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mso 这一节不知道是什么单词，我爱你。 不过如果是楼上的说的I'#39.的话，就会是“对不起l&M SO
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望及时采纳，但是我爱你我很抱歉。 不明白的再问哟，多谢
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出门在外也不愁The Association of OGG1 Ser326Cys Polymorphism and Urinary 8-OHdG Levels With Lung Cancer Susceptibility: A Hospital-Based Case-Control Study in Turkey (PDF Download Available)
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more authorsAbstractHigh incidence and poor prognosis of lung cancer make it a major health problem worldwide. Although smoking is a major cause of lung cancer, only some smokers develop lung cancer, which suggests that there is a genetic predisposition in some individuals. 8-OHG is an important oxidative base lesion and may elevate due to cancer and smoking. It is repaired by 8-hydroxyguanine DNA glycosylase 1 (OGG1), which has several polymorphisms. Although the Ser326Cys polymorphism is consistently associated with a range of cancers, findings about this polymorphism and lung cancer risk are contradictory. To date, no study has examined this association in the Turkish population. We conducted a case-control study to investigate the association between OGG1 Ser326Cys polymorphism and the risk of lung cancer using PCR-RFLP. We also evaluated gene-smoking interaction and excretion of urinary 8-OHdG. Our results suggest that the OGG1 Ser326Cys polymorphism is not a genetic risk factor for lung cancer, and that the heterozygous genotype is associated with a significantly reduced risk for lung cancer. The levels of 8-OHdG did not correlate with the polymorphism and smoking. Larger association studies are needed to validate our findings, and mechanistic studies are needed to elucidate the underlying molecular mechanisms of this association.Discover the world's research100 million publications2.5 million new publications each month10 million members
241DOI: 10.-8-1924Scientific PaperTHE ASSOCIATION OF OGG1 Ser326Cys POLYMORPHISM AND URINARY 8-OHdG LEVELS WITH LUNG CANCER SUSCEPTIBILITY: A HOSPITAL-BASED CASE-CONTROL STUDY IN TURKEYBensu KARAHALIL1, Esra EMERCE1, Bülent KO?ER2, Serdar HAN2, Necati ALKIS3,and Ali Esat KARAKAYA1Gazi University, Faculty of Pharmacy, Department of Toxicology1, Ankara Numune Education and Research Hospital, Department of Thoracic Surgery2, Ankara Oncology Education and Research Hospital, Department of Medical Oncology3, Ankara, TurkeyReceived in October 2008Accepted in November 2008High incidence and poor prognosis of lung cancer make it a major health problem worldwide. Although smoking is a major cause of lung cancer, only some smokers develop lung cancer, which suggests that there is a genetic predisposition in some individuals. 8-OHG is an important oxidative base lesion and may elevate due to cancer and smoking. It is repaired by 8-hydroxyguanine DNA glycosylase 1 (OGG1), which has several polymorphisms. Although the Ser326Cys polymorphism is consistently associated with a range of cancers, findings about this polymorphism and lung cancer risk are contradictory. To date, no study has examined this association in the Turkish population. We conducted a case-control study to investigate the association between OGG1 Ser326Cys polymorphism and the risk of lung cancer using PCR-RFLP. We also evaluated gene-smoking interaction and excretion of urinary 8-OHdG. Our results suggest that the OGG1 Ser326Cys polymorphism is not a genetic risk factor for lung cancer, and that the heterozygous genotype is associated with a significantly reduced risk for lung cancer. The levels of 8-OHdG did not correlate with the polymorphism and smoking. Larger association studies are needed to validate our findings, and mechanistic studies are needed to elucidate the underlying molecular mechanisms of this association.KEY WORDS: disease, ELISA, genetic variation, oxidative stress, pharmacogenomic, RFLPKarahalil B, et al. OGG1 GENE POLYMORPHISM AND 8-OHdG LEVELS IN LUNG CANCER PATIENTSArh Hig Rada Toksikol -250High incidence and poor prognosis of lung cancer make it a major health problem worldwide (1, 2). Lung cancer, which was initially considered an epidemic disease among men in industrialised nations, has now become the leading killer cancer in both sexes in the United States and an increasingly common disease of both sexes in developing countries (3).In the Turkish population, it is the most common cancer in men and the sixth most common in women. Its incidence is 14.19 per 100,000 men and 1.24 per 100,000 women (4). While more than 80 % of people who develop lung cancer are current or former smokers, only a small portion of smokers develop lung cancer, which suggests that there is a genetic predisposition in some individuals. To better understand the aetiology of this disease and more effectively target high-risk individuals in prevention and screening, it is important to identify factors that influence a smoker’s risk of developing lung cancer (5).Tobacco smoking which is the major cause of lung cancer, increases the rate of oxidative DNA damage (6), and tobacco smoke contains multiple carcinogens z
