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.Key Words: X-ray repair cross-complementing group 1 (XRCC1), gene polymorphism, childhood, acute lymphoblastic leukemia (ALL)     

XRCC1 and XRCC3 polymorphisms and their role as effect modifiers of unsaturated fatty acids and antioxidant intake on colorectal adenomas risk.

Whereas animal and in vitro studies support a role of unsaturated fatty acids in colon carcinogenesis, the epidemiologic evidence is inconclusive. Using a large sigmoidoscopy-based case-control study (753 cases and 799 controls) in Los Angeles County, we investigated possible associations between single-nucleotide polymorphisms in the XRCC1 (codons 194 Arg/Trp and codon 399 Arg/Gln) and XRCC3 (codon 241 Thr/Met) genes and colorectal adenoma risk and their possible role as modifiers of the effect of monounsaturated fatty acid, the ratio of omega-6/omega-3 polyunsaturated fatty acids, and antioxidant intake. We found no evidence of associations between the XRCC1 codon 194 Arg/Trp or Trp/Trp genotypes and the XRCC3 codon 241 Thr/Met or Met/Met genotypes. Subjects with the XRCC1 Gln/Gln genotype were inversely associated with adenoma risk (odds ratio, 0.6; 95% confidence interval, 0.4-0.9; P = 0.01) when compared with subjects with Arg/Arg and Arg/Gln genotypes combined. We found no evidence of gene-dietary fat interactions for the XRCC3 codon 241 polymorphism. However, our data suggest an XRCC1-unsaturated fat interaction. High monounsaturated fatty acid intake was associated with adenoma risk only among subjects with the XRCC1 codon 194 Arg/Arg and codon 399 Gln/Gln combined genotypes (P for interaction = 0.018). High omega-6/omega-3 polyunsaturated fatty acid ratios were associated with adenoma risk among subjects with the XRCC1 codon 194 Arg/Arg and codon 399 Gln/Gln or the codon 194 Arg/Trp or Trp/Trp and codon 399 Arg/Arg or Arg/Gln combined genotypes (P for interaction = 0.026). These interactions were not modified by antioxidant intake. However, low antioxidant intake was associated with an inverse association only among subjects with the XRCC1 codon 194 Arg/Trp or Trp/Trp and codon 399 Arg/Arg or Arg/Gln combined genotypes (P for interaction = 0.022), which was independent of unsaturated fat intake. Our data suggest that the XRCC1 codon 194 and codon 399 single nucleotide polymorphisms may modify the effect of unsaturated fatty acid and antioxidant intake and that this XRCC1 effect modification may explain, in part, previously reported inconsistencies on the role of unsaturated fatty acids and adenoma risk.     

A prospective study of XRCC1 (X-ray cross-complementing group 1) polymorphisms and breast cancer risk

Introduction

The gene XRCC1 (X-ray repair cross-complementing group 1) encodes a protein involved in DNA base excision repair. Two non-synonymous polymorphisms in XRCC1 (Arg194Trp and Arg399Gln) have been shown to alter DNA repair capacity in some studies in vitro. However, results of previous association studies of these two XRCC1 variants and breast cancer have been inconsistent. We examined the association between polymorphisms in XRCC1 and breast cancer in the American Cancer Society Cancer Prevention Study II (CPS-II) Nutrition Cohort, a large prospective study of cancer incidence in the USA.

Methods

Among the 21,965 women who were cancer-free in 1992 and gave blood between 1998 and 2001, 502 postmenopausal breast cancer cases were diagnosed between 1992 and 2001; 502 controls were matched to cases on age, race/ethnicity, and date of blood collection. Genotyping on DNA extracted from buffy coat was performed with Taqman. Conditional logistic regression was used to examine the association between each polymorphism and breast cancer risk controlling for breast cancer risk factors. We also examined whether factors associated with DNA damage, such as smoking and antioxidant intake, modified the association between XRCC1 polymorphisms and breast cancer.

