Predictive Value of Xrcc1 Gene Polymorphisms for Side Effects in Patients undergoing Whole Breast Radiotherapy: a Metaanalysis

Radiation-induced side effects on normal tissue are determined largely by the capacity of cells to repairradiation-induced DNA damage. X-ray repair cross-complementing group 1 (XRCC1) plays an important role inthe repair of DNA single-strand breaks. Studies have shown conflicting results regarding the association betweenXRCC1 gene polymorphisms (Arg399Gln, Arg194Trp, -77T>C and Arg280His) and radiation-induced side effectsin patients undergoing whole breast radiotherapy. Therefore, we conducted a meta-analysis to determine thepredictive value of XRCC1 gene polymorphisms in this regard. Analysis of the 11 eligible studies comprising2,199 cases showed that carriers of the XRCC1 399 Gln allele had a higher risk of radiation-induced toxicity thanthose with the 399 ArgArg genotype in studies based on high-quality genotyping methods [Gln vs. ArgArg: OR,1.85; 95% CI, 1.20-2.86] or in studies with mixed treatment regimens of radiotherapy alone and in combinationwith chemotherapy [Gln vs. ArgArg: OR, 1.60; 95% CI, 1.09-2.23]. The XRCC1 Arg399Gln variant allele wasassociated with mixed acute and late adverse reactions when studies on late toxicity only were excluded [Gln allelevs. Arg allele: OR, 1.22; 95% CI, 1.00-1.49]. In contrast, the XRCC1 Arg280His variant allele was protectiveagainst radiation-induced toxicity in studies including patients treated by radiotherapy alone [His allele vs.Arg allele: OR, 0.58; 95% CI, 0.35-0.96]. Our results suggest that XRCC1 399Gln and XRCC1 280Arg may beindependent predictors of radiation-induced toxicity in post-surgical breast cancer patients, and the selectionof genotyping method is an important factor in determining risk factors. No evidence for any predictive valueof XRCC1 Arg194Trp and XRCC1 -77T>C was found. So, larger and well-designed studies might be requiredto further evaluate the predictive value of XRCC1 gene variation on radiation-induced side effects in patientsundergoing whole breast radiotherapy.     

XRCC1 Polymorphisms are Associated with Cervical Cancer Risk and Response to Chemotherapy: a Systematic Review and Meta-analysis

Background: Functional single nucleotide polymorphisms of x-ray repair cross-complementing protein1 (XRCC1) have been suspected to contribute to uterine cervical cancer risk for a long time; however, mostprevious case-control studies were small sized and biased. Additionally, recent studies suggested that XRCC1polymorphisms could be a biomarker of response to platinum-based chemotherapy. Methods: A comprehensivesearch was conducted to retrieve eligible studies and odds ratios (ORs) and 95% confidence intervals (95% CIs)were calculated to measure association strength. Results: A total of 13 studies were identified and analyzed. Wefound that the Arg194Trp polymorphism (Trp vs. Arg, OR=1.342, 95% CI: 1.176) was associated with increasedrisk of cervical cancer, while no significant association was found with Arg280His (His vs. Arg, OR=1.059, 95%CI: 0.863, 1.299) or Arg399Gln (Gln vs. Arg, OR=1.144, 95% CI: 0.938, 1.394). As for response to platinumbasedchemotherapy, the variant XRCC1 399Gln allele (Gln vs. Arg, OR=0.345, 95% CI: 0.163, 0.729) waslinked with a poor response; however, the Arg194Trp polymorphism (TrpArg vs. ArgArg, OR=6.421, 95% CI:1.573, 26.205) predicted a good response. Conclusion: The Arg194Trp polymorphism of XRCC1 increases riskof cervical cancer; the variant 399Gln allele predicts poor response to platinum-based chemotherapy, while theArg194Trp polymorphism indicates a good response.     