242and reactive oxygen species (ROS) that are known to chemically modify DNA and lead to mutations. Accumulation of mutations in critical oncogenes and tumour suppressor genes promotes cancer (7, 8). Among many types of oxidative DNA damage, the 8-hydroxyguanine (8-OHG) residue is one of the most abundant oxidative products of cellular DNA and is a mutagenic agent causing GC-to-TA transversions (9, 10). Increase in 8-OHG DNA content has been shown to elevate the cancer risk (11). It can be repaired by the activity of 8-hydroxyguanine DNA glycosylase 1 (OGG1), which catalyses the removal of 8-OHG by cleaving the N-glycosyl bonds between the oxidised guanine and the deoxyribose backbone, leaving an apurinic/apyrimidinic site as an intermediate product (12). Studies on genetic structure have revealed the presence of several polymorphisms within the OGG1 locus (13). Among them, a C/G polymorphism at position 1245 in the 1α-specific exon 7 of the OGG1 gene results in an amino acid substitution from serine to cysteine in codon 326 (14). It is not clear whether the amino acid substitution affects the catalytic properties of the enzyme, and limited knowledge is available on the association between cancer susceptibility and single nucleotide polymorphisms in this critical DNA repair gene (15, 16). In some studies, the OGG1 polymorphism Ser326Cys has been associated with increased risk of lung cancer. On the other hand, contradictory results have been reported about the association of the OGG1 Ser326Cys polymorphism and lung cancer risk for different populations. So far, however, there no such association has been studied in the Turkish population (17-22).Among biomarkers used to identify cancer risk factors, p53 tumour suppressor gene mutations have been determined in several human cancers (23). It is well known that more than 50 % of lung cancers carry a p53 mutation. The most common type of p53 mutation is the guanine (G) to thymine(T) transversion (24), like OGG1. Furthermore, there are several distinct regions of frequent allele loss on chromosome 3p, indicating the presence of multiple tumour suppressor genes, including p53. Therefore, the OGG1 gene, located at 3p25 can be a strong tumor suppressor gene candidate (23) and partial or total loss of the mammalian Ogg1 proteins may predispose cells toward oncogenic transformation (25).In our case-control study of the Turkish population, we wanted to see whether OGG1 Ser326Cys polymorphism was associated with susceptibility to lung cancer. Furthermore, gene-smoking status analyses were conducted to establish the gene-environment interaction between OGG1 Ser326Cys polymorphism and cumulative cigarette smoking in lung cancer. We also evaluated urinary 8-hydroxy-2’-deoxyguanosine (8-OHdG) as a marker of cellular oxidative stress in lung cancer patients who did not receive any radiotherapy and/or chemotherapy and in control subjects. We investigated whether there was any change in urinary 8-OHdG levels due to smoking and cancer.MATERIALS AND METHODSStudy GroupWe conducted a molecular epidemiologic case-control study that included 165 lung cancer patients (20 women and 145 men) and 250 control subjects (83 women, and 167 men). The age of control subjects ranged from 20 to 82 years (53.2±0.75) and in lung cancer patients from 18 to 82 years (56.99±0.79). Details are given in Table 1.The lung cancer patients were from hospital-based, case-control studies of lung cancer carried out in Turkey. They were recruited at two hospitals, and the study was approved by the ethical committee of the Ankara Numune and Ankara Oncology Education and Research Hospitals. According to histological sub-types, lung cancer patients were classified as small cell lung cancer (SCLC, n=38) and non-small cell lung cancer (NSCLC, n=120). In general, the prevalence of NSCLC is significantly higher than the prevalence of SCLC. All cancer diagnoses (except for seven patients) were confirmed by histopathology and cytology. The histopathologic type was determined using the World Health Organization (WHO) lung tumour classification in clinical use during patient accrual.We asked the subjects to fill out a self-administered questionnaire that included general characteristics (age, sex, and socio-demographic characteristics), personal and family medical history, and smoking and drinking habits. Smoking was much more prevalent among lung cancer patients (85.5 %) than in control subjects (50.4 %). All study participants signed an informed consent form and completed a detailed questionnaire about smoking habits.Sample collectionFive millilitres of peripheral blood was collected in a sterile EDTA container (Sigma) via venipuncture Karahalil B, et al. OGG1 GENE POLYMORPHISM AND 8-OHdG LEVELS IN LUNG CANCER PATIENTSArh Hig Rada Toksikol -250
