Correlation between X-ray cross-complementing group 1 polymorphisms and the onset risk of glioma A meta-analysis

OBJECTIVE： To evaluate the association of X-ray cross-complementing group 1 （XRCC1） Arg399GIn, Arg194Trp and Arg280His polymorphisms with the risk of glioma. DATA SOURCES： A systematic literature search of papers published from January 2000 to August 2012 in PubMed, Embase, China National Knowledge Infrastructure database, and Wanfang da- tabase was performed. The key words used were ＂glioma＂, ＂polymorphism＂, and ＂XRCC1 or X-ray repair cross-complementing group 1＂. References cited in the retrieved articles were screened manually to identify additional eligible studies. STUDY SELECTION： Studies were identified according to the following inclusion criteria： case-control design was based on unrelated individuals; and genotype frequency was available to estimate an odds ratio （OR） and 95% confidence interval （CI）. Meta-analysis was performed for the selected studies after strict screening. Dominant and recessive genetic models were used and the relationship between homozygous mutant genotype frequencies and mutant gene frequency and glioma incidence was investigated. We chose the fixed or random effect model according to the heterogeneity to calculate OR and 95%CI, and sensitivity analyses were conducted. Publication bias was examined using the inverted funnel plot and the Egger＇s test using Stata 12.0 software. MAIN OUTCOME MEASURES： Association of XRCC1 Arg399GIn, Arg194Trp, and Arg280His polymorphisms with the risk of glioma, and subgroup analyses were performed according to differ- ent ethnicities of the subjects.RESULTS： Twelve articles were included in the meta-analysis. Eleven of the articles were concerned with the Arg399GIn polymorphism and glioma onset risk. Significantly increased glioma risks were found only in the dominant model （Gin/Gin ＋ GIn/Arg versus Arg/Arg： OR = 1.26, 95%CI= 1.03-1.54, P = 0.02）. In the subgroup analysis by ethnicity, significantly increased risk was found in Asian subjects in the recessive （OR = 1.46, 95%CI= 1.04-2.45, P = 0.03） and dominant models （OR = 1.40, 95%CI= 1.10-1.78, P = 0.007）, and homozygote contrast （OR = 1.69, 95%CI= 1.17-2.45, P = 0.005）, but not in Caucasian sub- jects. For association of the Arg194Trp （eight studies） and Arg280His （four studies） polymorphisms with glioma risk, the meta-analysis did not reveal a significant effect in the allele contrast, the recessive genetic model, the dominant genetic model, or homozygote contrast. CONCLUSION： The XRCC1 Arg399GIn polymorphism may be a biomarker of glioma susceptibility, espe- cially in Asian populations. The Arg194Trp and Arg280His polymorphisms were not associated with overall glioma risk.

Prognostic significance of X-ray cross-complementing gene 1 expression in gastric cancer

Objective： The aim of this study is to identify the prognostic significance of X-ray cross-complementing gene 1 （XRCCI） in patients with gastric cancer undergoing surgery and platinum-based adjuvant chemotherapy. Methods： Immunohistochemistry （IHC） was used to evaluate XRCCI protein expression profiles on surgical specimens of 612 gastric cancer patients. The relationship between XRCC1 expression and existing prognostic factors, platinum-based adjuvant chemotherapy, disease-free survival （DFS） and overall survival （OS） were analyzed. Results： Among 612 patients staged II/III in our study, 182 （29.74%） were evaluated as XRCC1 IHC positive. XRCC1 expression was not significantly related to OS （P=0.347） or DFS （P=0.297）. Compared with surgery only, platinum-based adjuvant chemotherapy significantly improved the OS （P=0.031）. And the patients with negative XRCC1 expression benefited more from platinum-based adjuvant chemotherapy （P=0.049）. Multivariate analysis demonstrated that tumor size, T category, N category, vascular or nerve invasion and platinum-based chemotherapy were good prognostic factors for OS （P〈0.05）. Though XRCCI plays an important role in DNA repair pathways, no significant relationship is found in XRCCI expression and OS among gastric cancer in our study. Conclusions： XRCC1 might be an alternative prognostic marker for the patients of gastric cancer after radical resection. The patients with negative XRCC1 expression can benefit more from platinum-based adjuvant chemotherapy.

