X-ray repair cross-complementing group 1 polymorphisms and hepatocellular carcinoma:A meta-analysis

AIM： To perform a systematic meta-analysis to in- vestigate the association between X-ray repair crosscomplementing group 1 （XRCC1） polymorphisms and hepatocellular carcinoma （HCC） risk. METHODS： Relevant studies extracted from PubMed, Embase, Wanfang, VIP and the Chinese National Knowledge Infrastructure databases up to March 2012 were included in the study. Stata software, version 11.0, was used for the statistical analysis. The odds ratios （ORs） and 95% confidence interval （CI） of the XRCC1 polymorphisms in HCC patients were analyzed and compared with healthy controls. The meta-analysis was performed using fixed-effect or random-effect methods, depending on the absence or presence of significant heterogeneity. RESULTS： Eleven studies with 2075 HCC cases and 2604 controls met our eligibility criteria （four studies, 888 cases and 938 controls for Arg194Trp, four studies, 858 cases and 880 controls for Arg280His, and nine studies, 1845 cases and 2401 controls for Arg399Gln）. The meta-analysis revealed no associations between the Arg194Trp and Arg399GIn polymorphisms of the XRCC1 gene and HCC risk under all contrast models （codominant, dominant and recessive models） in the overall analysis and sensitivity analysis （the studies with controls not in the Hardy-Weinberg equilibrium were excluded）. For XRCC1 Arg280His polymorphism, the overall analysis revealed the significant associa- tion between the His/His genotype and the increased risk of HCC （His/His vs Arg/Arg model, OR： 1.96, 95% CI： 1.03-3.75, P = 0.04）. However, sensitivity analysis showed an altered pattern of result and non-significant association （OR： 2.06, 95% CI： 0.67-6.25, P = 0.20）. The heterogeneity hypothesis test did not reveal any heterogeneity, and Begg＇s and Egger＇s tests did not find any obvious publication bias. CONCLUSION： The XRCC1 Arg194Trp and Arg399GIn polymorphisms are not associated with HCC risk. More rigorous association studies are needed to verify the involvement ofXRCC1 Arg280His polymorphism in HCC susceptibility.

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.

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.

APE1 polymorphisms are associated with colorectal cancer susceptibility in Chinese Hans

AIM: To study the association between four base excision repair gene polymorphisms and colorectal cancer risk in a Chinese population.

Prognostic significance of ERCC1 expression in postoperative patients with gastric cancer

Aim： This study explored the correlation between the expression of excision repair cross-complementation group 1 （ERCC1） and the prognosis of gastric cancer patients. Methods： From January 2005 to December 2008, 605 patients who underwent radical surgery in The First Affiliated Hospital of Nanjing Medical University were enrolled. We conducted the follow-up every 6 months and its contents included a comprehensive medical history, tumor markers and abdominal ultrasound or CT and other imaging findings. Deadline was April 30, 2013 and follow-up time between 51 to 91 months. Survival time is calculated from the date of diagnosis to death or last follow-up date. Immunohistochemistry （IHC） was used to assess the expression of ERCCI in resected samples. The relationship between ERCCI expression and survival of patients was investigated. The comparison of count data were analyzed by Chi-square test. Median survival time （MST） and the 5-year survival rate were calculated by life table analysis. The Kaplan-Meier curves were used for survival analysis. Results： ERCC1 expression was positive in 412 patients （68.1%）. There is no significant difference between ERCCl-positive group and ERCCl-negative group in terms of the MST and 5-year survival rate （P=0.455）. The MST and 5-year survival rate have no significant difference （P=0.162） between group with chemotherapy and group with no chemotherapy in patients with ERCCl-positive expression. However, the MST and 5-year survival rate in patients with ERCCl-negative expression benefited more from with chemotherapy （P=0.019）. The ERCCl-positive patients survived longer than those ERCCl-negative patients （P=0.183） in subgroup with no adjuvant chemotherapy. In the subgroup analysis, ERCC 1 expression had no significant relationship with overall survival in patients with stage II or llI gastric cancer （P〉0.05）. Conclusions： ERCC1 might be a good prognostic factor for the patients of gastric cancer after radical resection. Patients with ERCCl-negative expression could benefit more from adjuvant chemotherapy.

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.