243from each control subject and patient to determine OGG1 Ser326Cys polymorphism by PCR-RFLP. To detect urinary 8-OHdG levels 5-mL spot urine samples were collected from 72 of 165 patients who had never received any chemotherapy and/or radiotherapy and from 61 of 250 control subjects. We could collect urine samples from only 80 controls and the sixty-one were age- andsex-matched to lung cancer patients. All blood and urine samples were stored at -20 °C until analysis.DNA isolation and determination of OGG1 genotypeDNA was extracted from whole blood using a sodium perchlorate / chloroform extraction method (9). We used a simple PCR-RFLP method (9) to identify the Ser326Cys variant, because the C to G transversion creates a new Fnu4HI restriction site. Briefly, the 207 bp fragment was amplified by PCR in a 30 uL reaction volume that contained 100 ng genomic DNA, 0.2 mmol L-1 of dNTP (Fermentas Life Sciences, Lithuania), 1.5 mmol L-1 of MgCl2 (Fermentas Life Sciences, Lithuania), 0.3 pmol of each primer and 1 unit of Taq DNA polymerase (Fermentas Life Sciences, Lithuania). The primers used for amplification of OGG1 gene exon 7, containing Ser326Cys, were 5’-ACT GTC ACT AGT CTC ACC AG-3’ forward (Iontek)and 5’-TGA ATT CGG AAG GTG CTT GGG GAA T-3’ reverse(Iontek). Cycling conditions were as follows: initial denaturation at 94 °C for 2 min, then amplification by 33 cycles of denaturation at 94 °C for 15 s, annealing at 60 °C for 30 s, and elongation at 72 °C for 35 s, followed by extension at 72 °C for 10 min. The PCR product was digested with 3 units of Fnu4H1 (Fermentas, Lithuania) at 37 °C for 16 h, and then electrophoresed on a 6 % polyacrylamide gel (Applichem). The Cys/Cys homozygote is cleaved by Fnu4HI, and yields 2 bands (100 bp and 107 bp bands). The Ser/Ser homozygote is not cleaved by FNU4HI, and the single 207 bp band remains. The Ser/Cys heterozygote contains all 3 bands (100 bp, 107 bp, and 207 bp bands) following restriction digestion (26). Negative controls (no template) and positive controls were included in all sets.Detection of urinary 8-OHdG levelsStressgen’s StressXpress DNA Damage ELISA (enzyme-linked immunosorbent assay) (Stressgen Bioreagents) is a fast and sensitive competitive immunoassay for the detection and quantitation of 8-OHdG in spot urine samples. Measurement of urinary 8-OHdG is useful as an indicator of oxidative damage. Urine samples were diluted with sample diluents. We determined the optimal sample dilutions for our particular experiments to avoid being out of the range of the standard curve. Fifty microlitres of each prepared standard and samples were added to the wells of 8-OHdG immunoassay plate in duplicates, and then 50 uL of diluted anti-8-OHdG was added into each well, except for the blank. The plate was Table 1 General characteristics of lung cancer patients and controls Controls Patients p SCLC NSCLC pAge (mean ± SEM) 53.19±0.75 56.99±0.790.0001*57.79±1.42 56.58±0.98&0.05SexWomen / N (%) 83 (33.2) 20 (12.1) 6 (15.8) 14 (11.7)Men / N (%) 167 (66.8) 145 (87.9) 32 (84.2) 106 (88.3)BMI (mean ± SEM) 27.16±0.29 24.94±0.35 25.25±0.86 24.87±0.38SmokingstatusN (%)Never 121 (48.4) 24 (14.5) 5 (13.2) 19 (15.8)Smoker 126 (50.4) 141 (85.5) 33 (86.8) 101 (84.2)Smoker N (%) ≤20 cigarettes per day80 (62) 70 (49.6) 20 (60.6) 47 (46.5)&20 cigarettes per day26 (20.2) 64 (45.4) 13 (39.4) 48 (47.5)Karahalil B, et al. OGG1 GENE POLYMORPHISM AND 8-OHdG LEVELS IN LUNG CANCER PATIENTSArh Hig Rada Toksikol -250
244incubated at room temperature for one hour, and the wells were washed using the wash buffer, and 100 uL of diluted anti-Mouse IgG:HRP conjugate was added to each well, except for the blank. Again, the plate was incubated at room temperature for one hour, and the wells were washed using the wash buffer. One hundred microlitres of TMB substrate were added into each well and the plate was incubated at room temperature for 15 min in the dark. After adding 100 uL acid stop solution into each well, absorbance was measured at 450 nm. The standard curve was in the range of 0.94 ng mL-1 to 60 ng mL-1. The 8-OHdG calibration curve was plotted and 8-OHdG sample concentration was calculated. Urinary 8-OHdGper creatinine levels were expressed after correction for creatinine concentrations and presented as nmol per mmol creatinine.Statistical