Results

We observed a significant inverse association between Trp194 carriers (Trp/Trp and Trp/Arg) compared with Trp194 non-carriers in relation to breast cancer (Arg/Arg) (odds ratio (OR) 0.62, 95% confidence interval (CI) 0.40 to 0.95). The inverse association between breast cancer and Trp194 carriers compared with non-carriers was slightly stronger among smokers (OR 0.47, 95% CI 0.24 to 0.94) than never smokers (OR 0.78, 95% CI 0.43 to 1.40). An increased risk associated with the Arg399Gln polymorphism (Gln/Gln versus Arg/Arg) was observed only among women who reported ever smoking cigarettes (OR 2.76, 95% CI 1.36 to 5.63), and not in women who were lifelong non-smokers (OR 0.64, 95% CI 0.33 to 1.26). No other factor examined modified the association between XRCC1 polymorphisms and breast cancer risk.

Conclusion

Our results support the hypothesis that genetic variation in XRCC1, particularly in Arg194Trp, may influence postmenopausal breast cancer risk. In our study, genetic variation in XRCC1 Arg399Gln was associated with breast cancer risk only among women with a history of smoking cigarettes.     

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.     

XRCC1 polymorphisms and severe toxicity in lung cancer patients treated with cisplatin-based chemotherapy in Chinese population

Cisplatin kills tumor cells through DNA cross linking. Alterations in the function of DNA repair genes may affect DNA repair proficiency and influence cancer patients' response to cisplatin. The predictability of DNA repair XRCC1 (X-ray repair cross-complementing group 1 protein) single nucleotide polymorphisms (SNPs) for cisplatin-based grades 3 and 4 chemotherapy-related toxicity in patients with newly diagnosed advanced lung cancer was evaluated. The genotypes of XRCC1 at the Arg194Trp, and Arg399Gln sites were determined by PCR-based restriction fragment length polymorphism (RFLP) methods. There was no statistically significant association between either the Arg194Trp or the Arg399Gln polymorphisms and hematologic grade 3 or 4 toxicity. However, carrying at least one variant XRCC1 Arg399Gln allele (399Arg/Gln or 399Gln/Gln) was associated with a significantly increased risk of overall grade 3 or 4 toxicity (odds ratio, 2.05; 95% confidence interval, 1.02-4.10; p=0.04); and grade 3 or 4 gastrointestinal toxicity (odds ratio, 2.53; 95% confidence interval, 1.06-6.03; p=0.03). Our results suggested that patients carrying at least one variant XRCC1 Arg399Gln allele have a 2.5-fold increased risk of grade 3 or 4 gastrointestinal toxicity when treated with first-line cisplatin-based chemotherapy.     

XRCC1 单核苷酸多态性预测晚期NSCLC铂类药物化疗的敏感性

 目的 研究XRCC1单核苷酸多态性与晚期非小细胞肺癌（nowsmallcelllungcancer，NSCLC）对以顺铂（cisplatin，DDP）或卡铂（carDoplatin，CBP）为基础药物的化疗敏感性的关系。方法 经病理学确诊的晚期NSCLC患者97例，采用DDP或CBP为基础药物的方案化疗，3个周期后进行疗效评价。以聚合酶链反应（PCR）结合限制性片段长度多态性（RFLP）检测RiCelArg194Trp和Arg399G1n基因型，并比较基因型与化疗敏感性的关系。结果 （1）携带RiCel194Arg／Trp的患者有效率高于携带Arg／Arg、Trp／Trp基因型的患者（P〈0．05）；携带至少一个Trp等位基因基因型患者的化疗敏感性是携带Arg／Arg基因型的3．4倍（OR=3．39，95％，CI=1．3248．70，P〈0.05）。（2）携带RiCel399Arg／Arg、Arg／G1n、Gin／Gin基因型患者的有效率分别为36．4％、22．9％、28．6％，差异无统计学意义（P〉0.05）。尚未发现RiCelArg194Trp和Arg399Gln基因多态性存在联合作用。结论 XRCClArg194Trp单核苷酸多态性可能与晚期NSCLC对铂类药物的化疗敏感性相关。     

