The role of GSTM1, GSTT1, GSTP1, and OGG1 polymorphisms in type 2 diabetes mellitus risk: a case-control study in a Turkish population

The aim of the present study was to investigate the role of some polymorphisms in GSTs (GSTM1, GSTT1 and GSTP1) which are very important protective mechanisms against oxidative stress and in OGG1 gene which is important in DNA repair, against the risk of type 2 diabetes mellitus (T2DM). 127 T2DM and 127 control subjects were included in the study. DNA was extracted from whole blood. Analyses of GSTM1 and GSTT1 gene polymorphisms were performed by allele specific PCR and those of GSTP1 Ile105Val and OGG1 Ser326Cys by PCR-RFLP. Our data showed that GSTM1 null genotype frequency had a 2-6 times statistically significant increase in a patient group (OR=3.841, 95% CI=2.280-6.469, p<0.001) but no significance with GSTT1 null/positive and GSTP1 Ile105Val genotypes was observed. When T2DM patients with OGG1 Ser326Cys polymorphism were compared with patients with a wild genotype, a 2-3 times statistically significant increase has been observed (OR 1.858, 95% CI=1.099-3.141, p=0.021). The combined effect of GSTM1 null and OGG1 variant genotype frequencies has shown to be statistically significant. Similarly, the risk of T2DM was statistically increased with GSTM1 null (OR=3.841, 95% CI=2.28-6.469), GSTT1 null+GSTP1 (H+M) (OR=4.118, 95% CI=1.327-12.778) and GSTM1 null+OGG1 (H+M) (OR=3.322, 95% CI=1.898-5.816) and GSTT1 null+OGG1 (H+M) (OR=2.179, 95% CI=1.083-4.386) as compared to the control group. According to our study results, it has been observed that the combined evaluation of GSTM1-GSTT1-GSTP1 and OGG1 Ser326Cys gene polymorphisms can be used as candidate genes in the etiology of T2DM, especially in the development of T2DM.     

Association between the OGG1 Ser326Cys and APEX1 Asp148Glu polymorphisms and lung cancer risk: a meta-analysis

The previous published data on the association between the 8-oxo-guanine glycosylase-1 (OGG1) and apurinic/apyrimidinic-endonuclease-1 (APEX1/APE1) polymorphisms and lung cancer risk remained controversial. Several polymorphisms in the OGG1 and APEX1 gene have been described, including the commonly occurring Ser326Cys in OGG1 and Asp148Glu in APEX1. This meta-analysis of literatures was performed to derive a more precise estimation of the relationship. A total of 37 studies were identified to the meta-analysis, including 9,203 cases and 10,994 controls for OGG1 Ser326Cys (from 25 studies) and 3,491 cases and 4,708 controls for APEX1 Asp148Glu (from 12 studies). When all the eligible studies were pooled into the meta-analysis of OGG1 Ser326Cys polymorphism, significantly increased lung cancer risk was observed in recessive model (OR?=?1.17, 95?% CI?=?1.03–1.33) and in additive model (OR?=?1.21, 95?% CI?=?1.03–1.42). In the stratified analysis, significantly increased risk of lung cancer was also observed on the population-based studies (recessive model: OR?=?1.26, 95?% CI?=?1.08–1.46, additive model: OR?=?1.42, 95?% CI?=?1.06–1.73) and non-smokers (dominant model: OR?=?1.20, 95?% CI?=?1.02–1.42, recessive model: OR?=?1.20, 95?% CI?=?1.02–1.40, additive model: OR?=?1.35, 95?% CI?=?1.08–1.68). Additionally, when one study was deleted in the sensitive analysis, the results of OGG1 Ser326Cys were changed in Asians (recessive model: OR?=?1.16, 95?% CI?=?1.06–1.27, additive model: OR?=?1.23, 95?% CI?=?1.09–1.38). When all the eligible studies were pooled into the meta-analysis of APEX1 Asp148Glu polymorphism, there was no evidence of significant association between lung cancer risk and APEX1 Asp148Glu polymorphism in any genetic model. In the stratified analysis, significantly decreased lung adenocarcinoma risk was observed in recessive model (OR?=?0.68, 95?% CI?=?0.48–0.97, P _h?=?0.475, I²?=?0.0?%). Additionally, when one study was deleted in the sensitive analysis, the results of APEX1 Asp148Glu were changed in Asians (recessive model: OR?=?1.21, 95?% CI?=?1.03–1.43) and smokers (dominant model: OR?=?1.62, 95?% CI?=?1.08–2.44, additive model: OR?=?1.37, 95?% CI?=?1.02–1.84). In summary, this meta-analysis indicates that OGG1 Ser326Cys show an increased lung cancer risk in Asians and non-smokers, APEX1 Asp148Glu polymorphism may be associated with decreased lung adenocarcinoma risk, and APEX1 Asp148Glu polymorphism show an increased lung cancer risk in Asians and smokers. However, a study with the larger sample size is needed to further evaluated gene-environment interaction on OGG1 Ser326Cys and APEX1 Asp148Glu polymorphisms and lung cancer risk.     