AnalysesData analysis was performed using SPSS for Windows, version 11.5. Shapiro-Wilk test was used in order to detect whether the continuous variables were normally distributed or not. Descriptive statistics were shown as mean ± standard error for continuous data. The differences regarding continuous variables were evaluated using the Mann-Whitney U test or Kruskal-Wallis, according to the number of independent groups. When the p-value from the Kruskal-Wallis test was statistically significant, we applied the Kruskal Wallis multiple comparison tests to see which groups differed from which. Categorical comparisons were evaluated using the chi-square or Fisher’s exact test, where applicable. Multiple logistic regression analysis was adjusted for age, sex, BMI, and smoking status. Odds ratio and 95 %CIs for each independent variable were calculated. The Bonferroni correction was applied for all possible within-group comparisons. A p value of less than 0.05 was considered statistically significant.RESULTSWe tested the association between OGG1 Ser326Cys polymorphism and the risk of lung cancer in a population-based, case control study of 165 cases and 250 controls in the Turkish population. Among the lung cancer patients, 23 % (n=38) were diagnosed SCLC, 72.7 % (n=120) NSCLC, and the remaining 7.2 % (n=7) were of unknown histological type. The subtypes of NSCLC were adenocarcinoma (25 %), squamous cell carcinoma (34.2 %), and 40.8 % was unknown.The allele frequency of the variant G allele for OGG1 Ser326Cys was 0.28 for the lung cancer patients and 0.33 for controls. The prevalence of this polymorphism followed the Hardy-Weinberg equilibrium. The frequency distributions of alleles for OGG1 are shown in Table 2. To determine whether the OGG1 326Cys allele contributed to the increased risk of lung cancer, we compared the prevalence of OGG1 alleles in lung cancer patients and control subjects. The more common allele 326Ser was considered the reference genotype, whereas the less common allele 326Cys was examined as the variant. ORs were adjusted for age, sex, BMI, and smoking status. There was no association between the polymorphism in OGG1 Ser326Cys and the risk of lung cancer (OGG1 Ser326Cys ORadj=0.87; 95 % CI=0.551-1.36; p=0.531 and OGG1 Cys326Cys ORadj=0.59; 95 % CI=0.283-1.235; p=0.162).The contribution of the OGG1 Ser326Cys polymorphism in each histological sub-type is shown in Table 3. To assess whether OGG1 Ser326Cys polymorphism was associated with histological sub-types of the lung cancer, cases were stratified according to tumour histological classification. When stratified by histology, a significant decrease in risk was observed in SCLC sub-group for Ser326Cys genotype. However, it was no longer significant when the groups were adjusted for age, sex, and smoking. No association was observed between NSCLC and the OGG1 Ser326Cys polymorphism. The OGG1 polymorphism did not significantly alter lung cancer risk by sex (p&0.05 in the crude and adjusted analysis). This suggests that sex is not the confounder of lung cancer risk.Table 2 Association between the OGG1 genotypes and lung cancer risk GenotypeControlsn (%)Patientsn (%)Crude OR(CI 95 %)pAdjusted OR(CI 95 %)pSer/Ser 115 (46) 86 (52.1) 1 1Ser/Cys
106 (42.4) 65 (39.4) 0.82 (0.541-1.244) 0.35 0.87 (0.551-1.36) 0.531Cys/Cys 29 (11.6) 14 (8.5) 0.65 (0.322-1.295) 0.218 0.59 (0.283-1.235) 0.162Karahalil B, et al. OGG1 GENE POLYMORPHISM AND 8-OHdG LEVELS IN LUNG CANCER PATIENTSArh Hig Rada Toksikol -250
245The analysis of potential interaction between the OGG1 polymorphism and cigarette smoking on the risk of lung cancer (Table 4) showed no association between the OGG1 Ser326Cys polymorphism and lung cancer risk regarding to smoking status. Furthermore, variant genotypes were not individual risk factors in light smokers (&20 cigarettes per day). On the other hand, OGG1 variant genotypes were inversely associated with the risk of lung cancer in subjects who smoked more than 20 cigarettes per day, suggesting the protective effect of the genotype in heavy smokers. We also measured the levels of urinary 8-OHdG as a biomarker of oxidative DNA damage in urine samples from 72 lung cancer patients (13 women, 59 men) who did not receive any chemotherapy and radiotherapy as well as in 61 (age and sex matched) control subjects (17 women, 44 men). The mean age of lung cancer patients and controls did not significantly differ (mean ± SEM; 56.50±1.30 years vs. 54.84±1.38 years, p&0.05). Mean BMI of the control subjects was higher than in the lung cancer patients (p&0.05).Table 5 shows the levels of urinary 8-OHdG in lung cancer and control subjects according to sex, age, smoking status, and histological sub-types. There was no significant difference in the levels of urinary 8-OHdG between the lung cancer patients and control subjects. Neither sex nor age contributed (the subjects
