Implication of Polymorphisms in DNA Repair Genes in Prognosis of Hepatocellular Carcinoma

XRCC1 genetic polymorphisms could be associated with increased risk of various cancer, includinghepatocellular carcinoma (HCC), the fifth most common cancer. We here conducted a study to explore the roleof selective SNPs of the XRCC1 and XPD genes in the prognosis of HCC. A total of 231 cases were collected, andgenotyping of XRCC1 Arg194Trp, XRCC1 Arg399Gln, XPD Lys751Gln and XPD Asp312Asn was performedby duplex polymerase-chain-reaction with the confronting-two-pair primer method. Our findings indicatedXRCC1 399Gln/Gln genotype was associated with a significant difference in the median survival time comparedwith patients carrying Arg/Trp and Arg/Arg genotypes, and individuals with XPD 751 Gln/ Gln genotype had asignificantly greater survival time than patients carrying Lys/Lys and Lys/Gln genotypes. The Cox’s regressionanalysis showed individuals carrying XRCC1 399Trp/Trp genotype had 0.55 fold risk of death from HCC thanArg/Arg genotype. Similarly, XPD 751Gln/Gln had a strong decreasein comparison to XPD Lys/Lys carriers withan HR of 0.34. These results suggest that polymorphisms in XRCC1 and XPD may have functional significancein the prognosis of HCC.     

Polymorphisms of the XRCC1 and XPD Genes and Breast Cancer Risk: A Case-Control Study

The purpose of this case control study was to evaluate the role of X-ray repair cross-complementing group 1 (XRCC1) and xeroderma pigmentosum group D (XPD) genotypes as genetic indicators of susceptibility to breast cancer (BC). We analysed DNA samples from 114 breast cancer patients and 113 control subjects using polymerase chain reaction-restriction fragment length polymorphism. For the single nucleotide polymorphisms in XRCC1 exon 10 (Arg399Gln, G/A) and XPD exon 23 (Lys751Gln, A/C), no remarkable differences for genotype distribution and allele frequencies were observed between BC group and control group in the study. The genotype frequency for homozygote A/A in XPD exon 6 (Arg156Arg, C/A) were significantly different between BC and control groups (P < 0.0001, odds ratio = 2.14; 95% confidence interval 1.44-3.17). The data indicate a possible role for XPD (Arg156Arg, C/A) polymorphisms in BC susceptibility.     

XRCC1 and XPD Gene Polymorphisms in a South Indian Population

DNA repair systems play an important role in maintaining the integrity of the human genome. Deficiency inthe repair capacity due to either mutations or inherited polymorphisms in DNA repair genes may contribute tovariations in the DNA repair capacity and subsequently susceptibility to cancer. The interindividual variabilityas well as ethnic differences in DNA repair polymorphisms, stress the importance to establish genotype profilesunique to a population. Hence the present study aimed to determine the frequencies of XRCC1 and XPD genepolymorphisms in 255 healthy random unrelated individuals from South India. DNA was isolated from theperipheral blood sample of these individuals and the XRCC1 and XPD genotypes were determined by PCRRFLPwith Msp1 and Pst1 enzymes respectively. The XRCC1 genotype frequencies revealed 36% Arg/Arg,47% Arg/Gln and 17% Gln/Gln with Gln allele frequency of 0.41. Analysis of XPD genotypes revealed 51% Lys/Lys, 41% Lys/Gln and 8% Gln/Gln with Gln allele frequency of 0.29. No significant difference in the distributionof genotypes was seen based on gender. Comparison of the frequencies of XRCC1 and XPD polymorphismsobserved in the present study with other populations revealed a distinctive nature of the South Indian population.An understanding of DNA repair gene polymorphisms might not only enable risk assessment of humans exposedto environmental carcinogens but also response to therapy, which target the DNA repair pathway.     

