Genetic polymorphism of manganese superoxide dismutase (MnSOD) and breast cancer susceptibility (original) (raw)
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Jornal Brasileiro de …, 2007
INTRODUCTION: One of the several metabolic pathways involved in breast carcinogenesis is the human polymorphism in the mitochondrial targeting sequence Ala-9Val of the manganese superoxide dismutase (MnSOD) gene, which has been previously associated with increased risk of breast cancer in females. Since there is no previous report on this polymorphism in male breast cancer, the objective of this study is to analyze MnSOD polymorphism in a population of males and females with breast cancer from the southernmost state of Brazil, compared to healthy controls. METHODS: A case-control study of one hundred patients affected by breast cancer (11 men and 89 women) and 370 healthy age-adjusted database controls was performed. DNA was extracted from paraffin-embedded tumoral tissue. MnSOD polymorphism was determined by PCR-RFLP techniques using restriction enzyme Hae III. Chi-square test was used to compare MnSOD frequency distribution. RESULTS: MnSOD genotypic frequencies in all patients with breast cancer were AA = 15%; AV = 56%; VV = 29% and controls AA = 6.5%; AV = 68.1% and VV = 25.4%. Both male and female patients with breast cancer presented significantly higher AA frequencies compared to controls (p = 0.035), suggesting strong association of this genotype with breast cancer. A 2.15-fold (95% confidence interval [CI] 1.393-4.541) risk of breast cancer was found among individuals carrying the MnSOD AA allele-containing genotypes compared with the MnSOD VV and AV genotypes. DISCUSSION: These results confirm the already established association of MnSOD AA genotype with female breast cancer and further indicate a similar frequency distribution and increased risk in the male population.
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.
2004
Introduction It has been suggested that oxidative stress and mitochondrial DNA damage play important roles in breast cancer carcinogenesis. Manganese superoxide dismutase (MnSOD) is a major enzyme that is responsible for the detoxification of reactive oxygen species in the mitochondria. A T → C substitution in the MnSOD gene results in a Val → Ala change at the-9 position of the mitochondrial targeting sequence (Val-9Ala), which alters the protein secondary structure and thus affects transport of MnSOD into the mitochondria. Methods We evaluated this genetic polymorphism in association with breast cancer risk using data from the Shanghai Breast Cancer Study, a population-based casecontrol study conducted in urban Shanghai from 1996 to 1998. The MnSOD Val-9Ala polymorphism was examined in 1125 breast cancer cases and 1197 age-frequency-matched control individual. Results Breast cancer risk was slightly elevated in women with Ala/Ala genotype (odds ratio [OR] 1.3, 95% confidence interval [CI] 0.7-2.3), particularly among premenopausal women (OR 1.8, 95% CI 0.9-3.7), as compared with those with Val/Val genotype. The increased risk with the Ala/Ala genotype was stronger among premenopausal women with a higher body mass index (OR 2.5, 95% CI 0.9-7.0) and more years of menstruation (OR 2.6, 95% CI 0.8-8.0). The risk among premenopausal women was further increased twofold to threefold among those with a low intake of fruits, vegetables, vitamin supplements, selenium, or antioxidant vitamins, including carotenes and vitamins A, C, and E. However, the frequency of the Ala allele was low (14%) in the study population, and most of the ORs provided above were not statistically significant. Conclusion The present study provides some evidence that genetic polymorphism in the MnSOD gene may be associated with increased risk of breast cancer among Chinese women with high levels of oxidative stress or low intake of antioxidants. Studies with a larger sample size are needed to confirm the findings.
2016
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
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
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
Breast cancer research : BCR, 2004
A polymorphism in the manganese superoxide dismutase (MnSOD) gene, Ala-9Val, has been examined in association with breast cancer risk in several epidemiologic studies. Results suggest that the Ala allele increases the risk of breast cancer and modifies the effects of environmental exposures that produce oxidative damage to DNA. We examined the role of the MnSOD Ala-9Val polymorphism in a population-based case-control study of invasive and in situ breast cancer in North Carolina. Genotypes were evaluated for 2025 cases (760 African Americans and 1265 whites) and for 1812 controls (677 African Americans and 1135 whites). The odds ratio for MnSOD Ala/Ala versus any MnSOD Val genotypes was not elevated in African Americans (odds ratio = 0.9, 95% confidence interval = 0.7-1.2) or in whites (odds ratio = 1.0, 95% confidence interval = 0.8-1.2). Greater than additive joint effects were observed for the Ala/Ala genotype and smoking, radiation to the chest, and occupational exposure to ioniz...
Cancer Epidemiology Biomarkers Prevention a Publication of the American Association For Cancer Research Cosponsored By the American Society of Preventive Oncology, 2004
Oxidative stress may be involved in the development of breast cancer. Manganese superoxide dismutase (MnSOD) is one of the primary enzymes that directly scavenge potential harmful oxidizing species. A valine (Val) to alanine (Ala) substitution at amino acid 16, occurring in the mitochondrial targeting sequence of the MnSOD gene, has been associated with an increase in breast cancer risk. We conducted a nested casecontrol study within the Nurses' Health Study cohort to examine the role of this polymorphism and its interaction with environmental factors with breast cancer risk. MnSOD genotype data are available from 968 incident cases of breast cancer diagnosed after blood collection in 1989 and 1990, but before June 1, 1998 and 1,205 matched controls. Compared with women homozygous for the Val allele, women homozygous for the Ala allele were not at an increased risk of breast cancer (multivariate odds ratio, 0.96; 95% confidence interval, 0.74-1.24). We did not observe any significant interactions between MnSOD genotype with alcohol consumption, postmenopausal hormone use, plasma antioxidant levels, or dietary sources of antioxidants. We did observe evidence that the MnSOD Ala allele may modify the relation of cigarette smoking with breast cancer risk. A nonsignificant increased risk of breast cancer among current smokers was limited to women homozygous for the Ala alleles compared with Val/Val never smokers (multivariate odds ratio, 1.41; 95% confidence interval 0.77-2.60; P for interaction = 0.03). These data suggest that the Ala allele of MnSOD may modify breast cancer risk among current smokers, but is not an independent risk factor for breast cancer. (Cancer Epidemiol Biomarkers Prev 2004;13(6):989 -96) Downloaded from * LRT comparing the main effects model to the model with each level of exposure cross-classified with MnSOD genotype.
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.