Influence of the OGG1 Ser326Cys polymorphism on oxidatively damaged DNA and repair activity

Oxidatively damaged DNA base lesions are considered to be mainly repaired by 8-oxoguanine DNA glycosylase (OGG1) mediated pathways. We investigated the effect of the OGG1 Ser326Cys polymorphism on the level and repair of oxidatively damaged DNA in mononuclear blood cells (MNBC) by means of the comet assay. We collected blood samples from 1,019 healthy subjects and genotyped for the OGG1 Ser326Cys polymorphism. We found 49 subjects homozygous for the variant genotype (Cys/Cys) and selected same numbers of age-matched subjects with the heterozygous (Ser/Cys) and homozygous wild-type genotype (Ser/Ser). Carriers of the Cys/Cys genotype had higher levels of formamidopyrimidine DNA glycosylase (FPG) sensitive sites in MNBC (0.31 ± 0.03 lesions/10(6)bp) compared to Ser/Ser (0.19 ± 0.02 lesions/10(6)bp, P<0.01). The level of hOGG1 sensitive sites in MNBC from the Ser326Cys carriers (0.19 ± 0.16 lesions/10(6) bp) was also higher compared to the Ser/Ser genotype (0.11 ± 0.09 lesions/10(6) bp, P<0.05). Still, there was no genotype-related difference in DNA repair incision activity of MNBC extracts on nucleoids with oxidatively damaged DNA induced by Ro19-8022/white light (P=0.20). In addition, there were no differences in the expression of OGG1 (P=0.69), ERCC1 (P=0.62), MUTYH (P=0.85), NEIL1 (P=0.17) or NUDT1 (P=0.48) in whole blood. Our results indicate that the OGG1 Ser326Cys polymorphism has limited influence on the DNA repair incisions by extracts of MNBC, whereas the apparent increased risk of cancer in subjects with the Cys/Cys genotype may be because of higher levels of oxidatively damaged DNA.     

<Emphasis Type="Italic">MUTYH</Emphasis> Tyr165Cys, <Emphasis Type="Italic">OGG1</Emphasis> Ser326Cys and <Emphasis Type="Italic">XPD</Emphasis> Lys751Gln polymorphisms and head neck cancer susceptibility: a case control study

In the present study we investigated the association between three polymorphisms of the MUTYH (Tyr165Cys, rs34612342), the OGG1 (Ser326Cys, rs1052133) and the XPD (Lys751Gln, rs13181) genes with head and neck cancer risk. Genotypes were determined in DNA from peripheral blood lymphocytes of 265 patients with head and neck squamous cell carcinoma (HNSCC) as well as 280 cancer-free controls by PCR-restriction fragment lenght polymorphisms. We found an association between HNSCC and the Ser326Cys (OR 1.69; 95% CI 1.19–2.45) as well as Cys326Cys (OR 4.56; 95% CI 2.07–10.05) variants of the OGG1 gene. The gene–gene interaction between MUTYH and OGG1 as well as OGG1 and XPD polymorphic variants may contribute to higher prevalence of HNSCC. We also found an association between Ser326Cys and Cys326Cys variants of OGG1 gene and smoking status in HNSCC patients (OR 1.97; 95% CI 1.25–3.11), (OR 3.54; 95% CI 1.39–9.04), respectively. Moreover, we also observed a protective association between Tyr165Cys variant of the MUTYH gene and non-smoking status in HNSCC (OR 0.34; 95% CI 0.17–0.66). We also found a link between gene–gene interaction (MUTYH and OGG1 or OGG1 and XPD) and smoking (ORs 2.17–4.20 and 2.18–5.23) or non-smoking status (ORs 0.11 and 7.61) in HNSCC patients, respectively. In conclusion our data showed that the Ser326Cys polymorphism of the OGG1 gene may modify the risk of HNSCC associated with smoking. Finally we suggested that this polymorphism might be used as predictive factor for head and neck cancer in Polish population.     