XRCC1 Gene Polymorphism Increases the Risk of Hepatocellular Carcinoma in Egyptian Population

Several major risk factors for hepatocellular carcinoma (HCC) have been identified, including chronic infection of hepatitis B virus (HBV) and hepatitis C virus (HCV). Nevertheless, only a fraction of infected patients develops HCC during their lifetime suggesting that genetic factors might modulate HCC development. X-ray repair cross complementing group1 (XRCC1) participates in the repair pathways of DNA. Aim: to investigate the association between XRCC1 gene polymorphism and HCC in Egyptian chronic hepatitis C patients. Methods: This study was assessed on 40 patients with HCC secondary to chronic HCV infection who were compared to 20 cirrhotic HCV patients and 40- age and gender- matched healthy control group. After collection of relevant clinical data and basic laboratory tests, c.1517G>C SNP of XRCC1 gene polymorphism was performed by (PCR-RFLP) technique. Results: A statistically higher frequency of XRCC1 (CC, GC) genotypes and increased (C) allele frequency in patients with HCC was found in comparison to cirrhotic HCV patients as well as control group. In addition, patients with the XRCC1 (CC, GC) genotypes had significantly higher number and larger size of tumor foci and significantly higher Child Pugh grades. Multivariate analysis showed that the presence of c.1517G>C SNP of XRCC1 gene is an independent risk for the development of HCC in chronic HCV patients with 3.7 fold increased risk of HCC development. In conclusion: XRCC1 gene polymorphism could be associated with increased risk of HCC development in chronic HCV Egyptian patients.     

DNA Repair Gene Polymorphisms at XRCC1, XRCC3, XPD,and OGG1 Loci in the Hyderabad Population of India

Background: DNA repair is one of the crucial defense mechanism against mutagenic exposure. Inherited SNPs of DNA repair genes may contribute to variation in DNA repair capacity and susceptibility to cancer. Due to thepresence of these variants, inter-individual and ethnic differences in DNA repair capacity have been established in various populations. India harbors enormous genetic and cultural diversity. Materials and Methods: In the present study we aimed to determine the genotypes and allele frequencies of XRCC1 Arg399Gln (rs25487), XRCC3 Thr241Met (rs861539), XPD Lys751Gln (rs13181), and OGG1 Ser326Cys (rs1052133) gene polymorphisms in 186 healthy individuals residing in the Hyderabad region of India and to compare them with HapMap and otherpopulations. Results and Conclusions: The genotype and allele frequency distribution at the four DNA repairgene loci among Hyderabad population of India revealed a characteristic pattern. Comparison of these genepolymorphisms with other populations revealed a distinctiveness of Hyderabad population from the Deccanregion of India. To the best of our knowledge, this is the first report of such DNA repair gene polymorphisms inthe Deccan Indian population.     

Polymorphisms in DNA repair genes XPD and XRCC1 and p53 mutations in lung carcinomas of never-smokers

The etiology of lung cancer in population with little or no tobacco exposure is not well understood. Individual genetic susceptibility factors have been suggested to contribute to lung cancer risk in this population. Mutations in the p53 tumor suppressor gene are implicated in the development of lung cancer as they are frequently found in lung tumors from both smokers and never-smokers. In order to determine whether genetic polymorphisms affecting DNA repair capacity modulate p53 mutations in lung tumors from never-smokers, we compared p53 mutations with genotypes of XPD 312, XPD 751, and XRCC1 399 in lung tumors from 43 lifetime never-smokers. p53 mutations were identified in 10 (23%) cases and consisted mostly of G/C to A/T transitions. No statistically significant association was found between p53 mutations and genotypes of XPD 312 or XPD 751. However, patients with the XRCC1 399 Gln allele, that results in a lower base excision repair capacity, were more likely to have p53 mutations, compared with patients the wild-type Arg allele (P = 0.03). In addition, the p53 mutation frequency increased with an increasing number of combined genotypes associated with a lower DNA repair capacity of XPD 312, XPD 751, and XRCC1 399 (P = 0.02). These results suggest that individuals who never smoked and had XRCC1 399 Gln allele may be at a greater risk of p53 mutations, especially if combined with the genotypes of XPD 312 and XPD 751 that may result in a lower DNA repair capacity.     

An Updated Meta-analysis on the Association of X-Ray Repair Cross Complementing Group 1 Codon 399 Polymorphism with Hepatocellular Carcinoma Risk