XRCC1单核苷酸多态性与鼻咽癌铂类化疗敏感度的相关性

目的 探讨鼻咽癌铂类化疗敏感度与X射线交错互补修复基因1 codon194和codon399单核苷酸多态性的相关性。方法 收集广西医科大学第四附属医院2012年9月1日至2013年12月31日鼻咽部肿物活检确诊为鼻咽癌患者资料,采用限制性片段长度多态性聚合酶链反应技术检测鼻咽癌患者外周血DNA XRCC1 codon194和codon399单核苷酸多态性。顺铂+氟尿嘧啶方案诱导化疗2周期后复查MRI,按照RECIST 1.1标准评价其化疗敏感度,分析单核苷酸多态性（Single nucleotide polymorphism,SNP）与化疗敏感度的关系。结果 XRCC1 codon399 Gln/Gln基因型携带者化疗敏感度为Arg/Arg基因型携带者的3.500倍（P＜0.05）。XRCC1 codon399不含Arg基因型（即Gln/Gln）携带者化疗敏感度为含Arg基因型（Arg/Arg 和 Arg/Gln）携带者的3.274倍,（P＜0.05）。携带XRCC1 codon194各基因型患者化疗敏感度之间差异无明显统计学意义（P＞0.05）。结论 XRCC1 codon399 单核苷酸多态性有可能成为鼻咽癌铂类化疗敏感度的预测因子。     

Polymorphisms in the DNA repair gene XRCC1 and breast cancer.

X-ray repair cross complementing group 1 (XRCC1) encodes a protein involved in base excision repair. We examined the association of polymorphisms in XRCC1 (codon 194 Arg-->Trp and codon 399 Arg-->Gln) and breast cancer in the Carolina Breast Cancer Study, a population-based case-control study in North Carolina. No association was observed between XRCC1 codon 194 genotype and breast cancer, and odds ratios (ORs) were not modified by smoking or radiation exposure. A positive association for XRCC1 codon 399 Arg/Gln or Gln/Gln genotypes compared with Arg/Arg was found among African Americans (253 cases, 266 controls; OR = 1.7, 95% confidence interval, 1.1-2.4) but not whites (386 cases, 381 controls; OR =1.0, 95% confidence interval, 0.8-1.4). Among African-American women, ORs for the duration of smoking were elevated among women with XRCC1 codon 399 Arg/Arg genotype (trend test; P < 0.001) but not Arg/Gln or Gln/Gln (P = 0.23). There was no difference in OR for smoking according to XRCC1 codon 399 genotype in white women. ORs for occupational exposure to ionizing radiation were stronger for African-American and white women with codon 399 Arg/Arg genotype. High-dose radiation to the chest was more strongly associated with breast cancer among white women with XRCC1 codon 399 Arg/Arg genotype. Our results suggest that XRRC1 codon 399 genotype may influence breast cancer risk, perhaps by modifying the effects of environmental exposures. However, interpretation of our results is limited by incomplete knowledge regarding the biological function of XRCC1 alleles.     