Tea polyphenols increase X-ray repair cross-complementing protein 1 and apurinic/apyrimidinic endonuclease/redox factor-1 expression in the hippocampus of rats during cerebral ischemia/reperfusion injury

Recent studies have shown that tea polyphenols can cross the blood-brain barrier, inhibit apoptosis and play a neuroprotective role against cerebral ischemia. Furthermore, tea polyphenols can decrease DNA damage caused by free radicals. We hypothesized that tea polyphenols repair DNA damage and inhibit neuronal apoptosis during global cerebral ischemia/reperfusion. To test this hypothesis, we employed a rat model of global cerebral ischemia/reperfusion. We demonstrated that intraperitoneal injection of tea polyphenols immediately after reperfusion significantly reduced apoptosis in the hippocampal CA1 region; this effect started 6 hours following reperfusion. Immunohistochemical staining showed that tea polyphenols could reverse the ischemia/reperfusion-induced reduction in the expression of DNA repair proteins, X-ray repair cross-complementing protein 1 and apudnic/apyrimidinic endonuclease/redox factor-1 starting at 2 hours. Both effects lasted at least 72 hours. These experimental findings suggest that tea polyphenols promote DNA damage repair and protect against apoptosis in the brain.

XRCC1基因多态性与宫颈鳞癌放疗敏感性的关系

目的探讨XRCC1基因Arg194Trp、Arg399Gln单核苷酸多态性(SNP)与外生型宫颈鳞状细胞癌放疗敏感性的关系。方法选择经组织病理学确诊的外生型宫颈鳞状细胞癌患者73例。其中临床分期Ⅰ期4例,Ⅱ期36例,Ⅲ期30例,Ⅳ期3例。肿瘤直径≤4 cm 30例,肿瘤直径>4 cm 43例;A点剂量≤80 Gy者36例,A点剂量>80 Gy者37例。近期疗效为完全缓解者(CR组)47例,部分缓解者(PR组)26例。采用错配扩增聚合酶链式反应检测患者血液标本的XRCC1 Arg194Trp、Arg399Gln SNP的基因型频率分布,分析其与宫颈癌放疗敏感性的关系。结果 XRCC1基因Arg194Trp分型中,携带Arg/Arg、Arg/Trp、TrP/Trp分别有31例(42.5%)、37例(50.7%)、5例(6.8%);Arg399Gln分型中,携带Arg/Arg、Arg/Gln、Gln/Gln分别有26例(35.6%)、39例(53.4%)、8例(11.0%)。CR组与PR组Arg194Trp、Arg399Gln基因型分布差异均无统计学意义。影响放疗敏感性的多因素Logistic回归分析结果显示,临床分期晚为PR的危险因素。结论 XRCC1基因Arg194TrpSNP、Arg399Gln SNP与外生型宫颈鳞状细胞癌放疗敏感性无相关性。临床分期越晚放疗敏感性越差。

DNA repair gene XRCC1 polymorphisms and susceptibility to childhood acute lymphoblastic leukemia: a meta-analysis

Objective： To estimate the relationship between genetic polymorphisms of X-ray repair cross- complementing group 1 （XRCC1） and the susceptibility to childhood acute lymphoblastic leukemia （ALL）. Methods： Relevant case-control studies were enrolled in the meta-analysis. We applied Rev Man 4.2 software to pool raw data and test studies＇ heterogeneity and to calculate the incorporated odds ratio （OR） and 95% confidence interval （95% CI）. Results： Our data showed that the OR for the Gln allele of the Arg399Gln polymorphism, compared with the Arg allele, was 1.35 （95% CI, 1.16-1.57; P〈0.0001） for childhood ALL patients. Similarly, the homozygous genotype Gln/Gln and heterozygous genotype Arg/Gln both significantly increased the risk of childhood ALL compared with the wild genotype Arg/Arg （OR =1.58; 95% CI, 1.13-2.21; P=0.008; OR =1.51; 95% CI, 1.21-1.87; P=0.0002）. The dominant model of Arg399Gln was associated with childhood ALL risk （OR =1.54; 95% CI, 1.25-1.89; P〈0.0001）. The ethnic subgroup analysis demonstrated that the Gln allele in all five ethnic groups was prone to be a risk factor for childhood ALL just with different degrees of correlation while Arg194Trp SNP showed a protective or risk factor or irrelevant thing in different races. Conclusions： XRCC1 399 polymorphism may increase the risk of childhood ALL. Different ethnic groups with some gene polymorphism have different disease risks.