XRCC1 polymorphisms, cooking oil fume and lung cancer in Chinese women nonsmokers

X-ray repair cross-complementing group 1 (XRCC1) is one of the major DNA repair proteins involved in the base excision repair (BER) and single-strand break repair (SSBR) pathway. Single nucleotide polymorphisms (SNPs) in XRCC1 may alter protein function and repair capacity, thus lead to genetic instability and carcinogenesis. To establish our understanding of possible relationships between XRCC1 polymorphisms (5'UTR -77T>C, Arg194Trp, Arg280His and Arg399Gln) and the susceptibility to lung cancer among women nonsmokers, we performed a hospital-based case-control study of 350 patients with newly diagnosed lung cancer and 350 cancer-free controls, frequency matched by age. Our results showed that exposure to cooking oil fume was associated with increased risk of lung cancer in Chinese women nonsmokers [odds ratio (OR)=2.51, 95% confidence interval (CI) [1.80-3.51], P<0.001]. Individuals with homozygous XRCC1 399Gln/Gln genotype (OR=1.75, 95% CI [1.02-3.01]) and XRCC1 -77 combined TC and CC genotype (OR=1.66, 95% CI [1.13-2.42]) showed a slightly higher risk for lung cancer overall. In the subgroup of adenocarcinoma cases, adjusted ORs were increased for individuals with homozygous XRCC1 399Gln/Gln genotype (OR=2.62, 95% CI [1.44-4.79]) and XRCC1 -77 combined TC and CC genotype (OR=1.85, 95% CI [1.19-2.86]). Haplotype analysis showed that T-Trp-Arg-Gln haplotypes were associated with an increased risk of lung cancer among women nonsmokers (OR=2.26, 95% CI [1.38-3.68]), however, we did not observe a statistically significant joint effect of cooking oil fume and 399Gln or -77C variant allele on lung cancer among women nonsmokers. In conclusion, XRCC1 Arg399Gln and T-77C polymorphisms may alter the risk of lung cancer in women nonsmokers in China.     

The DNA repair gene XRCC1 and genetic susceptibility of lung cancer in a northeastern Chinese population

To evaluate the effect of DNA repair gene XRCC1 polymorphisms on the risk of lung cancer in a northeastern Chinese population, we studied five cSNPs in the XRCC1 gene, three that lead to non-synonymous changes: Arg194Trp, Arg280 His and Arg399Gln and two that lead to synonymous changes: Pro206Pro and Gln632Gln. A hospital-based case-control study consisted of 247 lung cancer cases and 253 cancer-free controls matched on age, gender and ethnicity. PCR-RFLP was used for genotyping. Carriers of the minor G-allele of Pro206Pro were at significantly increased risk of lung cancer (adjusted OR=1.96, 95% CI=1.26-3.06, P=0.003). Stratified analyses revealed a significantly decreased risk of lung cancer associated with the AG/AA genotype of Arg280His (AG+AA versus GG, OR=0.38, 95% CI=0.19-0.75, P=0.005) among never smokers, although there was no interaction between Arg280His and smoking. In a haplotype analysis, a haplotype defined by Arg194Trp(C)-Pro206Pro(G)-Arg280His(G)-Arg399Gln(G)-Gln632Gln(G) was associated with increased risk of lung cancer (OR=28.60, 95% CI=2.49-331.31, P=4.45x10(-5)). No associations were observed for the other polymorphisms or haplotypes. Our results suggest that the XRCC1 Pro206Pro polymorphism or the haplotype encompassing the minor allele may contribute to genetic susceptibility for lung cancer in this northeastern Chinese population. To our knowledge, this is first report that XRCC1 Pro206Pro influences cancer risk.     

DNA repair single-nucleotide polymorphisms in colorectal cancer and their role as modifiers of the effect of cigarette smoking and alcohol in the Singapore Chinese Health Study.