XRCC1基因多态性与卵巢癌对铂类药物化疗敏感性的相关性研究

目的 探讨X线修复交叉互补基因1（XRCC1）Arg194Trp和Arg399Gln位点多态性与卵巢癌对铂类药物化疗敏感性之间的关系。方法 选取82例首次术后以铂类为基础化疗达6个周期的卵巢癌患者,采用聚合酶链反应 限制性片段长度多态性分析（PCR RFLP）检测外周血XRCC1 Arg194Trp和Arg399Gln位点的基因型,分别比较两个位点的不同基因型与化疗敏感性及两个位点之间的关系。结果 XRCC1 Arg194Trp存在3个基因型,即Arg／Arg、Arg／Trp、Trp／Trp,基因分布频率分别为47.6％、43.9％、8.5％;XRCC1 Arg399Gln亦存在3个基因型,即Arg／Arg、Arg／Gln、Gln／Gln,基因分布频率分别为25.6％、40.2％、34.1％。XRCC1 Arg399Gln 的不同基因型在FIGO分期和年龄分组中的差异均有统计学意义（P＜0.05）。化疗敏感组与不敏感组两个位点多态性基因型之间的差异均有统计学意义（P＜0.05）。XRCC1 Arg194Trp的Trp／Trp和Arg 399Gln的Gln/Gln基因型比Arg／Arg基因型更易对铂类药物产生耐药性,比值比分别增加至13.50倍（95％CI：1.461～124.739）和7.65倍（95％CI：2.012～29.088）。同时携带Arg194Trp Arg／Trp和Arg399Gln Gln／Gln基因型的患者对化疗不敏感率高达84.62％（OR=22.00,95％CI：2.534～190.998;P＜0.05）。结论 XRCC1 Arg194Trp和Arg399Gln位点基因多态性与卵巢癌对铂类药物的化疗敏感性相关,并且两位点之间存在联合效应。     

XRCC1和XRCC3单核苷酸多态性与晚期非小细胞肺癌铂类药物化疗疗效的相关性

背景与目的 DNA修复基因多态性预测铂类药物化疗敏感性对非小细胞肺癌(non-small cell lung cancer,NSCLC)个体化治疗具有重要意义.本研究旨在探讨X线修复交错互补基因1(X-ray repair cross complementing gene 1,XRCC1)和X线修复交错互补基因3(X-ray repair cross complementing gene 3,XRCC3)单核苷酸多态性与晚期NSCLC患者对铂类药物化疗疗效的关系.方法 采用PCR-RFLP方法检测130例以含铂方案化疗的晚期NSCLC患者外周血DNA中XRCC1 Arg194 Trp、Arg399 Gln和XRCC3 Thr241 Met基因多态性,分析其基因型与化疗疗效的关系.结果 130例晚期NSCLC患者采用含铂方案化疗2个周期后,化疗总有效率为33.8％.XRCC1 194和399基因多态性与铂类药物化疗敏感性相关,而XRCC3 241基因多态性与化疗敏感性无关(P=0.145).携带至少1个XRCC1 194 Trp等位基因者化疗有效率至少是携带Arg/Arg基因型患者的2.5倍(42.1％vs22.2％,OR=2.545,95％CI:1.159-5.590,P=0.020).携带XRCC1399 Arg/Arg基因型者的化疗有效率为45.5％,明显高于携带至少1个Gln等位基因者(21.9％)(OR=0.336,95％CI:0.156-0.722,P=0.005).XRCC1 194和399基因多态性之间存在联合作用,同时携带至少1个XRCC1 194 Trp等位基因和399 Arg/Arg基因型者的化疗有效率明显高于同时携带194 Arg/Arg和399 Arg/Gln基因型者(44.4％ vs 18.8％,OR=3.467,95％CI:1.223-9.782,P=0.019).XRCC1和XRCC3基因多态性在化疗敏感性方面存在一定的联合作用,携带至少1个XRCC1 194 Trp等位基因和399 Arg/Arg野生型基因同时又携带XRCC3 241 Thr/Met基因型者的化疗有效率明显高于其它基因型携带者.结论 XRCC1和XRCC3的多态联合可能与晚期NSCLC患者对铂类药物化疗疗效具有相关性.     

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.     