DNA repair gene 8-oxoguanine DNA glycosylase Ser326Cys polymorphism and colorectal cancer risk in a Kashmiri population

8-Oxoguanine DNA glycosylase (OGG1) is one of the important base excision repair enzymes that repair 8-oxoguanine lesion incorporated within the DNA of an individual by reactive oxygen species. The aim of this study was to detect the role of OGG1 Ser326Cys polymorphism in susceptibility to colorectal cancer (CRC) in a Kashmiri population. We investigated the genotype distribution of the OGG1 gene in 114 CRC cases in comparison with 200 healthy subjects. There was no significant association between OGG1 Ser326Cys polymorphism and CRC, but the homozygous Cys/Cys variant genotype was associated with an increased risk of colon cancer (p<0.05). This study suggests that the OGG1 polymorphism is not associated with the risk of development of CRC in the Kashmiri population in general but modulates the risk of cancer development in colon via interaction with many dietary factors.     

The association between OGG1 Ser326Cys polymorphism and lung cancer susceptibility: a meta-analysis of 27 studies

Background

Numerous studies have investigated association of OGG1 Ser326Cys polymorphism with lung cancer susceptibility; however, the findings are inconsistent. Therefore, we performed a meta-analysis based on 27 publications encompass 9663 cases and 11348 controls to comprehensively evaluate such associations.

Methods

We searched publications from MEDLINE and EMBASE which were assessing the associations between OGG1 Ser326Cys polymorphism and lung cancer risk. We calculated pooled odds ratio (OR) and 95% confidence interval (CI) by using either fixed-effects or random-effects model. We used genotype based mRNA expression data from HapMap for SNP rs1052133 in normal cell lines among 270 subjects with four different ethnicities.

Results

The results showed that individuals carrying the Cys/Cys genotype did not have significantly increased risk for lung cancer (OR = 1.15, 95% CI = 0.98–1.36) when compared with the Ser/Ser genotype; similarly, no significant association was found in recessive, dominant or heterozygous co-dominant model (Ser/Cys vs. Cys/Cys). However, markedly increased risks were found in relatively large sample size (Ser/Ser vs. Cys/Cys: OR = 1.29, 95% CI = 1.13–1.48, and recessive model: OR = 1.19, 95% CI = 1.07–1.32). As to histological types, we found the Cys/Cys was associated with adenocarcinoma risk (Ser/Ser vs. Cys/Cys: OR = 1.32, 95% CI = 1.12–1.56; Ser/Cys vs. Cys/Cys: OR = 1.19, 95% CI = 1.04–1.37, and recessive model OR = 1.23, 95% CI = 1.08–1.40). No significant difference of OGG1 mRNA expression was found among genotypes between different ethnicities.

Conclusions

Despite some limitations, this meta-analysis established solid statistical evidence for an association between the OGG1 Cys/Cys genotype and lung cancer risk, particularly for studies with large sample size and adenocarcinoma, but this association warrants additional validation in larger and well designed studies.     

The association of polymorphisms in DNA base excision repair genes <Emphasis Type="Italic">XRCC1</Emphasis>, <Emphasis Type="Italic">OGG1</Emphasis> and <Emphasis Type="Italic">MUTYH</Emphasis> with the risk of childhood acute lymphoblastic leukemia

The aim of this study was to evaluate the association of polymorphisms in genes encoding three key proteins of DNA base excision repair (BER): the OGG1 Ser326Cys, the MUTYH Tyr165Cys and the XRCC1 Arg399Gln with the risk of childhood acute lymphoblastic leukemia (ALL). Our study included 97 children patients with ALL (mean age 5.4 ± 2.5) and 131 healthy children (mean age 6.2 ± 2.8) used as controls. Genetic polymorphisms in BER pathway genes were examined using PCR and restriction fragment length polymorphism (RFLP). We have demonstrated that the OGG1 Cys/Cys genotype increases the risk of ALL (OR 5.36) whereas the Ser/Ser genotype variant strongly reduces the risk of this cancer among Polish children (OR 0.45). Although we did not observe the differences in single nucleotide polymorphisms (SNPs) in MUTYH and XRCC1 genes between control group and children with ALL, we have shown that the combined genotypes of examined genes can modulate the risk of childhood ALL in Polish population. We found that the combined genotype Arg/Gln–Cys/Cys of XRCC1/OGG1 (OR 3.83) as well as the Cys/Cys–Tyr/Tyr of OGG1/MUTYH (OR 6.75) increases the risk of ALL. In contrast, the combined genotype Arg/Arg–Ser/Ser of XRCC1/OGG1 (OR 0.40) as well as the Ser/Ser–Tyr/Tyr of OGG1/MUTYH (OR 0.43) played a protective role against this malignant disease. In conclusion, we suggest that polymorphisms of BER genes may be used as an important predictive factor for acute lymphoblastic leukemia in children.     