≤60 and &60 years) to the levels of urinary 8-OHdG levels in either lung cancer patients or controls. Our data showed that smoking Table 3 Association between the OGG1 Ser326Cys polymorphisms and lung cancer risk, stratified by histology and sexGenotypeControlsn (%)Patientsn (%)Crude OR(CI 95 %)pAdjusted OR(CI 95 %)pHistologicalsub-typesSCLC(n=38)Ser/Ser 115 (46) 25 (65.8) 1 1Ser/Cys 106 (42.4) 10 (26.3) 0.43 (0.199-0.946) 0.036* 0.56 (0.232-1.331) 0.188Cys/Cys 29 (11.6) 3 (7.9) 0.48 (0.134-1.686) 0.25 0.55 (0.145-2.078) 0.378NSCLC(n=120)Ser/Ser 115 (46) 59 (49.2) 1 1Ser/Cys 106 (42.4) 50 (41.7) 0.92 (0.580-1.456) 0.72 1.01 (0.602-1.683) 0.980Cys/Cys 29 (11.6) 11 (9.2) 0.74 (0.345-1.584) 0.437 0.68 (0.299-1.542) 0.355SexWomenSer/Ser 37 (44.6) 10 (50) 1 1Ser/Cys 36(43.4) 9 (45) 0.93 (0.337-2.541) 0.880 0.92 (0.335-2.548) 0.878Cys/Cys 10 (12) 1(5) 0.37 (0.42-3.244) 0.369 0.37 (0.042-3.269) 0.371MenSer/Ser 78 (46.7) 76 (52.4) 1 1Ser/Cys 70 (41.9) 56 (38.6) 0.82 (0.512-1.317) 0.413 0.84 (0.503-1.404) 0.507Cys/Cys 19 (11.4) 13 (9) 0.70 (0.324-1.521) 0.370 0.65 (0.288-1.474) 0.304Table 4 Association between the OGG1 Ser326Cys polymorphisms and lung cancer risk according to smoking statusGenotypeControls PatientsCrude OR (CI 95 %)PAdjusted ORpn (%) n (%) (CI 95 %)SmokingstatusNeverSer/Ser 55 (45.5) 12 (50) 1
55 (45.5) 11 (45.8)
0.92 (0.373-2.253) 0.85 0.87 (0.349-2.166) 0.764Cys/Cys 11 (9) 1 (4.2) 0.42 (0.049-3.542) 0.423 0.41 (0.048-3.55) 0.419SmokerSer/Ser 59 (46.8) 74 (52.5) 1
49 (38.9) 54 (38.3) 0.88 (0.524-1.472) 0.623 0.84 (0.487-1.464) 0.547Cys/Cys 18 (14.3) 13 (9.2) 0.58 (0.261-1.270) 0.172 0.62 (0.266-1.431) 0.26Smokers≤20cigarettesper daySer/Ser 37 (46.3) 33 (47.1) 1
33 (41.2) 32 (45.7) 1.09 (0.553-2.137) 0.808 1.11 (0.543-2.266) 0.777Cys/Cys 10 (12.5) 5 (7.2) 0.56 (0.174-1.809) 0.333 0.76 (0.218-2.668) 0.671&20cigarettesper daySer/Ser 9 (34.6) 38 (59.4) 1
11 (42.3) 18 (28.1) 0.39 (0.136-1.101) 0.075 0.30 (0.095-0.939) 0.039*Cys/Cys 6 (23.1) 8 (12.5) 0.32 (0.87-1.140) 0.078 0.22 (0.055-0.915) 0.037*Karahalil B, et al. OGG1 GENE POLYMORPHISM AND 8-OHdG LEVELS IN LUNG CANCER PATIENTSArh Hig Rada Toksikol -250
246had no effect on the levels of urinary 8-OHdG in either group (p&0.05). Furthermore, control 8-OHdG levels did not significantly differ from those in SCLC or NSCLC patients. In this study, we further investigated the association between urinary 8-OHdG levels and OGG1 Ser326Cys polymorphism (Table 6) and found that the excretion of 8-OHdG was not associated with the OGG1 Ser326Cys polymorphism. In lung cancer patients, there was no effect of the OGG1 Ser326Cys polymorphism on the levels of urinary 8-OHdG. On the other hand, in the control subjects, urinary 8-OHdG levels of subjects with the Ser326Ser genotype were found to be higher than in subjects with the Ser326Cys (p=0.006) and Cys326Cys (p=0.008) genotypes. However, no difference was observed between variant genotypes (p=0.179). Our data demonstrated that the urinary 8-OHdG excretion was not affected by the OGG1 Ser326Cys polymorphism in respect to smoking.Table 5 The effect of 8-OHdG excretion (nmol mmol-1 of creatinine) according to demographic characteristics GroupsControls Lung cancer patientsp**n8-OHdG /nmol mmol-1mean±SEMpn8-OHdG /nmol mmol-1mean±SEMpTotal 61 70.03±7.11
72 67.26 ±5.63
0.946SexWomen: 17 65.46±11.650.98713 66.90±13.400.8780.967Men: 44 71.80±8.83 59 67.34±6.26 0.920Age&60 year 39 67.25±8.050.92843 59.74±6.270.2300.659≥60 year 22 74.96±13.82 29 78.41±10.24 0.834SmokingstatusNever 35 63.81±8.650.33718 66.68±9.670.7000.523Former 15 77.32±11.33 29 69.52±8.65 0.480Current 11 79.90±24.43 25 65.06±10.99 0.919Histologicalsub-typesSCLC 61 70.03±7.11 10 89.05±15.970.1240.173NSCLC 61 70.03±7.11 61 63.93±6.04 0.619p**: Statistical analysis between lung cancer patients and controlsTable 6 Effect of the OGG1 Ser326Cys genotypes on the levels of urinary 8-OHdG (nmol mmol-1 of creatinine)GenotypeControls Patientsp**n8-OHdG /nmol mmol-1mean±SEMpn#8-OHdG /nmol mmol-1mean±SEMpTotalSer/Ser 26 87.65±11.350.015*33 65.96±9.280.8600.079Ser/Cys 31 59.50±9.28 24 67.01±8.14 0.186Cys/Cys 4 37.12±21.08 7 82.05±24.52 0.648SmokingstatusNeverSer/Ser 16 83.46±14.690.036o9 53.61±12.830.6060.207Ser/Cys 15 49.96±9.78 5 70.73±14.92 0.197Cys/Cys 4 37.12±21.08 1 158.79FormerSer/Ser 5 78.98±18.000.85913 72.23±14.230.9550.703Ser/Cys 10 76.49±15.08 12 69.70±13.52 0.674Cys/Cys 0 0 2 64.43±20.51
CurrentSer/Ser 5 109.74±33.410.12611 68.65±20.320.9190.267Ser/Cys 6 55.03±34.23 7 59.74±13.35 0.101Cys/Cys 0 0 4 71.67±38.16