Recently, we reported that among Singapore Chinese, cigarette smoking and alcohol drinking were independent risk factors for colorectal cancer. Both tobacco smoking and alcohol use are plausible colorectal cancer risk factors, partly due to their ability to induce mutations in the colorectal lumen. In the present study, we investigated the role in colorectal cancer of single-nucleotide polymorphisms in five DNA repair genes: XRCC1 (Arg(194)Trp and Arg(399)Gln), PARP (Val(762)Ala, Lys(940)Arg), XPD (Asp(312)Asn, Lys(751)Gln), OGG1 (Ser(326)Cys), and MGMT (Leu(84)Phe). We conducted this study within the Singapore Chinese Health Study, a population-based cohort of 63,257 middle-aged and older Singapore Chinese men and women enrolled between 1993 and 1998. Our study included 1,176 controls and 310 cases (180 colon and 130 rectum cancer). We observed a positive association between the PARP codon 940 Lys/Arg and Arg/Arg genotypes and colorectal cancer risk [odds ratio (OR), 1.8; 95% confidence interval (95% CI), 1.1-3.1], and an inverse association between the MGMT codon 84 Leu/Phe or Phe/Phe genotypes and colon cancer risk (OR, 0.6; 95% CI, 0.3-0.9), but not rectal cancer (test of heterogeneity by tumor site, P=0.027). We observed evidence that XRCC1 may modify the effects of smoking (interaction P=0.012). The effect of smoking among carriers of the Arg(194)-Gln(399) haplotype was OR=0.7 (95% CI, 0.4-1.1), whereas, among carriers of the Trp(194)-Arg(399) haplotype, it was OR=1.6 (95% CI, 1.1-2.5). We also observed a nonstatistically significant modification of XRCC1 on the effects of alcohol (P=0.245). Whereas alcohol had no effect among carriers of the codon 194 Arg/Arg (OR, 1.0; 95% CI, 0.6-1.7) or Arg/Trp genotypes (OR, 1.1; 95% CI, 0.6-1.9), there was a positive association among carriers of the Trp/Trp genotype (OR, 2.8; 95% CI, 1.0-8.1). Our results support a role for reactive oxygen species as relevant genotoxins that may account for the effects of both smoking and alcohol on colorectal cancer risk.     

Inheritance of the 194Trp and the 399Gln variant alleles of the DNA repair gene XRCC1 are associated with increased risk of early-onset colorectal carcinoma in Egypt

Patients under age 40 constitute 35.6% of all colorectal cancer cases in Egypt, an unusual disease pattern to which both environmental exposures and inefficient DNA repair may contribute. While a number of polymorphisms in DNA repair genes have been recently identified, their role as cancer risk modifiers is yet to be determined. In a pilot case-control study, we tested the hypothesis that polymorphisms in the gene for the DNA repair enzyme XRCC1 are associated with increased risk of colorectal cancer among Egyptians. Using a multiplex polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology, allelic variants of the XRCC1 gene at codons 194 (Arg-->Trp) (194Trp) and 399 (Arg-->Gln) (399Gln), were analyzed in DNA from lymphocytes of 48 newly-diagnosed colorectal cancer cases and 48 age- and sex-matched controls. Overall, the inheritance of 194Trp allele (Arg/Trp genotype) and 399Gln allele (combined Arg/Gln and Gln/Gln genotypes) was associated with increased colorectal cancer risk (odds ratio (OR)=2.56, 95% confidence limits (CL) 0.73-9.40, and P=0. 08 for 194Trp allele and OR=3.98, 95% CL 1.50-10.6, and P<0.001 for 399Gln allele). Interestingly, the frequencies of 194Trp and 399Gln genotypes were higher in colorectal cancer cases under age 40 than in corresponding controls, and an association between both polymorphisms and early age of disease onset was observed (OR=3.33, 95% CL 0.48-35.90, and P=0.16 for 194Trp and OR=11.90, 95% CL 2.30-51.50, and P=0.0003 for 399Gln). Analysis of the data after adjustment for place of residence indicated that the frequencies of the genotypes with the 194Trp and the 399Gln alleles were higher among urban residents (OR=3.33, 95% CL 0.48-35.90, and P=0.16 for 194Trp and OR=9.97, 95% CL 1.98-43.76, and P<0.001 for 399Gln) than among rural residents (OR=2.00, 95% CL 0.36-26.00, and P=0.30 for 194Trp and OR=1.90, 95% CL 0.50-7.53, and P=0.20 for 399Gln). These findings support our hypothesis and suggest that polymorphisms in the XRCC1 gene, in conjunction with place of residence, may modify disease risk. This first demonstration that polymorphisms in DNA repair genes may contribute to colorectal cancer susceptibility and may increase the risk of early onset of the disease opens the door for future studies in that direction.     