OGG1 expression and OGG1 Ser326Cys polymorphism and risk of lung cancer in a prospective study

Oxidative DNA damage is believed to be implicated in lung carcinogenesis. 8-OxodG is a mutagenic and abundant oxidative modification induced in DNA. OGG1, NEIL1 and MUTYH are all involved in the repair and prevention of 8-oxodG-derived mutations and may be up-regulated by oxidative stress. The polymorphism OGG1 Ser326Cys has in some studies been associated with risk of lung cancer. In a population-based cohort of 57,053 Danes, we examined associations between mRNA levels of OGG1, NEIL1, MUTYH and NUDT in buffy coat material and subsequent lung cancer risk. 260 cases with lung cancer were identified and a sub-cohort of 263 individuals was matched on sex, age and smoking duration. We found that OGG1 mRNA levels in healthy individuals were not associated with risk of subsequent getting lung cancer. However, subjects with the OGG1 Cys326/Cys326 genotype had a higher expression level of OGG1 mRNA than wildtype-allele carriers. For homozygous Cys326 carriers, the incidence rate ratio (IRR) was 1.51 (95% CI: 1.09-2.08) for a doubling of the OGG1 mRNA level and there was a statistically significant interaction between the genotype and mRNA level. Among never-smokers, the IRR was 4.29 (1.09-16.9) per doubling of the OGG1 mRNA level, which was not found among smokers. Furthermore, we found a positive correlation between OGG1 mRNA expression and urinary excretion of 8-oxodG (RS=0.18; p<0.005). NUDT1 mRNA levels were omitted due to low and unreliable expression levels. The results suggest that OGG1 mRNA levels should be regarded as a biomarker of exposure to oxidative stress with induction of DNA rather than a marker of inborn DNA repair capacity.     

DNA repair genetic polymorphisms and risk of colorectal cancer in the Czech Republic

Colorectal cancer represents a complex disease where susceptibility may be influenced by genetic polymorphisms in the DNA repair system. In the present study we investigated the role of nine single nucleotide polymorphisms in eight DNA repair genes on the risk of colorectal cancer in a hospital-based case-control population (532 cases and 532 sex- and age-matched controls). Data analysis showed that the variant allele homozygotes for the Asn148Glu polymorphism in the APE1 gene were at a statistically non-significant increased risk of colorectal cancer. The risk was more pronounced for colon cancer (odds ratio, OR: 1.50; 95% confidence interval, CI: 1.01-2.22; p=0.05). The data stratification showed increased risk of colorectal cancer in the age group 64-86 years in both individuals heterozygous (OR: 1.79; 95% CI: 1.04-3.07; p=0.04) and homozygous (OR: 2.57; 95% CI: 1.30-5.06; p=0.007) for the variant allele of the APE1 Asn148Glu polymorphism. Smokers homozygous for the variant allele of the hOGG1 Ser326Cys polymorphism showed increased risk of colorectal cancer (OR: 4.17; 95% CI: 1.17-15.54; p=0.03). The analysis of binary genotype combinations showed increased colorectal cancer risk in individuals simultaneously homozygous for the variant alleles of APE1 Asn148Glu and hOGG1 Ser326Cys (OR: 6.37; 95% CI: 1.40-29.02; p=0.02). Considering the subtle effect of the DNA repair polymorphisms on the risk of colorectal cancer, exploration of gene-gene and gene-environmental interactions with a large sample size with sufficient statistical power are recommended.     

Green tea consumption, genetic susceptibility, PAH-rich smoky coal, and the risk of lung cancer

Experimental evidence suggests that green tea (Camellia sinesis) may reduce the risk of lung cancer through several hypothesized mechanisms including scavenging oxidative radicals, inhibition of tumor initiation, and modulation of detoxification enzymes. However, epidemiologic results have not been consistent as to the relationship between green tea consumption and lung caner prevention. We employed a population-based case-control study of 122 cases and 122 controls to investigate the effect that green tea consumption may have on the risk of lung cancer and whether polymorphisms in 8-oxoguanine-DNA glycosylase (OGG1), glutathione-S-transferase M1 (GSTM1), and aldo-keto reductase 1C3 (AKR1C3) modify such an association. Daily green tea consumption was associated with a non-significant reduction in lung cancer risk. However, the effect of smoky coal exposure was higher for non-drinkers (odds ratio (OR)=4.93; 95% confidence interval (95% CI)=1.27-19.13) than for drinkers (OR=1.88; 95% CI=1.01-3.48). Further, among individuals with the OGG1 Cys(326) allele, daily consumption was associated with a 72% reduction (95% CI=0.09-0.94). Among GSTM1 null homozygotes, those who consumed green tea daily had a non-significant reduction in risk compared with non-consumers. Green tea consumption had no effect among OGG1 Ser(326) homozygotes or GSTM1 carriers. In addition, AKR1C3 genotype did not modulate the effect of green tea consumption. The chemopreventive effects of green tea in this population may be restricted to individuals who are particularly susceptible to oxidative stress and oxidative DNA damage.     