Background: A number of studies have reported the association of X-ray repair cross-complementing group1 (XRCC1) Arg399Gln polymorphism with susceptibility to hepatocellular carcinoma (HCC). However, theresults were inconsistent and inconclusive. The aim of this study was to comprehensively explore the associationof XRCC1 Arg399Gln variant with HCC risk. Materials and Methods: Systematic searches of PubMed, Elsevier,Science Direct, CNKI and Chinese Biomedical Literature Database were performed. Pooled odds ratio (OR)with 95% confidence intervals (CI) was calculated to estimate the strength of association. Results: Overall,we observed an increased HCC risk among subjects carrying XRCC1 codon 399 Gln/Gln, Arg/Gln and Gln/Gln+Arg/Gln genotypes (OR=1.20, 95%CI: 1.05-1.38, OR=1.16, 95%CI: 1.05-1.28, and OR=1.14, 95%CI:1.04-1.24, respectively) based on 20 studies including 3374 cases and 4633 controls. In subgroup analysis, weobserved an increased risk of XRCC1 codon 399 Gln/Gln, Arg/Gln and Gln/Gln+Arg/Gln polymorphisms forHCC in hospital-based study (OR=1.25, 95%CI: 1.03-1.51, OR=1.21, 95%CI: 1.07-1.36 and OR=1.18, 95%CI:1.06-1.31, respectively) and in Asian population (OR=1.19, 95%CI: 1.03-1.38, OR=1.17, 95%CI: 1.04-1.30 andOR=1.14, 95%CI: 1.04-1.25, respectively). Limiting the analysis to the studies with controls in agreement withHardy-Weinberg equilibrium (HWE), we observed an increased HCC risk among Gln/Gln, Arg/Gln and Gln/Gln+Arg/Gln genotype carriers (OR=1.17, 95%CI: 1.05-1.29, OR=1.12, 95%CI: 1.00-1.25 and OR=1.11, 95%CI:1.02-1.21, respectively). Conclusions: This updated meta-analysis results suggest that XRCC1 Arg399Gln variantsmay contribute to HCC risk. Well-designed studies with larger sample size were required to further verify ourfindings.     

The Investigation of Polymorphisms in DNA Repair Genes (XRCC1, APE1 and XPD) in Women with Polycystic Ovary Syndrome

Background: PCOS was reported to arise from the interaction of genetic and environmental factors. Some studies reported that women with PCOS have DNA damage and chromosome breakage. Such studies bring to mind the genes that are involved in DNA repairing. At present, several DNA repair genes and, as products of these genes, certain polymorphisms that alter the activity of proteins are known in the literature. The aim of this dissertation is to study the genomic instability that have been reported in PCOS cases along with the relationship between XRCC1 Arg194Trp, XRCC1 Arg399Gln, APE1 Asp148Glu, and XPD Lys751Gln polymorphisms in order to contribute to the pathogenesis of PCOS. Methods: Polymorphisms in DNA repair genes have been associated with the increased risk of various diseases and could also be related to the etiology of PCOS. Therefore, we conducted a study including 114 women with PCOS and 91 controls. These polymorphisms were determined by quantitative real time PCR and melting curve analysis using LightCycler. Results: Comparing the control groups at the end of the study, the results have not shown any statistically significant difference as far as XRCC1 Arg194Trp, XRCC1 Arg399Gln, and XPD Lys751Gln polymorphisms are concerned. However, there were notable differences between the groups in terms of APE1 Asp148Glu polymorphism. Associated with this condition, it has been noted that both mutant allele (Glu) frequency (37.72 % in the study group; 19.23% in the control group, p=0.0001) and homozygous mutant genotype (Glu/Glu) frequency (%12.28 in the study group; %6.60 in the control group, p=0.015) have been higher in the study group.     

Polymorphisms of XRCC1 and XRCC2 DNA Repair Genes and Interaction with Environmental Factors Influence the Risk of Nasopharyngeal Carcinoma in Northeast India

Multiple genetic and environmental factors have been reported to play key role in the development of nasopharyngeal carcinoma (NPC). Here, we investigated interactions of XRCC1 Arg399Gln and XRCC2 Arg188His polymorphisms and environmental factors in modulating susceptibility to NPC in Northeast India. One-hundred NPC patients, 90 first-degree relatives of patients and 120 controls were enrolled in the study. XRCC1 Arg399Gln and XRCC2 Arg188His polymorphisms were determined using PCR-RFLP, and the results were confirmed by DNA sequencing. Logistic regression (LR) and multifactor dimensionality reduction (MDR) approaches were applied for statistical analysis. The XRCC1 Gln/Gln genotype showed increased risk (OR=2.76; P<0.024) of NPC. However, individuals with both XRCC1 and XRCC2 polymorphic variants had 3.2 fold elevated risk (P<0.041). An enhanced risk of NPC was also observed in smoked meat (OR=4.07; P=0.004) and fermented fish consumers (OR=4.34, P=0.001), and tobacco-betel quid chewers (OR=7.00; P=0.0001) carrying XRCC1 polymorphic variants. However, smokers carrying defective XRCC1 gene showed the highest risk (OR = 7.47; P<0.0001). On MDR analysis, the best model for NPC risk was the five-factor model combination of XRCC1 variant genotype, fermented fish, smoked meat, smoking and chewing (CVC=10/10; TBA=0.636; P<0.0001); whereas in interaction entropy graphs, smoked meat and tobacco chewing showed synergistic interactions with XRCC1. These findings suggest that interaction of genetic and environmental factors might increase susceptibility to NPC in Northeast Indian populations.     