Variant Alleles in XRCC1 Arg194Trp and Arg399Gln Polymorphisms Increase Risk of Gastrointestinal Cancer in Sabah,North Borneo

Background: The XRCC1 protein facilitates various DNA repair pathways; single-nucleotide polymorphisms (SNPs) in this gene are associated with a risk of gastrointestinal cancer (GIC) with inconsistent results, but no data have been previously reported for the Sabah, North Borneo, population. We accordingly investigated the XRCC1 Arg194Trp and Arg399Gln SNPs in terms of GIC risk in Sabah. Materials and Methods: We performed genotyping for both SNPs for 250 GIC patients and 572 healthy volunteers using a polymerase chain reaction- restriction fragment length polymorphism approach. We validated heterozygosity and homozygosity for both SNPs using direct sequencing. Results: The presence of a variant 194Trp allele in the Arg194Trp SNP was significantly associated with a higher risk of GIC, especially with gastric and colorectal cancers. We additionally found that the variant 399Gln allele in Arg399Gln SNP was associated with a greater risk of developing gastric cancer. Our combined analysis revealed that inheritance of variant alleles in both SNPs increased the GIC risk in Sabah population. Based on our etiological analysis, we found that subjects 50 years and males who carrying the variant 194Trp allele, and Bajau subjects carrying the 399Gln allele had a significantly increased risk of GIC. Conclusions: Our findings suggest that inheritance of variant alleles in XRCC1 Arg194Trp and Arg399Gln SNPs may act as biomarkers for the early detection of GIC, especially for gastric and colorectal cancers in the Sabah population.     

Polymorphisms in DNA Repair Genes and Risk of Glioma and Meningioma

Polymorphisms in DNA repair genes have been shown to influence DNA repair processes and to modifycancer susceptibility. Here we conducted a case-control study to assess the role of potential SNPs of DNA repairgenes on the risk of glioma and meningioma. We included 297 cases and 458 cancer-free controls. Genotypingof XRCC1 Gln399Arg, XRCC1 Arg194Trp, XRCC2 Arg188His, XRCC3 Thr241Met, XRCC4 Ala247Ser,ERCC1 Asn118Asp, ERCC2 Lys751Gln and ERCC5 Asp1558His were performed in a 384-well plate formaton the Sequenom MassARRAY platform. XRCC1 Arg194Trp (rs1799782) and ERCC2 Asp312Asn rs1799793did not follow the HWE in control group, and genotype distributions of XRCC1 Gln399Arg rs25487, XRCC2Arg188His rs3218536 and ERCC2 Asp312Asn rs1799793 were significantly different between cases and controls(P<0.05). We found XRCC1 399G/G, XRCC1 194 T/T and XRCC3 241T/T were associated with a higher riskwhen compared with the wild-type genotype. For ERCC5 Asp1558His, we found G/G genotype was associatedwith elevated susceptibility. In conclusion, our study has shown that XRCC1 Gln399Arg, XRCC1 Arg194Trp,XRCC3 Thr241Met and ERCC5 Asp1558His are associated with risk of gliomas and meningiomas. This findingcould be useful in identifying the susceptibility genes for these cancers.     

Polymorphisms in the base excision repair pathway modulate prognosis of platinum-based chemotherapy in advanced non-small cell lung cancer

Purpose

Platinum-based chemotherapy is the most common treatment for patients with advanced non-small cell lung cancer (NSCLC). Genetic polymorphisms in the base excision repair (BER) pathway are suspected to influence the response of patients to this type of therapy. In this study, we investigated whether nonsynonymous single nucleotide polymorphisms (SNPs) in the BER pathway were associated with the response, progression-free survival (PFS) and overall survival (OS) of NSCLC patients following platinum-based chemotherapy.

Methods

We used TaqMan to genotype four SNPs (APE1 Asp148Glu, PARP1 Va1762Ala, XRCC1 Arg194Trp and XRCC1 Arg399Gln) in 147 patients with advanced NSCLC who had undergone routine platinum-based chemotherapy.