MS-920: DNA repair gene polymorphisms, diet and colorectal cancer risk in Taiwan

This hospital-based case-control study examined whether polymorphic DNA repair genes: XRCC1 Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln, play a role in the susceptibility to colorectal cancer. We genotyped these polymorphisms for 727 newly diagnosed colorectal adenocarcinoma cases and 736 age and sex matched healthy controls in Taiwan. Although the colorectal cancer risk was not significantly associated with these genes, the risk was significantly elevated in younger subjects (< or =60 years) with the XRCC1 399Arg/Arg genotype compared to those with XRCC1 399Gln allele (OR=1.46, 95% CI=1.06-2.99, P=0.02). The stratified analysis showed that XRCC3 interacted with meat consumption (P for interaction=0.02), but was limited to the low meat consumption (OR=2.34, 95% CI=1.28-4.29). Our results suggest that the XRCC1 Arg399Gln polymorphism may contribute to the risk of early-onset colorectal cancer and the XRCC3 Thr241Met polymorphism may modify the risk for meat-associated colorectal cancer.     

X-Ray Repair Cross-Complementing Group 1(XRCC1) Genetic Polymorphisms and Thyroid Carcinoma Risk: a Meta-Analysis

A number of studies have been conducted to explore the association of XRCC1 polymorphisms with thyroidcancer risk, but the results have been inconsistent. Thus we performed the present meta-analysis to clarify thisissue based on all of the evidence available to date. Relevant studies were retrieved by searching PubMed andstatistical analysis conducted using Stata software. Nine studies were included in this meta-analysis (1,620 casesand 3,557 controls). There were 6 studies (932 cases and 2,270 controls) of the Arg194Trp polymorphism, 7 studies(1432 cases and 3356 controls) of the Arg280His polymorphism and 9 studies (1,620 cases and 3,557 controls) forthe Arg399Gln polymorphism. No association of XRCC1 Arg194Trp, Arg280His and Arg399Gln polymorphismwith thyroid cancer risk was observed in the overall analysis. However, subgroup analysis revealed: 1) anelevated risk in aa vs AA analysis (OR=2.03, 95%CI= 1.24-3.31) and recessive genetic model analysis (OR=1.93,95%CI= 1.20-3.08) in the larger sample size trials for XRCC1 Arg194Trp polymorphism; 2) a decreased thyroidcancer risk on subgroup analysis based on ethnicity in Aa vs AA analysis (OR=0.84, 95%CI= 0.72-0.98) and ina dominant genetic model (OR=0.84, 95%CI= 0.72-0.97) in Caucasian populations for the XRCC1 Arg399Glnpolymorphism; 3) a decreased thyroid cancer risk on subgroup analysis based on design type in Aa vs AA analysis(OR=0.72, 95% CI= 0.54-0.97) among the PCC trials for the Arg399Gln polymorphism. Our results suggest thatthe XRCC1 Arg399Gln polymorphism may be associated with decreased thyroid cancer risk among Caucasiansand XRCC1 Arg194Trp may be associated with a tendency for increased thyroid cancer risk in the two largersample size trials.     

Genetic polymorphisms of XRCC1 and risk of gastric cancer

Coding polymorphisms of the DNA repair gene XRCC1 have been shown to affect the DNA repair capacity and to be associated with genetic susceptibility to carcinogenesis. In our association study between three amino acid substitution polymorphisms of XRCC1 (Arg194Trp, Arg280His, and Arg399Gln) and the risk of gastric cancer in the Korean population, none of the polymorphisms were associated with increased risk of gastric cancer. We then extended our study by building haplotypes of the entire XRCC1 gene with six single neuclotide polymorphisms (SNPs), including two novel polymorphisms at the 5'-flanking sequence. When haplotype frequencies in cases and controls and haplotype-specific odds ratios (ORs) were estimated, haplotype A (194Trp, 280Arg, and 399Arg) was associated with significant reduction in gastric cancer risk (adjusted OR=0.65, 95% CI=0.43-0.99) whereas haplotype D (194Arg, 280Arg, and 399Arg alleles) was a risk type for gastric cancer (adjusted OR=1.57, 95% CI=0.93-2.65). The association with the haplotype D was more pronounced in the cancers of antrum (adjusted OR=2.06, 95% CI=1.03-2.00). Our results suggest that the haplotype estimation is advantageous for association studies of such a complex disease as gastric cancer.     