Association of the XRCC1 c.1178G>A Genetic Polymorphism with Lung Cancer Risk in Chinese

The X-ray repair cross-complementing group 1 protein (XRCC1) plays important roles in the DNA baseexcision repair pathway which may influence the development of lung cancer. This study aimed to evaluatethe potential association of the XRCC1 c.1178G>A genetic polymorphism with lung cancer risk. The createdrestriction site-polymerase chain reaction (CRS-PCR) and DNA sequencing methods were utilized to evaluatethe XRCC1 c.1178G>A genetic polymorphism among 376 lung cancer patients and 379 controls. Associationsbetween the genetic polymorphism and lung cancer risk were determined with an unconditional logistic regressionmodel. Our data suggested that the distribution of allele and genotype in lung cancer patients was significantlydifferent from that of controls. The XRCC1 c.1178G>A genetic polymorphism was associated with an increasedrisk of lung cancer (AA vs GG: OR=2.91, 95%CI 1.70-4.98, p<0.001; A vs G: OR=1.52, 95%CI 1.22-1.90, p<0.001).The allele A and genotype AA may contribute to risk of lung cancer. These preliminary results suggested thatthe XRCC1 c.1178G>A genetic polymorphism is statistically associated with lung cancer risk in the Chinesepopulation.     

Polymorphisms of DNA repair genes XRCC1 and XPD and their associations with risk of esophageal squamous cell carcinoma in a Chinese population

Esophageal squamous cell carcinoma (ESCC), which is prevalent in China, is believed to be induced by environmental carcinogens. Accumulating evidence has shown that individual variation in DNA repair capacity resulting from genetic polymorphism influences risk of environmental carcinogenesis. We therefore investigated the associations between genetic polymorphisms in the DNA repair genes XRCC1 (Arg194Trp and Arg399Gln) and XPD (Asp312Asn and Lys751Gln) and risk of ESCC in an at-risk Chinese population. Genotypes were determined by a PCR-based approach in 433 patients with ESCC and 524 frequency-matched normal controls. We found that individuals with Trp/Trp genotype at XRCC1 Arg194Trp site had a 2-fold increased risk of this disease compared to Arg/Arg genotype (adjusted OR = 1.98; 95% CI 1.26-3.12). Furthermore, when compared to Arg/Arg and Arg/Trp genotype combined, homozygote for Trp/Trp genotype significantly increased the risk of developing ESCC, with the adjusted OR being 2.07 (95% CI 1.34-3.20). However, the XRCC1 Arg399Gln polymorphism was not significantly associated with risk of ESCC, with the adjusted OR being 0.87 (95% CI 0.55-1.37). Neither Asp312Asn nor Lys751Gln polymorphisms in the XPD gene influenced risk of ESCC in our study. These findings suggest that DNA repair gene XRCC1 but not XPD might play a role in esophageal carcinogenesis and might represent a genetic determinant in the development of the cancer.     

Association Between the c.3751G>A Genetic Variant of MDR1 and Hepatocellular Carcinoma Risk in a Chinese Han Population

The objective of this study was to evaluate the influence of a genetic variant in the multidrug resistance 1 gene(MDR1) on hepatocellular carcinoma (HCC) risk. This case-control study was conducted in a Chinese populationof 645 HCC cases and 658 cancer-free controls. The genotype of the c.3751G>A genetic variant in the MDR1 genewas investigated by created restriction site-polymerase chain reaction (CRS-PCR) and DNA sequencing methods.Our data demonstrated significantly differences detected in the allelic and genotypic frequencies between HCCcases and those of cancer-free controls. Association analyses indicated that there were statistically increasedrisk of HCC in the homozygote comparison (AA versus (vs.) GG: OR = 2.22, 95% CI 1.51-3.27, χ2 = 16.90, P< 0.001), dominant model (AA/GA vs. GG: OR = 1.25, 95% CI 1.00-1.55, χ2 = 3.98, P = 0.046), recessive model(AA vs. GA/GG: OR = 2.14, 95% CI 1.47-3.09, χ2 = 16.68, P < 0.001) and allele comparison (A vs. G: OR = 1.33,95% CI 1.13-1.57, χ2 = 11.66, P = 0.001). The allele-A and genotype-AA may contribute to HCC susceptibility.These preliminary findings suggest that the c.3751G>A genetic variant in the MDR1 gene is potentially relatedto HCC susceptibility in a Chinese Han population, and might be used as a molecular marker for evaluatingHCC susceptibility.     