n#: no genotype data for 8 lung cancer subjectsp**: statistical analysis between lung cancer patients and controlso: not significant according to Bonferroni correction(p&0.025)Karahalil B, et al. OGG1 GENE POLYMORPHISM AND 8-OHdG LEVELS IN LUNG CANCER PATIENTSArh Hig Rada Toksikol -250
247DISCUSSIONOxidative DNA damage is believed to be implicated in lung carcinogenesis. The potential mechanism of carcinogenesis in the lung tissue may involve tissue damage and regeneration in the presence of a high ROS release from inflammatory cells that can interact with DNA in epithelial cells to produce permanent genomic mutations (27). One of them, 8-OHG is a mutagenic and most common oxidative modification of guanine, and has a pivotal role in the development of lung cancer. Base excision repair (BER) is a highly conserved essential mechanism for maintaining genome integrity. Impaired BER function can give rise to the accumulation of 8-OHG lesion and other DNA base lesions, which may influence the initiation and progression of cancer (28). OGG1 is a key enzyme in short-patch BER because it recognises and performs initial excision of the most common form of oxidative DNA base damage, 8-OHG (29). OGG1 encodes an 8-oxoguanine DNA glycosylase/AP lyase that catalyzes the removal of 8-OHG from DNA (30). There are many polymorphisms found in the OGG1 gene. The most studied is the single nucleotide polymorphism at codon 326 (Ser326Cys). Homozygous carriers of the variant form of the OGG1 Ser326Cys gene appear to have reduced repair capacity for oxidised DNA lesions (31, 32), but this association has not been found in all investigations (33).Epidemiological studies of the OGG1 Ser326Cys polymorphism in relation to cancer have yielded mixed results with a weak association between the OGG1 Ser326Cys genotype and the risk of lung cancer (18, 33-35). Since there have been contradictory findings so far, we conducted a case-control study of 165 lung cancer cases and 250 controls using PCR-RFLP method to identify the Ser326Cys and a questionnaire approach to investigate its association with lung cancer risk and possible interaction with smoking. We found that the distribution of the OGG1 Ser326Cys genotypes in controls (Ser/Ser, 46.0 %; Ser/Cys, 42.4 %; and Cys/Cys 11.6 %) did not significantly differ from lung cancer patients (52.1 %, 39.4 %, and 8.5 %, respectively) (p&0.05). No statistically significant associations between the OGG1 Ser326Cys polymorphism and lung cancer risk were observed. Our results are similar to Wikman et al. and some other authors (19, 36-38). Wikman et al. carried out a case-control study to investigate the association between the OGG1 Ser326Cys polymorphism and the risk of lung cancer. They found no major difference in Ser326Cys genotype distribution between lung cancer patients and controls and suggested the studied hOGG1 polymorphisms were probably not major contributors to individual lung cancer susceptibility in Caucasians (19). Hung et al. also observed that there were no such associations between them (36, 37).Sorensen et al. examined the associations between polymorphism and the intake of fruits and vegetables and smoking in the development of lung cancer in 431 lung cancer patients and 796 controls. They found no overall association between the OGG1 polymorphism and lung cancer (38). Vogel et al. did not find any association between the polymorphisms OGG1 Ser326Cys and the risk of lung cancer (37). Sugimura et al. found that the Ser326Cys polymorphism was not associated with an increased risk of lung ca however, when homozygous Cys326Cys were compared with other genotypes in combination, an increased risk was observed for the squamous cell carcinoma and nonadenocarcinoma after adjustment for age and smoking (17). On the other hand, Ito et al. did not find any effects of the OGG1 Ser326Cys polymorphism on the development of either adenocarcinomas or small cell carcinoma (39). In our study, we found a significant decrease in the risk of SCLC for the Ser326Cys genotype, but this significance disappeared after adjusting for age, sex, and smoking. A reduced cancer risk associated with the OGG1 Ser326Cys polymorphism, as found in our study, has previously been reported by De Ruyck et al. (22). We believe that this may be due to an adaptive response with alternative pathyways. Thus, proteins that play an important role in other repair pathways (NER), especially NEIL1 and MUTYH proteins, may be involved in the repair and prevention of 8-oxodG-derived mutations and may be up-regulated by oxidative stress in subjects with the Ser326Cys polymorphism. Furthermore, NEIL1 is able to excise lesions where OGG1 has very limited activity.We could not find any modifying effect of smoking combined with the OGG1 Ser326Cys polymorphism that may contribute to lung cancer development. The OR for smoking was not statistically different across the genotypes, but the sample size was too small to detect even a moderate interaction. Our results corroborate the findings by Ito et al. (39). Additional studies, especially on mRNA expression levels, need to be conducted to confirm this association.In this study, there was no difference between lung cancer patients and control subjects in the levels of urinary 8-OHdG. Our results are similar to Loft et Karahalil B, et al. OGG1 GENE POLYMORPHISM AND 8-OHdG LEVELS IN LUNG CANCER PATIENTSArh Hig Rada Toksikol -250