XRCC1 polymorphisms increase bladder cancer risk in Asians: a meta-analysis

X-ray cross complementing group 1 (XRCC1) polymorphisms and bladder cancer risk has been investigated for years, but the result in Asian population is till inconclusive. Thus, we performed this meta-analysis to determine the association of XRCC1 Arg194Trp, Arg280His, and Arg399Gln polymorphisms with bladder cancer risk in the Asian population. PubMed, EMBASE, and China National Knowledge Infrastructure were searched up to January 2013 to identify eligible studies. The association strength was measured with odd ratios (ORs) and 95 % confidence intervals (95 % CIs). A total of nine eligible studies, including 1,931 bladder cancer patients and 2,192 controls, were identified. Significant increased risk of bladder cancer was observed for Arg194Trp polymorphism (allele comparison OR?=?1.20, 95 % CI: 1.06–1.36, P_{heterogeneity}?=?0.11; dominant model OR?=?1.20, 95 % CI: 1.02–1.41, P_{heterogeneity}?=?0.37) and Arg280His polymorphism (heterozygote comparison OR?=?1.87, 95 % CI: 1.21–2.90, P_{heterogeneity}?=?0.01; dominant model OR?=?1.75, 95 % CI: 1.05–2.90, P_{heterogeneity}?=?0.01); however, Arg399Gln was not associated with susceptibility to bladder cancer. No evidence of publication bias was detected. Our meta-analysis results suggest that XRCC1 Arg194Trp and Arg280His polymorphisms are associated with significantly increased risk of bladder cancer in Asians.     

XRCC1 polymorphisms and cancer risk: a meta-analysis of 38 case-control studies.

Several potential functional polymorphisms (Arg194Trp, Arg280His, Arg399Gln) in the DNA base excision repair gene X-ray repair cross-complementing group 1 (XRCC1) have been implicated in cancer risk. Our meta-analysis on total of 11,957 cancer cases and 14,174 control subjects from 38 published case-control studies showed that the odds ratio (OR) for the variant genotypes (Trp/Trp + Arg/Trp) of the Arg194Trp polymorphism, compared with the wild-type homozygote (Arg/Arg), was 0.89 [95% confidence interval (95% CI), 0.81-0.98] for all tumor types without between-study heterogeneity. Similarly, the overall risk for the combined variant genotypes (His/His + Arg/His) of the Arg280His, compared with the wild homozygote (Arg/Arg), was 1.19 (95% CI, 1.00-1.42). However, there was no main effect in either recessive or dominant modeling for the Arg399Gln, and the variant Gln/Gln homozygote was not associated with overall cancer risk (OR, 1.01; 95% CI, 0.90-1.14). The analyses suggest that XRCC1 Arg194Trp, Arg280His polymorphisms may be biomarkers of cancer susceptibility and a single larger study with thousands of subjects and tissue-specific biochemical and biological characterization is warranted to further evaluate potential gene-to-gene and gene-to-environment interactions on XRCC1 polymorphisms and cancer risk.     

Prediction Value of XRCC 1 Gene Polymorphism on the Survival of Ovarian Cancer Treated by Adjuvant Chemotherapy

Objective: We conducted a prospective study to test the association between three amino acid substitutionpolymorphismic variants of DNA repair genes, XRCC1 (Arg194Trp), XRCC1(Arg280His) and XRCC1(Arg399Gln), and clinical outcome of ovarian cancer patients undergoing adjuvant chemotherapy. Methods:195 patients with primary advanced ovarian cancer and treated by adjuvant chemotherapy were included in ourstudy. All were followed-up from Jan. 2007 to Jan. 2012. Genotyping of XRCC1 polymorphisms was conductedby TaqMan Gene Expression assays. Results: The XRCC1 194 Trp/Trp genotype conferred a significant riskof death from ovarian cancer when compared with Arg/Arg (HR=1.56, 95%CI=1.04-3.15). Similarly, thosecarrying the XRCC1 399 Gln/Gln genotype had a increased risk of death as compared to the XRCC1 399Arg/Arg genotype with an HR (95% CI) of 1.98 (1.09-3.93). Conclusion: This study is the first to provide evidencethat XRCC1 gene polymorphisms would well be useful as surrogate markers of clinical outcome in ovariancancer cases undergoing adjuvant chemotherapy.     

