val: OR = 2.6, 95% CI: 1.0-6.4
DNA and Cell Biology, 2008
Two functional polymorphisms within the manganese superoxide dismutase (MnSOD) gene have been reported to lead to increased oxidative stress damage. The MnSOD 58T > C single nucleotide polymorphism (SNP) within exon 3 changes isoleucine to threonine, leading to decreased thermal stability and reduced enzymatic activity in vivo and in vitro. The MnSOD 60C > T polymorphism within exon 3 changes leucine to phenylalanine, rendering the protein sensitive to redox regulation by intracellular thiols. Thus, the goal of this study was to evaluate the 58T > C and 60C > T MnSOD polymorphisms in a large case-control study. Taqman allelic discrimination assays were developed to identify the 58T > C and 60C > T SNPs in exon 3. Two hundred and eight lung cancer cases and 141 controls were evaluated for these two SNPs, and all 349 subjects were of the wild-type homozygous genotype for both 58C and 60T in exon 3. This study suggests that although the 58T > C and 60C > T polymorphisms reduce MnSOD enzymatic activity, these polymorphisms were not identified in the present case-control study population.
Asian Pacific Journal of Cancer Prevention, 2015
Background: Oxidative stress caused by the generation of reactive oxygen species plays an important role in human carcinogenesis. Manganese superoxide dismutase (MnSOD) Val-9Ala in the mitochondrial target sequence is the best known polymorphism of this enzyme. The purpose of the current research was to assess the association of MnSOD Val-9Ala genotypes with the risk of gastric cancer. Materials and Methods: This casecontrol study covered 54 gastric cancer patients compared to 100 cancer free subjects as controls. Extraction of DNA was performed on bioptic samples and genotypes were identified with a polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) method. Results: The frequencies of MnSOD Ala/Ala, Ala/Val and Val/Val genotypes in healthy individuals were 24.3, 66.7 and 9%, respectively. However, in gastric cancer patients, Ala/Ala, Ala/Val and Val/Val were observed in 24.0, 48.0 and 28.0% (p=0.01). In patients the frequency of MnSOD Val allele was higher (52%) compared to that in controls (42%). Conclusions: The results of this study show a positive association between MnSOD Val-9Ala gene polymorphism and risk of gastric cancer disease in Iranian population.
Journal of Surgical Research, 2005
Background. Manganese superoxide dismutase (Mn-SOD) plays a critical role in the detoxification of mitochondrial reactive oxygen species, constituting a major cellular defense mechanism against agents that induce oxidative stress. A genetic polymorphism in the mitochondrial targeting sequence of this gene has been associated with increased cancer risk. This one base pair transition (؊9 T>C) leads to a Val to Ala amino acid change in the mitochondrial targeting sequence. In addition, the MnSOD promoter contains an activator protein-2 (AP-2) binding site that modifies transcription of MnSOD. Mutations have been identified in the proximal region of the promoter in human tumor cell lines. One of these mutations (؊102 C>T) has been shown to change the binding pattern of AP-2, leading to a reduction in transcriptional activity. The aim of our study was to investigate possible associations of the (؊9 T>C) and (؊102 C>T) polymorphisms with gastric cancer in a population-based case-control study conducted in Warsaw, Poland. Materials and methods. DNA was obtained from a population based case-control study of stomach cancer conducted in Warsaw, Poland, between 1994 and 1996. The MnSOD-9 T>C genotype was determined by PCR-RFLP assay. The MnSOD-102 C>T genotype was determined using a TaqMan allele discrimination assay. Results. The frequency of the-102 C>T polymorphism was 41% (38/91) in gastric cancer cases and 38% (50/130) in the controls (odds ratio [OR] 1.1, 95% confidence interval [CI] 0.6-2.1). The frequency of the-9 T>C polymorphism was 44% (202/464) in cases and 56% (262/464) in controls (OR 1.1; 95% CI 0.9-1.37). The lack of association was observed in both non-smokers (OR 1.5; 95% CI 0.7-2.34) and smokers (OR 1.1; 95% CI 0.7-1.7). Furthermore, the association was not significant when smokers were segregated by extent of smoking history. Conclusion. The association of the manganese superoxide dismutase polymorphisms at-102 C>T and the-9 T>C were not found to be associated with gastric cancer in a Polish case-control study.
BMC genetics, 2004
Manganese superoxide dismutase (MnSOD) plays a critical role in the detoxification of mitochondrial reactive oxygen species constituting a major cellular defense mechanism against agents that induce oxidative stress. The MnSOD promoter contains an activator protein-2 (AP-2) binding site that modifies transcription of MnSOD. Mutations have been identified in the proximal region of the promoter in human tumor cell lines. One of these mutations (-102C>T) has been shown to change the binding pattern of AP-2 leading to a reduction in transcriptional activity. The aim of our study was to develop a method to identify and determine the frequency of this (-102C>T) polymorphism in human tissues. A new TaqMan allelic discrimination genotype method was successfully applied to genomic DNA samples derived from blood, buccal swabs, snap frozen tissue and paraffin blocks. The polymorphism was shown to be in Hardy-Weinberg Equilibrium in an evaluation of 130 Caucasians from Warsaw, Poland: 44 ...