Polymorphisms of UGT1A7 and XRCC1 are Associated with an Increased Risk of Hepatocellular Carcinoma in Northeast China

Objective： Hepatocellular carcinoma （HCC） is a complex disease which associates with both environmental and genetic factors. The purpose of this study was to investigate whether the genetic polymorphisms of UDP-glucuronosyltransferase（UGT1A7）, an important phase II biotransformation enzyme, and X-ray repair cross-complementing group 1（XRCC1）, a pivotal DNA-repair gene, were related to the risk of HCC in Northeast China. Methods： One hundred and thirty six HCC patients and one hundred and thirty six frequency-matched controls were included in this hospital-based case-control study. Genotypes of UGT1A7 and XRCC1 were determined using allele-specific polymerase chain reaction （AS-PCR） and PCR-restriction fragment length polymorphism （RFLP）, and for which the odds ratio （OR） with 95% confidence interval （95% CI） were calculated. Results： The proportion of UGT1A7 low enzymatic allele （＊2 or ＊3） was higher in HCC patients than those in controls. The UGT1A7＊1/＊2 and ＊3/＊3 genotypes were associated with higher HCC risk （OR=2.09, 95%CI： 1.10-3.97; OR=5.67, 95%CI： 1.76-18.30, respectively）. The XRCC1 codon 399 Arg/Gln genotype could also elevate HCC risk （OR=2.16, 95% CI 1.29-3.61）. In addition to polymorphisms of UGT1A7 and XRCC1, multivariate logistic regression analysis demonstrated that other significant independent factors associated with HCC were HBV infection （OR=68.07, 95%CI： 28.03-165.26）, HCV infection （OR=30.97, 95%CI： 8.06-118.94） and family history of HCC （OR=10.62, 95%CI： 2.22-50.77）. Conclusion： The study shows that the polymorphisms of UGT1A7 and XRCC1 are associated with HCC risk. Determination of the polymorphisms of UGT1A7 and XRCC1 may provide an important clue to preventive measure against HCC.

Neuronal effects of SP600125 pretreatment in a rat model of cerebral ischemia/reperfusion injury Inhibited down-regulation of DNA repair protein

BACKGROUND： Recent studies have shown that the selective inhibitor of c-Jun N-terminal kinases （JNKs） signaling pathway, SP600125, exhibits neuronal protective effects in a rat model of brain ischemia/reperfusion. OBJECTIVE： To determine the mechanisms of neuroprotective effects of SP600125 in a rat model of brain ischemia/reperfusion, and determine the role of the JNK signaling pathway in SP600125-induced effects. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Animal Experiment Center, Medical School of Xi＇an Jiaotong University from June 2007 to September 2008. MATERIALS： SP600125 was provided by Biosource, USA; rabbit anti-phospho-JNK （Thr183/Tyr185） polyclonal antibody from Cell Signaling Technology, USA; rabbit anti-X-ray repair cross-complementing protein 1 （XRCC1） and anti-Ku70 polyclonal antibodies from Santa Cruz Biotechnology, USA; and TUNEL kit from Beijing Huamei Biology, China. METHODS： A total of 108 male, 4-month-old, Sprague Dawley rats were randomly assigned to three groups, with 36 rats per group. The sham operation group and ischemia/reperfusion group （I/R group） were intracerebroventricularly injected with 10 μL 1% DMSO. The SP600125-treated group （pre-SP group） was given 10 μL SP600125 （3 μg/μL）. Thirty minutes later, brain ischemia was induced in the I/R and pre-SP groups using the four-vessel occlusion method. Specifically, whole brain ischemia was induced for 6 minutes, and the clips were released to restore carotid artery blood flow. Rats from each group were observed at 2, 6, 12, 24, 48, and 72 hours, with 6 rats for each time point. The sham operation group was treated with the same surgical exposure procedures, with exception of occlusion of the carotid artery. MAIN OUTCOME MEASURES： Hematoxylin-eosin staining was used to observe neuronal survival in the hippocampal CA1 region, TUNEL was used to detect apoptosis in the hippocampal CA1 region, and immunohistochemistry was used to detect expression of phospho-JNK, XRCC1, and Ku70. RESULTS： Following brain ischemia/reperfusion, neuronal survival significantly decreased, and the number of apoptotic cells significantly increased （P 〈 0.01）. Compared with the I/R group, neuronal survival significantly increased in the pre-SP group, and the number of apoptotic cells significantly decreased （P 〈 0.01）. Expression of phospho-JNK increased, and XRCC1 and Ku70 significantly decreased （P 〈 0.05） following ischemia/reperfusion. Compared with the I/R group, expression of phospho-JNK decreased, and XRCC1 and Ku70 significantly increased in the pre-SP group （P 〈 0.05）. Correlation analysis revealed an inverse correlation between phospho-JNK gray value and XRCC1 and Ku70 gray values in the hippocampal CA1 region （r = -0.983, -0.953, P 〈 0.01）. CONCLUSION： SP600125 treatment decreased apoptosis induced by global brain ischemia/reperfusion in the rat hippocampal CA1 region. Results suggested that the neuroprotective effects were due to inhibited phosphorylation of JNK and reduced down-regulation of XRCC1 and Ku70.