XRCC1 polymorphisms and risk of nasopharyngeal carcinoma: a meta-analysis

Objective: Previous studies on the association between X-ray repair cross-complementing protein 1 (XRCC1) polymorphisms and nasopharyngeal carcinoma (NPC) risk showed inconsistent results. The aim of this study was to evaluate the effects of XRCC1 variants on NPC risk. Methods: A meta-analysis was performed with all eligible studies covering a total of 1,341 cases and 1,425 controls for the Arg194Trp polymorphism, 1,260 cases and 1,207 controls for the Arg280His polymorphism, and 1,644 cases and 1,678 controls for the Arg399Gln polymorphism. Results: No associations was found between Arg194Trp and Arg280His polymorphisms with NPC risk under all contrast models (co-dominant, dominant, and recessive models). However a deleterious effect of the 399Gln genotype was observed under the co-dominant model (Gln/Gln versus Arg/Arg, OR = 1.30, 95% CI : 1.01-1.69, P = 0.04). Under the recessive model (Gln/Gln versus Arg/Arg+Arg/Gln), the P value was marginally significant (OR = 1.28, 95% CI : 1.00-1.65, P = 0.05). However, the effect of the 399Gln genotype on NPC became non-significant after excluding one study from the meta-analysis because of departure from Hardy-Weinberg equilibrium. Conclusions: No associations was found between Arg194Trp and Arg280His polymorphisms with NPC risk, whereas the Arg399Gln genotype was associated with increased risk.     

An association of polymorphism of DNA repair genes XRCC1 and XRCC3 with colorectal cancer

Variability in DNA repair genes may contribute to human cancer risk. We performed a case-control study (51 cases and 100 controls) to test the association between two polymorphisms: Arg399Gln in the XRCC1 gene and Thr241Met in the XRCC3 gene and colorectal cancer risk. Genotypes were determined in tumour tissue and distant mucosa samples by PCR RFLP with the NciI restriction enzyme for XRCC1 and NcoI for XRCC3. Cancer occurrence was strongly associated with the XRCC3 Met/Met polymorphic variant (OR = 9.45; (95% CI 8.77-11.65)), whereas Thr/Thr and Thr/Met variants were associated with significant reduction in colorectal cancer risk (OR = 0.16; 95% CI 0-0.26 and OR = 0.26; 95% CI 0.25-0.27, respectively). Weak association was found between the XRCC1 Arg/Arg and Gln/Gln variants and the risk of colorectal cancer (OR = 1.28; 95% CI 1.00-1.84 and OR = 1.13; 95% CI 0.85-2.34, respectively). Gene-gene interaction between the XRCC1 Arg/Arg and XRCC3 Met/Met homozygous variants slightly increased the risk (OR = 10.50; 95% CI 5.67-14.79). Both polymorphisms were not associated with colorectal cancer progression.     

Evaluation of DNA repair gene XRCC1 polymorphism in prediction and prognosis of hepatocellular carcinoma risk