Results

Logistic regression analysis showed that subjects with the XRCC1-399 A allele had a significantly better response to platinum-based chemotherapy than those with the XRCC1-399 GG genotype (AA/AG vs. GG: adjusted OR = 2.35, 95 % CI = 1.11–5.00). Furthermore, multivariate Cox proportional hazard regression analysis showed that the PARP1-762 CC genotype was a significantly unfavorable prognostic factor for PFS (CC vs. CT/TT: adjusted HR = 1.90, 95 % CI = 1.02–3.52). In contrast, the APE1-148 GG genotype was a significantly protective prognostic factor for OS (GG vs. TT: adjusted HR = 0.33, 95 % CI = 0.12–0.92).

Conclusions

We found that XRCC1 Arg399Gln, PARP1 Va1762Ala and APE1 Asp148Glu SNPs in the BER pathway may influence the prognosis of advanced NSCLC patients following platinum-based chemotherapy.     

Association of the Arg194Trp and the Arg399Gln Polymorphisms of the XRCC1 Gene With Risk Occurrence and the Response to Adjuvant Therapy Among Polish Women With Breast Cancer

BackgroundThe XRCC1 gene encoding the X-ray cross-complementing group 1 protein (XRCC1) is involved in the base excision repair (BER) pathway.MethodsThe aim of this study was to investigate an association of the Arg194Trp and Arg399Gln polymorphisms of the XRCC1 gene with a risk of breast cancer occurrence and the response to adjuvant treatment among Polish women. Overall survival (OS) and disease-free survival (DFS) were investigated in groups of patients with breast cancer treated with (1) all types of adjuvant therapy, (2) concomitant radiotherapy and chemotherapy, (3) chemotherapy alone, or (4) radiotherapy alone. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was used to evaluate the genotype distribution of the XRCC1 gene among 185 patients with breast cancer and 205 female controls.ResultsWe showed a higher risk of breast cancer occurrence for the Trp allele and the Arg194Trp genotype of the XRCC1 gene. However there was no significant difference in distribution of the Arg399Gln genotype of XRCC1 between patients and the control group. In the patient subgroup treated with adjuvant therapy, Kaplan-Meier survival analysis showed a significantly higher OS as well as DFS for carriers of the Gln399Gln genotype when compared with carriers of the Arg399Gln and Arg399Arg genotypes. The Gln399Gln genotype was associated with a significantly higher DFS in the subgroup of patients treated with chemotherapy alone or with concomitant radiotherapy and chemotherapy.ConclusionWe suggest that the polymorphism of the XRCC1 gene may be considered a predictive factor associated with the risk of occurrence and the survival outcome in breast cancer among Polish women.     

ERCC1/BRCA1 expression and gene polymorphisms as prognostic and predictive factors in advanced NSCLC treated with or without cisplatin

Background:

The FAST was a factorial trial in first-line treatment of advanced non-small-cell lung cancer (NSCLC), addressing the role of replacing cisplatin with a non-platinum agent. The prognostic and predictive effect of ERCC1/BRCA1 expression and ERCC1/XPD/XRCC1–3 gene polymorphisms on outcomes of patients was examined.

Methods:

Patients were randomised to receive treatment with or without cisplatin. ERCC1/BRCA1 expression was determined by immunohistochemistry. ERCC1 (C8092A, C118T), XPD (Lys751Gln), XRCC1 (Arg399Gln) and XRCC3 (Thr241Met) gene polymorphisms were evaluated on tumour DNA by TaqMan allelic discrimination assay.

Results:

Tumour samples were available from 110 of 433 patients enrolled: 54.7% were ERCC1 positive and 51.4% were BRCA1 positive. Overall, ERCC1-negative patients had better response rate (P=0.004), progression-free survival (P=0.023) and overall survival (P=0.012) compared with positive ones, with no statistically significant treatment interaction. The BRCA1-positive patients showed numerically better outcomes, although not statistically significant, with no treatment interaction. Among DNA repair gene polymorphisms, only XRCC1 Gln/Gln genotype evidenced a potential prognostic role (P=0.036).