XRCC1 Arg194Trp Polymorphism and Risk of Chronic Obstructive Pulmonary Disease

The DNA damage, caused by cigarette smoking, can cause airway cell apoptosis and death, which may be associated with the development of chronic obstructive pulmonary disease （COPD）. However, just 20%-30% smokers develop COPD, which suggests that different degrees of DNA repair cause different outcomes in smokers. X-ray repair cross-complementing group 1 （XRCC 1）, a base excision repair protein, has multiple roles in repairing ROS-mediated, basal DNA damage and single-strand DNA breaks. The present study investigated the association between polymorphism in XRCC1 （Arg399Gln） and susceptibility of COPD. A total of 201 COPD cases and 309 controls were recruited and frequency-matched on age and sex. XRCC1 genotype was determined by PCR-restriction fragment length polymorphism analysis. Overall, compared with those with the XRCC1 Arg/Arg genotype, the risk for COPD had no significant difference among individuals with Trp/Trp genotype. However, after stratifying by smoking status, in former smokers, compared with those with the XRCC1 Arg/Arg genotype, the risk for COPD was significantly reduced among individuals with Trp/Trp genotype （adjusted OR=0.22, 95% CI 0.06-0.85, P=0.028）; after stratifying by smoking exposure, in light smokers, compared with those with the XRCC1 Arg/Arg genotype, the risk for COPD was significantly reduced among individuals with Arg/Trp genotype and Trp/Trp genotype （adjusted OR=0.39, 95% CI 0.16=0.94, P=0.036; 0.24, 95% CI 0.07-0.79, P=0.019, respectively）. In conclusion, XRCC1 Arg194Trp genotype is associated with a reduced risk of developing COPD among former and light smokers.

XRCC1 Polymorphisms and Pancreatic Cancer:A Meta-Analysis

Objective：To assess the association between X-ray repair cross-complementating group 1 （XRCC1） polymorphisms and pancreatic cancer.Methods：We searched MEDLINE,Web of Science and HuGE Navigator at June 2010,and then quantitatively summarized associations of the XRCC1 polymorphisms with pancreatic cancer risk using meta-analysis.Results：Four studies with 1343 cases and 2302 controls were included.Our analysis found：at codon 194,the Trp allele did not decrease pancreatic cancer risk （Arg/Arg versus Trp/Trp：OR=0.97;95% CI：0.48-1.96;P=0.97;Arg/Arg versus Arg/Trp：OR=0.89;95% CI：0.70-1.13;P=0.55;Arg/Trp versus Trp/Trp：OR=1.06;95% CI：0.52-2.16;P=0.90）;at codon 280,only a study showed a nonsignificant association between single nucleotide polymorphism with pancreatic cancer risk;at codon 399,the Gln allele also showed no signi？cant effect on pancreatic cancer compared to Arg allele （Arg/Arg versus Gln/Gln：OR=0.94;95% CI：0.74-1.18;Arg/Arg versus Arg/Gln：OR=0.97;95% CI：0.83-1.13;Arg/Gln versus Gln/Gln：OR=0.97;95% CI：0.77-1.22）.The shape of the funnel plot and the Egger＇s test did not detect any publication bias.Conclusion：There is no evidence that XRCC1 polymorphisms （Arg194Trp,Arg280His,and Arg399Gln） are associated with pancreatic cancer risk.