The Joint Effect of hOGG1, APE1, and ADPRT Polymorphisms and Cooking Oil Fumes on the Risk of Lung Adenocarcinoma in Chinese Non-Smoking Females

Background

The human 8-oxoguanine DNA glycosylase 1 (hOGG1), apurinic/apyrimidinic endonuclease 1 (APE1), and adenosine diphosphate ribosyl transferase (ADPRT) genes play an important role in the DNA base excision repair pathway. Single nucleotide polymorphisms (SNPs) in critical genes are suspected to be associated with the risk of lung cancer. This study aimed to identify the association between the polymorphisms of hOGG1 Ser326Cys, APE1 Asp148Glu, and ADPRT Val762Ala, and the risk of lung adenocarcinoma in the non-smoking female population, and investigated the interaction between genetic polymorphisms and environmental exposure in lung adenocarcinoma.

Methods

We performed a hospital-based case-control study, including 410 lung adenocarcinoma patients and 410 cancer-free hospital control subjects who were matched for age. Each case and control was interviewed to collect information by well-trained interviewers. A total of 10 ml of venous blood was collected for genotype testing. Three polymorphisms were analyzed by the polymerase chain reaction-restriction fragment length polymorphism technique.

Results

We found that individuals who were homozygous for the variant hOGG1 326Cys/Cys showed a significantly increased risk of lung adenocarcinoma (OR = 1.54; 95% CI: 1.01–2.36; P = 0.045). When the combined effect of variant alleles was analyzed, we found an increased OR of 1.89 (95% CI: 1.24–2.88, P = 0.003) for lung adenocarcinoma individuals with more than one homozygous variant allele. In stratified analyses, we found that the OR for the gene-environment interaction between Ser/Cys and Cys/Cys genotypes of hOGG1 codon 326 and cooking oil fumes for the risk of lung adenocarcinoma was 1.37 (95% CI: 0.77–2.44; P = 0.279) and 2.79 (95% CI: 1.50–5.18; P = 0.001), respectively.

Conclusions

The hOGG1 Ser326Cys polymorphism might be associated with the risk of lung adenocarcinoma in Chinese non-smoking females. Furthermore, there is a significant gene-environment association between cooking oil fumes and hOGG1 326 Cys/Cys genotype in lung adenocarcinoma among female non-smokers.     

SNPs in DNA repair genes associated to meningitis and host immune response

In vitro and in animal models, APE1, OGG1, and PARP-1 have been proposed as being involved with inflammatory response. In this work, we have investigated if the SNPs APE1 Asn148Glu, OGG1 Ser326Cys, and PARP-1 Val762Ala are associated to meningitis. The patient genotypes were investigated by PIRA-PCR or PCR-RFLP. DNA damages were detected in genomic DNA by Fpg treatment. IgG and IgA were measured from plasma and the cytokines and chemokines were measured from cerebrospinal fluid samples using Bio-Plex assays. A higher frequency (P<0.05) of APE1 Glu allele in bacterial meningitis (BM) and aseptic meningitis (AM) patients was observed. The genotypes Asn/Asn in control group and Asn/Glu in BM group was also higher. For the SNP OGG1 Ser326Cys, the genotype Cys/Cys was more frequent (P<0.05) in BM group. The frequency of PARP-1 Val/Val genotype was higher in control group (P<0.05). The occurrence of combined SNPs is significantly higher in BM patients, indicating that these SNPs may be associated to the disease. Increasing in sensitive sites to Fpg was observed in carriers of APE1 Glu allele or OGG1 Cys allele, suggesting that SNPs affect DNA repair activity. Alterations in IgG production were observed in the presence of SNPs APE1 Asn148Glu, OGG1 Ser326Cys or PARP-1 Val762Ala. Moreover, reduction in the levels of IL-6, IL-1Ra, MCP-1/CCL2 and IL-8/CXCL8 was observed in the presence of APE1 Glu allele in BM patients. In conclusion, we obtained indications of an effect of SNPs in DNA repair genes on the regulation of immune response in meningitis.     