248al. (40) and Erhola et al.(41). Increased 8-OHdG excretion in controls indicates that their repair capacity is more effective than in the lung cancer patients.Accumulating evidence seems to support the association between the OGG1 Ser326Cys polymorphism and smoking-related cancers, but the small sample size in our study and the presence of many conflicting data call for further studies on the association between the OGG1 Ser326Cys polymorphism and lung cancer, especially for studies that would include the smoking status in different populations with larger sample sizes. In conclusion, the OGG1 Ser326Cys polymorphism cannot explain individual variation in lung cancer susceptibility in humans. Future studies that investigate the mRNA expression, the activity of OGG1 protein, DNA repair capacity and excretion of DNA repair products are required to better understand the role of DNA damage in lung cancer.AcknowledgementThis study was supported by Gazi University Scientific Research Foundation of Turkey (Project No: 02/2006-12)Conflict of Interest StatementThe authors declare that they have no competing financial interests.REFERENCES1.
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250Sa`etakPOVEZANOST OGG1 Ser326Cys POLIMORFIZMA I RAZINA 8-OHdG U MOKRA]I SA SKLONOSTI OBOLIJEVANJU OD KARCINOMA PLU]A: REZULTATI ISPITIVANJA NA BOLESNICIMA I KONTROLNOJ POPULACIJI U TURSKOJKarcinom plu}a velik je javnozdravstveni problem u ~itavom svijetu zbog svoje visoke u~estalosti i lo{e prognoze. Premda je navika pu{enja jedan od glavnih uzro~nika karcinoma plu}a, od ove bolesti oboli samo dio populacije pu{a~a, {to govori u prilog postojanju genetske predispozicije za njezin nastanak. 8-OHG je oksidativno o{te}enje baze u molekuli DNA ~ija se u~estalost mo`e pove}ati zbog zlo}udnih tumora i pu{enja. U popravku tog o{te}enja sudjeluje enzim 8-hidroksigvanin DNA-glikozilaza (OGG1) za koji je dokazano postojanje polimorfizma. Iako se polimorfizam Ser326Cys ~esto dovodi u vezu s razli~itim vrstama zlo}udnih bolesti, dosada{nji su rezultati o vezi izme|u polimorfizma tog enzima i rizika od pojave karcinoma plu}a kontradiktorni. Do danas na turskoj populaciji nisu provedena istra`ivanja koja bi dala jasne odgovore o toj povezanosti. Ovo je istra`ivanje usporedo provedeno u bolesnika i u zdravoj populaciji primjenom metode PCR-RFLP s ciljem utvr|ivanja mogu}e povezanosti polimorfizma OGG1 Ser326Cys i rizika od karcinoma plu}a. Nadalje, istra`ena je interakcija gena i navike pu{enja te ekskrecija 8-OHdG u mokra}i. Dobiveni rezultati pokazuju da polimorfizam OGG1 Ser326Cys nije genetski ~imbenik rizika od pojave karcinoma plu}a, a pokazalo se da je heterozigotni genotip povezan sa zna~ajno ni`im rizikom od karcinoma plu}a. Razine 8-OHdG izmjerene u mokra}i nisu bile u korelaciji ni s polimorfizmom ni s navikom pu{enja. Zaklju~ujemo da su za vrednovanje dobivenih rezultata potrebna istra`ivanja na jo{ ve}em broju ispitanika te mehanisti~ka istra`ivanja koja bi mogla razjasniti molekularne mehanizme koji su u pozadini ove povezanosti.KLJU^NE RIJE^I: bolest, ELISA, farmakogenomika, genetska varijacija, oksidativni stres, RFLPCORRESPONDING AUTHOR:Professor Bensu KarahalilGazi University, Faculty of PharmacyDepartment of Toxicology 06330, Hipodrom, Ankara, TurkeyE-mail: Karahalil B, et al. OGG1 GENE POLYMORPHISM AND 8-OHdG LEVELS IN LUNG CANCER PATIENTSArh Hig Rada Toksikol -250
&The studies by Liang et al21, Zienolddiny et al22, and Liu et
al23 were excluded because the genotype distribution among the controls was deviated significantly from HWE (P&0.05). Finally, 20 articles, including 8739 lung cancer cases and 10385 controls were ascertained for use in our meta-analysis4041.We treated each ethnic population within each paper as a separate study to perform an ethnicity-based subgroup analysis. In a multi-ethnic study by Le et al27, the data were extracted into Asian, Caucasian, and Hawaiian subgroups. &ABSTRACT: hOGG1 encodes a DNA repair enzyme responsible for the excision of reactive oxygen species (ROS) in damaged DNA. Previous studies have obtained inconsistent results. To validate the association between the hOGG1Ser326Cys polymorphism and lung cancer risk, we performed an updated meta-analysis of 20 studies (8739 cases and 10385 controls) using STATA version 11.1. With this approach, we tested the overall and subgroup association between the SNP and lung cancer susceptibility stratified by ethnicity, control sources, cell histotypes, and smoking status. We demonstrated a novel, significant correlation between the hOGG1 Ser326Cys polymorphism and increased lung cancer susceptibility in Caucasians. Our findings indicate a need for larger-scale studies to verify the association of this SNP with lung cancer risk in Caucasians. Full-text · Article · Jul 2012 +1more author...