We conducted a case-control study in China to clarify the association between XRCC1-Arg399Gln polymorphism and HCC risk. A total of 150 cases and 158 controls were selected from the the Affiliated Hospital of Qingdao University from May 2008 to May 2010. XRCC1-Arg399Gln polymorphism was based upon duplex polymerase-chain-reaction with the confronting-two-pair primer (PCR-CTPP) method. All analyses were performed using the STATA statistical package. A significantly increased risk was associated with the Arg/Gln genotype (adjusted OR 1.78, 95%CI=1.13-2.79) compared with genotype Arg/Arg. In contrast, the Gln/Gln genotype had non-significant increased risk of HCC with adjusted OR (95%CI) of 1.69 (0.93-2.66). A significant association was found between positive HBsAg and Arg/Gln, with an OR of 3.43 (95% CI=1.45-8.13). Patients carrying Gln/Gln genotypes showed significantly lower median survival than Arg/Arg genotypes (HR=1.38, 95% CI=1.04-1.84). Further Kaplan-Meier analysis showed decreased median survival in Arg/Gln+Gln/Gln genotype carriers in comparison to Arg/Arg carriers (HR=1.33, 95% CI=1.02-1.76). In conclusion, we observed that XRCC1-Arg399Cln polymorphism is associated with susceptibility to HCC, and XRCC1 Gln allele genotype showed significant prognostic associations.     

Genetic polymorphisms of XRCC1 and risk of the esophageal cancer

A variety of environmental factors were identified to be associated with the risk of esophageal cancer. The variation in capacity of DNA repair might influence environmental chemical-associated carcinogenesis. We hypothesized that the polymorphic XRCC1 genes might modify cancer susceptibility of the esophagus. To investigate the effect of XRCC1 genetic polymorphisms on codons 194, 280 and 399, we evaluated data from 105 patients of esophageal squamous cell carcinoma and 264 healthy controls, matching with age (+/-3 years), gender and ethnicity. The distribution of the 3 genotypes were not significantly different among patients and controls. However, among alcohol drinkers, the XRCC1399 Arg/Arg genotype was more frequently found in patients with esophageal cancer. After adjustment with other environmental confounders, the OR for the genotype of XRCC1399 Arg/Arg was 2.78 (95% CI =1.15-6.67) as compared with the XRCC1(399) Arg/Gln and XRCC1(399) Gln/Gln genotypes in the alcohol drinkers. Similar trends were observed among cigarette smokers and areca chewers. However, they did not reach a statistical significance. Our findings suggest that the polymorphic XRCC1 genes might modify the risk of alcohol-associated esophageal cancers.     

Three polymorphisms of DNA repair gene XRCC1 and the risk of glioma: a case–control study in northwest China

Three polymorphisms of X-ray repair cross-complementing groups 1 (XRCC1) Arg194Trp, Arg280His, and Arg399Gln may be associated with the individual susceptibility to glioma. The aim of this study was to investigate any association between three polymorphisms of the XRCC1 gene at codon 194, 280, and 399 and potential glioma risk. We conducted a hospital-based case–control study in northwest China. A total of 1,772 subjects, including 886 glioma patients and 886 healthy controls, were recruited in this study. The peripheral blood samples were extracted. Polymerase chain reaction–restriction fragment length polymorphism method was used to test genotypes. Glioma patients had a significantly higher frequency of XRCC1 194 TT (odds ratio [OR]?=?1.76, 95 % confidence interval [CI]?=?1.14, 2.72; P?=?0.01) and XRCC1 399 AA genotype (OR?=?1.62, 95 % CI?=?1.09, 2.40; P?=?0.02) than controls. When stratified by the grade of glioma, patients with WHO IV glioma had a significantly higher frequency of XRCC1 194 TT (OR?=?1.60, 95 % CI?=?1.02, 2.51; P?=?0.04) and XRCC1 399 AA genotype (OR?=?1.59, 95 % CI?=?1.04, 2.42; P?=?0.03). When stratified by the histology of glioma, there was no significant difference in the distribution of each genotype. This study suggested that XRCC1 Arg194Trp and Arg399Gln polymorphisms were associated with the risk of glioma.     