Direct visualization of repair of oxidative damage by OGG1 in the nuclei of live cells

Oxidative DNA damage caused by intracellular reactive oxygen species (ROS) is widely considered to be important in the pathology of a range of human diseases including cancer as well as in the aging process. A frequently occurring mutagenic base lesion produced by ROS is 8-oxo deoxyguanine (8-oxo dG) and the major enzyme for repair of 8-oxo dG is 8-oxoguanine-DNA glycosylase 1 (OGG1). There is now substantial evidence from bulk biochemical studies that a common human polymorphic variant of OGG1 (Ser326Cys) is repair deficient, and this has been linked to individual risk of pathologies related to oxidative stress. In the current study, we have used the technique of multiphoton microscopy to induce highly localized oxidative DNA damage in discrete regions of the nucleus of live cells. Cells transfected with GFP-tagged OGG1 proteins demonstrated rapid (<2 min) accumulation of OGG1 at sites of laser-induced damage as indicated by accumulation of GFP-fluorescence. This was followed by repair as evidenced by loss of the localized fluorescence over time. Quantification of the rate of repair confirmed that the Cys326 variant of OGG1 is repair deficient and that the initial repair rate of damage by Cys326 OGG1 was 3 to 4 fold slower than that observed for Ser326 OGG1. These values are in good agreement with kinetic data comparing the Ser326 and Cys326 proteins obtained by biochemical studies.     

Are genetic polymorphisms in OGG1, XRCC1 and XRCC3 genes predictive for the DNA strand break repair phenotype and genotoxicity in workers exposed to low dose ionising radiations?

Identification of higher risk individuals carrying genetic polymorphisms responsible for reduced DNA repair capacity has substantial preventive implications as these individuals could be targeted for cancer prevention. We have conducted a study to assess the predictivity of the OGG1, XRCC1 and XRCC3 genotypes and the in vitro single strand break repair phenotype for the induction of genotoxic effects. At the population level, a significant contribution of the OGG1 genotypes to the in vitro DNA strand break repair capacity was found. At an individual level, the OGG1 variants Ser/Cys and Cys/Cys genotypes showed a slower in vitro DNA repair than the Ser/Ser OGG1genotype. A multivariate analysis performed with genotypes, age, cumulative dose, exposure status and smoking as independent variables indicated that in the control population, repair capacity is influenced by age and OGG1 polymorphisms. In the exposed population, DNA damage is greater in older men and in smokers. Repair capacity is slower in individuals with Ser/Cys or Cys/Cys OGG1 genotypes compared to those with the Ser/Ser OGG1 genotype. Micronuclei (MN) frequencies increased with age and the cumulative dose of gamma-rays. Analysis of the total population revealed that genetic polymorphisms in XRCC1 resulted in higher residual DNA (RDNA) values and the Met/Met variant of XRCC3 resulted in an increased frequency of micronuclei. The analysis confirms that MN frequencies are reliable biomarkers for the assessment of genetic effects in workers exposed to ionising radiation (IR). A combined analysis of the three genotypes, OGG1, XRCC1 and XRCC3 polymorphisms is advised in order to assess individual susceptibility to ionising radiation. As an alternative or complement, the in vitro DNA strand break repair phenotype which integrates several repair pathways is recommended. Smokers with OGG1 polymorphisms who are exposed to ionising radiation represent a specific population requiring closer medical surveillance because of their increased mutagenic/carcinogenic risk.     

hOGG1 Ser326Cys polymorphism and renal cell carcinoma risk in a Chinese population

Oxidative DNA damage caused by reactive oxygen species plays an important role in cancer development. Human 8-oxoguanine DNA glycosylase (hOGG1) is involved in base excision repair of 8-oxoguanine from damaged DNA. We hypothesized that variants in the hOGG1 gene are associated with risk of renal cell carcinoma (RCC). In a hospital-based case-control study of 572 RCC patients and 575 cancer-free controls frequency matched by age and sex, we genotyped the functional polymorphism Ser326Cys (rs1052133) and assessed its associations with risk of RCC in a Chinese population. We found that individuals with the Cys allele were associated with an increased risk of RCC (odds ratio [OR]?=?1.40, 95% confidence interval [CI]?=?1.02-1.90), compared with those with the Ser/Ser genotype, particularly among subgroups of body mass index >24?kg/m(2) (OR?=?1.75, 95% CI?=?1.12-2.73) and non-smokers (OR?=?1.60, 95% CI?=?1.07-2.38). Further, the polymorphism was associated with risk of developing localized stage and well-differentiated RCC. Our results suggested that the polymorphism is involved in the etiology of RCC and thus may be a marker for genetic susceptibility to RCC.     