[...]&However, these were not found in ours, may be attributed to a larger sample size. Previous studies demonstrated that genetic variation in OGG1 affects c the frequency of the OGG1 326Cys allele was found to be significantly higher in patients when compared with controls [22,24,25,37,38] ; however, this association was not replicated by other studies [9,. Overall, we did not found that individuals carrying the Cys/Cys genotype had significantly increased risk of lung cancer when compared with the Ser/Ser genotype, no significant association with lung cancer risk was found in dominant model, recessive model and heterozygous co-dominant model (Ser/Cys vs. Cys/Cys). &ABSTRACT: Numerous studies have investigated association of OGG1 Ser326Cys polymorphism with lung c 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.
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.
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/S 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.
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. Full-text · Article · Apr 2012 +1more author...[...]&The hOGG1, which is generally involved in DNA repair, has been studied extensively on its relationship with different types of cancer, such as breast, prostate25, pancreatic [26,27], bladder34, gallbladder, gastric, colorectal6263, esophageal, lung, cervical cancers [86,87], and so on100101. Previous conclusions of numerous studies on the association between the hOGG1 Ser326Cys polymorphism and cancer risk remain conflicting and contradictory. &ABSTRACT: Human oxoguanine glycosylase 1 (hOGG1) in base excision repair (BER) pathway plays a vital role in DNA repair. Numerous epidemiological studies have evaluated the association between hOGG1 Ser326Cys polymorphism and the risk of cancer. However, the results of these studies on the association remain conflicting. To derive a more precise estimation of the association, we conducted a meta-analysis.
A comprehensive search was conducted to identify the eligible studies of hOGG1 Ser326Cys polymorphism and cancer risk. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. We found that the hOGG1 Ser326Cys polymorphism was significantly associated with overall cancer risk (Cys/Cys vs. Ser/Ser: OR = 1.19, 95%CI = 1.09-1.30, P&0.001; Cys/Cys vs. Cys/Ser+Ser/Ser: OR = 1.16, 95%CI = 1.08-1.26, P&0.001). Moreover, in subgroup analyses by cancer types, the stronger significant association between hOGG1 Ser326Cys polymorphism and lung cancer risk was found (Cys/Cys vs. Ser/Ser: OR = 1.29, 95%CI = 1.16-1.44, P&0.001; Cys/Cys vs. Cys/Ser+Ser/Ser: OR = 1.22, 95%CI = 1.12-1.33, P&0.001). The significant effects of hOGG1 Ser326Cys polymorphism on colorectal, breast, bladder, prostate, esophageal, and gastric cancer were not detected. In addition, in subgroup analyses by ethnicities, we found that the hOGG1 Ser326Cys polymorphism was associated with overall cancer risk in Asians (Cys/Cys vs. Ser/Ser: OR = 1.21, 95%CI = 1.10-1.33, P&0.001).
This meta-analysis showed that hOGG1 326Cys allele might be a low-penetrant risk factor for lung cancer. Full-text · Article · Nov 2011 +1more author...[...]ArticleJuly 2016 · Cancer Epidemiology Biomarkers & Prevention · Impact Factor: 4.13+1 more author…ArticleJuly 2016 · Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis · Impact Factor: 3.68+5 more authors…ArticleJuly 2016 · Lung Cancer · Impact Factor: 3.96+2 more authors…ArticleJuly 2016 · Molecular Biology Reports · Impact Factor: 2.02+1 more author…Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.Author can archive a pre-print versionPublished source must be acknowledgedMust link to journal homepage with DOICreative Commons Attribution Non-Commercial No Derivatives LicensePublisher's version/PDF may be usedNIH Authors articles will be automatically submitted to PubMed Central upon online publicationIf required by funding agency, authors may use a Creative Commons Attribution LicenseAll titles are open access journalsPublisher last contacted on 27/03/2014'De Gruyter Open' is an imprint of 'De Gruyter'Last Updated: 17 Jul 16
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