A Meta-Analysis for Association of XRCC1, XRCC2 and XRCC3 Polymorphisms with Susceptibility to Thyroid Cancer

Background: We conducted a comprehensive meta-analysis to explore the association of polymorphisms at XRCC1, XRCC2 and XRCC3 genes with susceptibility to thyroid cancer (TC). Methods: We searched PubMed, EMBASE, Web of Science, and CNKI for relevant available studies. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of the associations. Results: A total of 67 studies including 17 studies with 6,806 cases and 5,229 controls on XRCC1 Arg399Gln, 13 studies with 3,234 cases and 4,807 controls on XRCC1 Arg280His, 13 studies with 2,956 cases and 3,860 controls on XRCC1 Arg194Trp, five studies with 1,287 cases and 1,422 controls on XRCC2 Arg188His, 13 studies with 2,488 cases and 3,586 controls on XRCC3 Thr241Met, and six studies with 1,828 cases and 2,060 controls on XRCC3 IVS5-14 polymorphism were selected. Polled data revealed that the XRCC1 Arg399Gln, Arg280His, Arg194Trp, XRCC2 Arg188His and XRCC3 Thr241Met and IVS5-14 polymorphisms were not significantly associated with an increased risk of TC. Stratified analyses by ethnicity showed that the XRCC1 Arg399Gln polymorphism was associated with TC risk in Caucasians, but not in Asians. Conclusions: Our meta-analysis indicated that the XRCC1 Arg399Gln, Arg280His, Arg194Trp, XRCC2 Arg188His, XRCC3 Thr241Met and IVS5-14 polymorphisms were not associated with risk of TC in the global population.  Further well-designed investigations with large sample sizes are required to confirm our results.     

DNA损伤修复基因XRCC1和XPD遗传多态与晚期非小细胞肺癌对铂类药物的敏感性

目的 探讨DNA损伤修复基因XRCC1和XPD的遗传多态与晚期非小细胞肺癌（NSCLC）对以铂类为主化疗药物敏感性的关系。方法 以聚合酶链反应（PCR）结合限制性片段长度多态性（RFLP）,检测200例以顺铂（DDP）或卡铂（CBP）为主要化疗方案的NSCLC患者XRCC1 Arg194Trp和XPD Lys751Gln多态基因型,并比较不同基因型与化疗敏感性的关系。结果 化疗总有效（CR＋PR）率为36．0％,其中CR1例,PR71例,SD94例,PD34例。携带XRCC1第194位密码子Arg／Trp或Trp／Trp基因型的个体化疗敏感性是XRCC1第194位密码子Arg／Arg基因型携带者的2．48倍（95％CI为1．36～4．51,P=0．003）;未发现XPD Lys751Gln多态与化疗敏感性的相关性。联合分析这两个遗传多态发现,XRCC1 Arg194Trp和XPD Lys751Gln多态在NSCLC对铂类药物敏感性中存在一定的联合作用（趋势检验,P=0．004）。结论XRCC1 Arg194Trp和XPDLys751Gin遗传多态可能与NSCLC铂类药物敏感性有关。     

Lack of any Relationship between Chemotherapy Toxicity in Non-small Cell Lung Cancer Cases and Polymorphisms in XRCC1 Codon 399 or XPD Codon 751

Purpose: To examine the association between genetic polymorphisms (at XRCC1codon 399 or XPD codon751) and chemotherapy related toxicities of non-small cell lung cancer. Methods: One hundred and fifteenpatients with histologically or cytologically confirmed stage IIIB and IV NSCLC recruited from Department ofChemotherapy of Jiangsu Cancer Hospital and Research Institute from 2005 to 2008, to evaluated the occurrenceof chemotherapy related toxicities and the association with single nucleotide polymorphisms in XRCC1codon399 or XPD codon 751. Results: No significant association was observed between grade 0 or grade 1-4 overalltoxicity and XRCC1 codon 399 (odds ratio=1.40, 95% confidence interval,0.73-2.66; adjusted odds ratio =1.43,95% confidence interval,0.71-2.88), or XPD codon 751 genetic polymorphisms (odds ratio =0.87, 95% confidenceinterval,0.33-2.26; adjusted odds ratio=0.74, 95% confidence interval,0.26-2.13); similar results were foundbetween hematologic, hepatic, gastrointestinal toxicities and XRCC1 399 or XPD 751 genetic polymorphisms.Conclusion: No statistically significant association was found between either XRCC1codon 399 or XPD codon751 genetic polymorphisms and chemotherapy related toxicities.     