Polymorphisms in base-excision repair and nucleotide-excision repair genes in relation to lung cancer risk

Polymorphisms in DNA repair genes may be associated with differences in DNA repair capacity, thereby influencing the individual susceptibility to smoking-related cancer. We investigated the association of 10 base-excision and nucleotide-excision repair gene polymorphisms (XRCC1 -77 T/C, Arg194Trp, Arg280His and Arg399Gln; APE1 Asp148Glu; OGG1 Ser326Cys; XPA -4 G/A; XPC PAT; XPD Asp312Asn and Lys751Gln) with lung cancer risk in Caucasians. Genotypes were determined by PCR-RFLP and PCR-single base extension assays in 110 lung cancer patients and 110 age- and sex-matched controls, and the results were analyzed using logistic regression adjusted for relevant covariates. A significant association between the APE1 Asp148Glu polymorphism and lung cancer risk was found, with adjusted odds ratios (OR) of 3.38 (p=0.001) for the Asp/Glu genotype and 2.39 (p=0.038) for the Glu/Glu genotype. Gene-smoking interaction analyses revealed a statistically significant interaction between cumulative cigarette smoking and the XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms: these polymorphisms were significantly associated with lung cancer in nonsmokers and light smokers (<25 PY; OR=4.92, p=0.021 for XRCC1 399 Gln/Gln; OR=3.62, p=0.049 for XPD 751 Gln/Gln), but not in heavy smokers (> or =25 PY; OR=0.68, p=0.566 for XRCC1 399 Gln/Gln; OR=0.46, p=0.295 for XPD 751 Gln/Gln). Both the XRCC1 Arg194Trp and Arg280His as well as the OGG1 Ser326Cys heterozygous genotypes were associated with a significantly reduced risk for lung cancer (OR=0.32, p=0.024; OR=0.25, p=0.028; OR=0.51, p=0.033, respectively). No associations with lung cancer risk were found for the XRCC1 -77 T/C, the XPA -4 G/A and the XPC PAT polymorphisms. In conclusion, the APE1 Asp148Glu polymorphism is highly predictive for lung cancer, and cumulative cigarette smoking modifies the associations between the XRCC1 Arg399Gln and the XPD Lys751Gln polymorphisms and lung cancer risk.     

Association of hOGG1 Ser326Cys polymorphism with gastric cancer risk: a meta-analysis

Studies investigating the association between human 8-oxoguanine glycosylase 1(hOGG1) Ser326Cys polymorphism and gastric cancer (GC) risk have reported conflicting results. We performed a meta-analysis of published case–control studies to better compare results between studies. 11 eligible studies with 2,180 GC cases and 3,985 controls were selected. There were 5 studies involving Caucasians and 5 studies involving Asians. The combined result based on all studies did not show significant difference in any genetics models. Ser/Cys + Cys/Cys versus Ser/Ser (OR = 0.91, 95% CI 0.81–1.03), Cys/Cys versus Ser/Cys + Ser/Ser (OR = 1.07, 95% CI 0.80–1.44), Ser/Cys versus Ser/Ser (OR = 0.91, 95% CI 0.80–1.03), Sys/Cys versus Ser/Cys (OR = 1.10, 95% CI 0.83–1.47), Cys/Cys versus Ser/Ser (OR = 0.99, 95% CI 0.74–1.34), Cys versus Ser (OR = 1.01, 95% CI 0.88–1.17).When stratifying for ethnicity, there was still no significant association found between hOGG1 Ser326Cys polymorphism and GC risk. Funnel plot and Egger’s test showed some evidence of publication bias on the basis of all studies. Two studies were the main reason because their samples were too small. However, the result of sensitivity analysis suggested that the influence of these two studies and one mixed population study on the pooled OR was weak. Our result could explain the association between hOGG1 Ser326Cys polymorphism and GC risk. In conclusion, we did not found the evidence that the Cys allele at codon 326 of hOGG1 could increase GC risk in our analysis.     