Relationship between ERCC1 (C8092A) single nucleotide polymorphism and efficacy/toxicity of platinum based chemotherapy in advanced non-small cell lung cancer patients

To assses the effect of single nucleotide polymorphism of excision repair cross-complementation group 1 C8092A on the clinical outcome and toxicity in advanced stage non-small cell lung cancer patients receiving first line platinum based chemotherapy.MethodsThis article is a review of the current research on single nucleotide polymorphism and its effect on treatment outcome and toxicity of advanced stage lung cancer.Conclusion The observations indicate that more advanced studies and trials on C8092A SNPs are needed so as to assess if it could be used as a potential biomarker in the future.

hOGG1 Ser326Cys and XRCC1 Arg399Gln polymorphisms associated with chronic obstructive pulmonary disease

Background Cigarette-smoke induced DNA damage can cause airway cell apoptosis and death, which may be associated with the development of chronic obstructive pulmonary disease （COPD）. However, only 20%-30% of smokers develop COPD, suggesting that different degrees of DNA repair produce different outcomes in smokers, i.e., part of them develop COPD. We investigated the association between polymorphisms in DNA repair genes hOGG1 （Ser326Cys） and XRCC1 （Arg399GIn）, alone or in combination, and susceptibility of COPD. Methods Altogether 201 COPD patients and 309 controls were recruited and frequency-matched on age and sex. hOGG1 and XRCC1 genotypes were determined by PCR-restriction fragment length polymorphism analysis. Results The risk of COPD was not significantly different among individuals with Ser/Cys and Cys/Cys genotypes compared with those with hOGG1 Ser/Ser genotype. The risk of COPD was not significantly different among individuals with Gin/Gin genotype compared with those with XRCC1 Arg/Arg genotype, but it was significantly elevated among individuals with Arg/GIn genotype （adjusted odds ratios （OR）=1.55, 95% confidence intervals （CI） 1.05-2.29, P=0.029）. Assessment of smoking status in current smokers compared with those with hOGG1 Ser/Ser genotype revealed that the risk of COPD was significantly elevated among individuals with Cys/Cys genotype （adjusted OR=5.07, 95% CI 1.84-13.95, P=0.002）. Compared with those with XRCC1 Arg/Arg genotype, the risk of COPD was significantly elevated among individuals with Arg/GIn genotype （adjusted OR=2.77, 95% CI 1.52-5.07, P=-0.001）. Assessment of smoking exposure in light smokers compared with those with hOGG1 Ser/Ser genotype showed that the risk of COPD was significantly elevated among individuals with Cys/Cys genotype （adjusted OR=4.02, 95% CI 1.05-16.80, P=0.042）. Compared with those with XRCC1 Arg/Arg genotype, the risk of COPD was significantly elevated among individuals with Gin/Gin genotype （adjusted OR=4.48, 95% CI 1.35-14.90, P=0.014）. In heavy smokers compared with those with XRCC1 Arg/Arg genotype, the risk of COPD was significantly elevated among individuals with Arg/GIn genotype （adjusted OR= 2.55, 95% CI 1.42-4.58, P=0.002）. When hOGG1 Ser326Cys and XRCC1 Arg399GIn polymorphisms were evaluated together, compared with those with 0-1 of hOGG1 326Cys and XRCC1 399Gin alleles, the risk of COPD was significantly elevated among individuals with 3-4 of hOGG1 326Cys and XRCC1 399Gin alleles （adjusted OR=3.18, 95% CI 1.86-5.43, P=0.000）. Assessment of smoking status and smoking exposure in current/light/heavy smokers showed that the risk of COPD was significantly elevated among individuals with 3-4 of hOGG1 326Cys and XRCC1 399Gin alleles （adjusted OR=8.32, 95% CI 3.59-19.27, P=0.000; OR=5.46, 95% CI 2.06-14.42, P=0.001; OR=2.93, 95% CI 1.43-6.02, P=0.003; respectively）. Conclusions hOGG1 Ser326Cys and XRCC1 Arg399GIn polymorphisms are associated with the susceptibility to COPD. The risk of COPD is significantly elevated among current/light smokers with hOGG1 326Cys and XRCC1 399Gin.