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.     

Polymorphisms at XPD and XRCC1 DNA repair loci and increased risk of oral leukoplakia and cancer among NAT2 slow acetylators

Polymorphisms at N-acetyl transferase 2 locus (NAT2) lead to slow, intermediate and rapid acetylation properties of the enzyme. Improper acetylation of heterocyclic and aromatic amines, present in tobacco, might cause DNA adduct formation. Generally, DNA repair enzymes remove these adduct to escape malignancy. But, tobacco users carrying susceptible NAT2 and DNA repair loci might be at risk of oral leukoplakia and cancer. In this study, 389 controls, 224 leukoplakia and 310 cancer patients were genotyped at 5 polymorphic sites on NAT2 and 3 polymorphic sites on each of XRCC1 and XPD loci by PCR-RFLP method to determine the risk of the diseases. None of the SNPs on these loci independently could modify the risk of the diseases in overall population but variant genotype (Gln/Gln) at codon 399 on XRCC1 and major genotype (Lys/Lys) at codon 751 on XPD were associated with increased risk of leukoplakia and cancer among slow acetylators, respectively (OR = 4.2, 95% CI = 1.2-15.0; OR = 1.6, 95% CI = 1.1-2.3, respectively). Variant genotype (Asn/Asn) at codon 312 on XPD was also associated with increased risk of cancer among rapid and intermediate acetylators (OR = 1.9, 95% CI = 1.2-2.9). Variant C-G-A haplotype at XRCC1 was associated with increased risk of leukoplakia (OR = 1.7, 95% CI = 1.2-2.4) but leukoplakia and cancer in mixed tobacco users (OR = 3.1, 95% CI = 1.4-7.1, OR = 2.4, 95% CI = 1.1-5.4, respectively) among slow acetylators. Although none of the 3 loci could modulate the risk of the diseases independently but 2 loci in combination, working in 2 different biochemical pathways, could do so in these patient populations.     

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.     

Polymorphisms of ERCC1, XPD, XRCC1 and XPG predict clinical outcome in advanced gastric cancer patients receiving oxaliplatin-based chemotherapy in Chinese population

OBJECTIVE To investigate whether polymorphisms in ERCC1, XPD, XPG, XRCC1 genes are associated with clinical outcomes in advanced gastric cancer （AGC） patients treated with oxaliplatinbased chemotherapy. METHODS The genetic polymorphisms in ERCCI, XPD, XPG, XRCC1 were determined in 94 advanced gastric cancer patients treated with oxaliplatin-based chemotherapy, using TaqMan-MGB probes. The clinical response of 60 patients with stage IV disease, time to progression （TTP） and overall survival （OS） of 94 patients were evaluated. RESULTS The overall disease control rate （CR ＋ PR ＋ SD） of the 60 patients in stage IV was 70% （42/60）. Patients with XRCC1 399 G/G, XPG 46 C/C genotypes showed enhanced response to the oxaliplatin-based chemotherapy compared to those with other genotypes （P 〈 0.05）. The median OS and TTP of the patients were 5.5 months and 9.0 months, respectively. Among the 4 types of polymorphisms in the study, XRCC1 399 G/A ＋ A/A, XPG 46 C/T ＋ T/T genotypes were regarded to be associated with chemoresistance and poor survival （P 〈 0.05）. Combination analysis of the 2 polymorphisms using the Kaplan-Meier method revealed that the TTP and OS of the patients with a number of risk genotypes were significantly shortened （P 〈 0.05）. No significant association was found between the genotypes of the XPD codon 751, the ERCC1 codon 118 and the clinical outcome （P 〉 0.05）. CONCLUSION Testing for XRCC1 399, XPG 46 polymorphisms may allow identification of the gastric cancer patients who will benefit from oxaliplatin-based chemotherapy. Specific polymorphisms may influence clinical outcomes of AGC patients. Selecting specific chemotherapy based on pretreatment genotyping represents an innovative strategy that warrants prospective studies.