Polymorphisms in DNA repair gene XRCC1 and increased genetic susceptibility to glioma

Background: The XRCC1 gene encodes the XRCC1 protein, which complexes with three other DNA repair enzymes involved in the base-excision repair (BER) pathways. Different XRCC1 polymorphisms may increase the risk of cancers by impairing interaction with other enzymatic proteins and consequently altering DNA repair activity, and result in carcinogenesis. Our study aimed to investigate any association between three polymorphisms of the XRCC1 gene at codon 194, 280 and 399 and potential glioma risk. Methods: We collected 127 patients with primary glioma and 249 controls who requested general health examinations from Union Hospital of Tongji Medical College hospital from March 2007 to September 2010. A total of 5 ml venous blood was drawn from each subject. The polymorphisms of XRCC1 gene at codons 194, 280 and 399 were analyzed based on duplex polymerase-chain-reactions with the confronting-two-pair primer (PCR-CTPP) method. Results: The homozygous Trp/Trp and heterozygotes Arg/Trp variants of codon 194 had a 2.12 fold and 1.46 fold increased risk of glioma compared to the homozygous Arg/Arg wide genotypes. The same effect was found in codon 399, the codon 399 Gln/Gln and Arg/Gln genotypes being associated with a 2.24 fold and 1.67 fold increased risk in glioma. When comparing the codon 194 Arg/Arg and 399 Arg/Arg genotypes, the combination of codon 194 Trp allele and 399 Gln allele had a heavy increase in glioma risk (OR=2.87, 95%CI=1.56-6.73). Conclusion: The present study provided evidence of a potential role for XRCC1 codon 194 and 399 polymorphisms in genetic predisposition to glioma among the Chinese population. This analysis of correlation of DNA repair genes and glioma may provide a deeper insight into the genetic and environment factors for cancer risk.     

DNA repair gene XRCC1 polymorphisms, smoking, and esophageal cancer risk

To investigate the effect of X-ray repair cross complementing 1 (XRCC1) genetic polymorphisms on esophageal cancer risk, we determined XRCC1 polymorphisms at codon 194 (Arg --> Trp) and codon 399 (Arg --> Gln) in 135 patients with esophageal squamous cell carcinoma (ESCC) and 152 normal controls from hospitals. Although polymorphism at codon 194 was not associated with risk for ESCC, we found that the frequency of XRCC1 399 Gln/Gln genotype in ESCC patients (14.1%) was significantly higher than that in normal controls (3.3%), and that XRCC1 399 Gln/Gln genotype was associated with an increased risk of ESCC (odds ratio (OR) = 5.15, 95% confidence interval (CI): 2.42-0.93). In addition, we found that the risk for smoker increased 4.2-fold than non-smokers in the 399 Gln/Gln genotype (OR = 4.20, 95% CI: 2.37-7.44). These results suggest that XRCC1 399 Gln/Gln genotype may contribute to the risk of ESCC and modify risk associated with smoking.     

Association Between Polymorphisms of XRCC1 Arg399Gln and XPD Lys751Gln Genes and Prognosis of Colorectal Cancer in a Chinese Population

We conducted this study to detect associations between XRCC1 Arg399Gln and XPD Lys751Gln genotypesand survival of colorectal cancer patients treated with 5-FU/oxalipatin chemotherapy. We included 289 Chinesepatients with advanced colorectal cancer, who had received 5-FU/oxalipatin chemotherapy as first-line treatmentfrom January 2005 to January 2007. All patients were followed up till Nov. 2011. Genotyping for XRCC1Arg399Gln and XPD Lys751Gln polymorphisms was based upon duplex polymerase-chain-reaction with thePCR-RFLP method. In our study, we found the XRCC1 399 Gln/Gln genotype to confer significantly higherrates of response to chemotherapy when compared to the Arg/Arg genotype [OR (95% CI)= 2.56(1.57-2.55)].patients with the XPD 751 Gln/Gln genotype had significantly higher rates of response to chemotherapy [OR(95% CI)= 1.54(0.87-2.65)] and those with the XRCC1 399 Gln/Gln genotype had a longer average survivaltime and significantly lower risk of death than did those with the Arg/Arg genotype [HR (95% CI)= 0.66(0.36-0.95)]. Similarly, those carrying the XPD 751Gln/Gln genotype had 0.51-fold the risk of death of those with XPD751Lys/Lys [HR (95% CI)= 0.51(0.33 -0.94)]. In conclusion, it is suggested that the XRCC1 Arg399Gln and XPDLys751Gln polymorphisms should be routinely assessed to determine colorectal patients who are more likely tobenefit from 5-FU/oxalipatin chemotherapy.