Conclusion:

This study confirms the prognostic role of ERCC1 expression and XRCC1 (Arg399Gln) polymorphism in advanced NSCLC treated with first-line chemotherapy. None of these biomarkers was shown to be a specific predictive factor of cisplatin efficacy.     

DNA repair gene XPD and XRCC1 polymorphisms and the risk of childhood acute lymphoblastic leukemia

Polymorphisms have been identified in several DNA repair genes. These polymorphisms may effect DNA repair capacity and modulate cancer susceptibility. In this study, we aimed to determine the four polymorphisms in two DNA repair genes, xeroderma pigmentosum complementation group D (XPD) and X-ray repair cross-complementing group 1 (XRCC1), in a sample of Turkish patients with childhood acute lymphoblastic leukemia (ALL), and evaluate their association with childhood ALL development. We used polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP), to analyze XPD Asp312Asn, XPD Lys751Gln, XRCC1 Arg194Trp, and XRCC1 Arg399Gln polymorphisms in 70 patients with childhood ALL and in 75 disease-free controls, who were of a similar age. No significant differences were observed among the study groups with regard to the XPD codon 312, XPD codon 751, XRCC1 codon 194, and XRCC1 codon 399 polymorphisms. However, the combined XRCC1 Arg194Trp/Trp194Trp variant genotypes were associated with increased risk for ALL in females (OR = 5.47; 95% CI = 1.49–20.10; p = 0.008). This finding indicates that females carrying XRCC1 194Trp allele are at increased risk of developing childhood ALL. These results suggest that the risk of childhood ALL may be associated with DNA repair mechanisms, and understanding these mechanisms will help identify individuals at increased risk of developing childhood ALL, and also should be lead to improved treatment of ALL.     

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.     

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.     

Role of XRCC3, XRCC1 and XPD single-nucleotide polymorphisms in survival outcomes following adjuvant chemotherapy in early stage breast cancer patients

Introduction

Anthracyclines have various mechanisms of action that in the end lead to DNA double-strand breaks. Single-nucleotide polymorphisms (SNPs) in DNA repair genes may alter the protein function, affecting DNA repair proficiency and, therefore, the efficiency of DNA damaging chemotherapy. We have analysed whether SNPs in DNA repair genes (XRCC1, XRCC3 and XPD) could be useful to predict the response to anthracyclines in patients with early-stage breast cancer (EBC).

Methods

Peripheral blood samples from 150 patients with EBC were used for genotyping XRCC3Thr241Met, XRCC1Arg399Gln and XPDLys751Gln. Genotypes were correlated with survival outcomes.

Results

Eighty-four patients received treatment with chemotherapy regimens containing anthracyclines. In this group, patients with XRCC1Arg399Arg had a significant improvement in 5-year Disease Free Survival (DFS) compared with those with the Arg/Gln and Gln/Gln variants (84 vs 46 %, p = 0.026). In the multivariate analysis, XRCC1Arg399Arg was reported as an independent prognostic factor for DFS (HR 0.4, CI-95 % 0.2–0.9, p = 0.035). Patients with the XRCC3 Met241Met genotype presented better 5-year OS than those carrying the Thr/Thr and Met/Thr variants (100 vs 70 %, p = 0.030). A multivariate analysis for OS confirmed the independent prognostic value of XRCC3 Met241Met (HR 0.15, CI-95 % 0.02–0.90, p = 0.048). These differences were not significant when patients receiving other chemotherapy treatments, different from anthracyclines, were also considered (n = 150). XPDLys751Lys was associated with older age at diagnosis than the Lys/Gln and Gln/Gln genotypes (65 vs 58 years, p < 0.0001).

Conclusions

XRCC3Thr241Met and XRCC1Arg399Gln may be predictive of survival outcome in EBC patients treated with anthracycline-based chemotherapy regimens.