Association between DNA damage, DNA repair genes variability and clinical characteristics in breast cancer patients

The cell's susceptibility to DNA damage and its ability to repair this damage are important for cancer induction, promotion and progression. In the present work we determined the level of basal (total endogenous) and endogenous oxidative DNA damage as well as polymorphism of the DNA repair genes: RAD51 (135 G/C), XRCC3 (Thr241Met), OGG1 (Ser326Cys) and XPD (Lys751Gln) in peripheral blood lymphocytes of 41 breast cancer patients and 48 healthy individuals. DNA damage was evaluated by alkaline comet assay with DNA repair enzymes: Endo III and Fpg, preferentially recognizing oxidized DNA bases. The genotypes of the polymorphisms were determined by restriction fragment length polymorphism PCR. We observed a strong association between breast cancer occurrence and the genotypes C/C of the RAD51-135G/C polymorphism, Ser/Ser of the OGG1-Ser326Cys and Lys/Gln of the XPD-Lys751Gln, whereas the genotypes G/C of the RAD51-135G/C and Lys/Lys of the XPD-Lys751Gln exerted a protective effect against breast cancer. We also found that individuals with the G/C genotype of the RAD51-135G/C polymorphism and with the Lys/Lys genotype of the XPD-Lys751Gln polymorphism displayed a lower extent of basal and oxidative DNA damage. A strong association between higher level of oxidative DNA damage and the Lys/Gln genotype of the latter polymorphism was found. We also correlated genotypes with clinical characteristics of breast cancer patients. We observed a strong association between the G/C genotype of the RAD51-135 G/C polymorphism and the expression of the progesterone receptor and between both alleles of the OGG1-Ser326Cys polymorphism and lymph node metastasis. Our results suggest that the polymorphism of the RAD51, OGG1 and XPD genes may be linked with breast cancer by the modulation of the cellular response to oxidative stress and these polymorphisms may be considered as markers in breast cancer along with the genetic or/and environmental indicators of oxidative stress.     

Association of the Ser326Cys polymorphism in the OGG1 gene with type 2 DM

The association of the Ser326Cys polymorphism of the 8-oxoguanine glycosylase 1 (OGG1) gene with type 2 diabetes was examined using a Japanese population (n (M/W): 4585 (2085/2500); age: 62.6 ± 10.9 years). HbA1c levels and frequency of diabetic subjects were significantly higher in subjects with genotypes with Cys allele than in those without (p = 0.032 and 0.037, respectively). Multiple logistic regression analysis showed that genotypes with Cys allele were significantly associated with diabetes (OR: 1.32, p = 0.0289). In subjects whose glucose tolerance was classified by FPG and 2-h PG (n = 1.634), the association was more substantial (genotypes with Cys allele vs. without, OR: 1.70, p = 0.0059; genotypes Cys/Cys vs. Ser/Ser, OR: 2.19, p = 0.0008). In subjects with genotype Ser/Ser, the insulin secretion index, HOMA-β, increased in the subjects with glucose intolerance and decreased in the subjects with diabetes, while, in subjects with genotypes Ser/Cys + Cys/Cys, HOMA-β decreased as the glucose tolerance progressed (p for trend = 0.010).     

The BARD1 Cys557Ser variant and risk of familial breast cancer in a South-American population

Since the discovery of the BRCA1 and BRCA2 genes, much work has been carried out to identify further breast cancer (BC) susceptibility genes. BARD1 (BRCA1-associated ring domain) was originally identified as a BRCA1-interacting protein but has also been described in tumor-suppressive functions independent of BRCA1. Some association studies have suggested that the BARD1 Cys557Ser variant might be associated with increased risk of BC, but others have failed to confirm this finding. To date, this variant has not been analyzed in Spanish or South-American populations. In this study, using a case-control design, we analyzed the C-terminal Cys557Ser change in 322 Chilean BC cases with no mutations in BRCA1 or BRCA2 and in 570 controls in order to evaluate its possible association with BC susceptibility. BARD1 Cys557Ser was associated with an increased BC risk (P = 0.04, OR = 3.4 [95 % CI 1.2-10.2]) among cases belonging to families with a strong family history of BC. No difference between single cases affected with age <50 years at diagnosis (n = 117) and controls was observed for carriers of Cys/Ser genotype. It is likely that this variant is not involved in BC risk in this group of women. We also analyzed a possible interaction between BARD1 557Ser/XRCC3 241Met variants considering the role of both genes in the maintenance of genome integrity. The combined genotype Cys/Ser-carrier with the XRCC3 241Met allele was associated with an increased BC risk (P = 0.02, OR = 5.01 [95 % CI 1.36-18.5]) among women belonging to families with at least three BC and/or ovarian cancer cases. Our results suggest that BARD1 557Ser and XRCC3 241Met may play roles in BC risk in women with a strong family history of BC. Nevertheless there is no evidence of an interaction between the two SNPs. These findings should be confirmed by other studies and in other populations.