ERCC1 Asn118Asn polymorphism as predictor for cancer response to oxaliplatin-based chemotherapy in patients with advanced colorectal cancer

Objective： To assess whether the polymorphism of ERCC1 Asn118Asn （C → T） had effects on cancer response to chemotherapy and outcome in Chinese patients treated with oxaliplatin as first-line chemotherapy regimen for advanced colorectal cancer. Methods： ERCC1 Asn 118Asn polymorphism was analyzed in 99 patients with stages Ⅲ and Ⅳ advanced colorectal cancer treated with oxaliplatin-based chemotherapy, For all of the patients, ERCC1 Asnl18Asn genotype was analyzed for associations with treatment response and time to disease progress （TTP）. Results： The allele frequencies of the ERCC1 gene codon 118 were C/C 50.51% （50/99）, C/T 41.41% （41/99）, T/T 8.08% （8/99）, respectively. Patients with C/C genotype showed higher response rate than those with C/T ＋ T/T （OR = 3.764, 95% CI： 1.310-10.813）. The median TTP of all patients was 7 months （95% CI： 5.569--8.431）. Patients with C/C genotype showed a median TTP of 10 months （95% CI： 8.924-11.076）, which was longer than 5 months （95% CI： 4.424-5.576） in patients with C/T ＋ T/T genotypes. Conclusion： Our results showed a link between ERCC1 Asn118Asn genetic polymorphism and cancer response to oxaliplatin-based chemotherapy and time to disease progress in Chinese patients with advanced colorectal cancer. ERCC1 Asn 118Asn genotyping may be of predictive benefit in selecting treatment regimen for advanced colorectal cancer.

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.

宫颈鳞癌中ERCC1甲基化与顺铂为基础同期放化疗敏感性关系研究

目的：探讨核苷酸切除修复交叉互补基因1（ ERCC1）甲基化状态与宫颈鳞癌患者以顺铂为基础同期放化疗敏感性关系及与临床病理特征的关系。方法采用甲基化特异性PCR法检测20例正常宫颈组织和60例宫颈鳞癌组织中ERCC1基因甲基化状态，宫颈鳞癌患者均接受以顺铂为基础同期放化疗。按照RECIST标准评价疗效，根据疗效结果将CR定为放化疗敏感组， PR＋SD＋PD为放化疗抗拒组。采用χ2检验比较两组间ERCC1基因甲基化状态差异，采用Logistic多元回归进行多因素分析ERCC1基因甲基化状态与各临床病理特征的关系和放化疗敏感性的相关性。结果宫颈鳞癌组织中 ERCC1甲基化概率为60％，高于正常宫颈组织0％（ P＝0.000）。多因素分析显示ERCC1甲基化是影响宫颈鳞癌以顺铂为基础的同期放化疗敏感性因素（ P＝0.022）；ERCC1基因甲基化与宫颈鳞癌患者组织学分级具有相关性（ P＝0.030），与患者年龄、肿瘤大小、淋巴结转移、FIGO分期、治疗前血红蛋白及血小板计数等临床病理特征关系差异均相近（ P＝0.729、0.707、0.340、0.747、0.073、1？000）。结论 ERCC1基因启动区甲基化状态可能参与宫颈鳞癌的发生发展，可能影响宫颈鳞癌以顺铂为基础同期放化疗敏感性，可能参与了细胞分化过程。

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.

Methylenetetrahydrofolate reductase C677T polymorphism predicts response and time to progression to gemcitabine-based chemotherapy for advanced non-small cell lung cancer in a Chinese Han population

Objective： The aim of this study was to evaluate the association between the methylenetetrahydrofolate reductase （MTHFR） C677T excision repair cross-complementation group 1 （ERCC1） genetic polymorphisms and the clinical efficacy of gemcitabine-based chemotherapy in advanced non-small cell lung cancer （NSCLC）. Methods： A total of 135 chemonaive patients with unresectable advanced NSCLC were treated with gemcitabine/platinum regi- mens. The polymorphisms of MTHFR C677T, ERCC1 C8092A, and ERCC1 Cl18T were genotyped using the TaqMan methods. Results： The overall response rate was 28.9%. Patients with MTHFR CC genotype had a higher rate of objective response than patients with variant genotype （TT or CT） （41.2% versus 19.1%, P=0.01 ）. Median time to progression （TTP） of patients with MTHFR CC genotype was longer than that of patients with variant genotype （7.6 months versus 5.0 months, P=0.003）. No significant associations were obtained between ERCC1 C118T and C8092A polymorphisms and both response and survival. Conclusions： Our data suggest the value of MTHFR C677T polymorphism as a possible predictive marker of response and TTP in advanced NSCLC patients treated with gemcitabine/platinum.