XRCC1 and GSTP1 polymorphisms and prognosis of oxaliplatin-based chemotherapy in colorectal cancer: a meta-analysis

Purpose

Genetic variations are related to individual differences of DNA repair ability and drug metabolism, which can greatly influence prognosis of antineoplastic agents, such as oxaliplatin. The aim was to explore the influences of X-ray repair cross-complementing 1(XRCC1) and Glutathione S-transferase P1 (GSTP1) genetic variants on prognosis of oxaliplatin-based chemotherapy in colorectal cancer patients.

Methods

We performed a meta-analysis including 13 original studies with a total number of 1,234 patients in advanced or metastatic colorectal cancer. Tumor responses [complete response, partial response, stable disease (SD) and progressive disease (PD)] and progression-free survival were estimated.

Results

Our results showed that XRCC1 Arg399Gln polymorphism was significantly associated with tumor chemotherapy when SD or PD was considered as non-response [risk ratio (RR) = 1.29; 95 % confidence intervals (CI): 1.05–1.60; P = 0.02]. No significant association was found between GSTP1 Ile105 Val polymorphism and tumor response (RR = 0.63; 95 % CI: 0.35–1.14; P = 0.13). In addition, our results also showed that there was no significant association between XRCC1 codon 399 Arg/Gln or Gln/Gln genotypes and hazard ratio for progression-free survival (Hazards ratio = 1.04 and 1.92; 95 % CI: 0.75–1.43 and 0.62–1.37; P = 0.826 and 0.677, respectively).

Conclusion

In our meta-analysis, XRCC1 Arg399Gln polymorphism may be a valuable genetic marker for oxaliplatin-based chemotherapy in colorectal cancer, and the results still need further confirmation.     

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.     

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.     

Genetic polymorphisms in DNA repair genes as modulators of Hodgkin disease risk

BACKGROUND:

Although the pathogenesis of Hodgkin disease (HD) remains unknown, the results of epidemiologic studies suggest that heritable factors are important in terms of susceptibility. Polymorphisms in DNA repair genes may contribute to individual susceptibility for development of different cancers. However, to the authors' knowledge, few studies to date have investigated the role of such polymorphisms as risk factors for development of HD.

METHODS:

The authors evaluated the relation between polymorphisms in 3 nucleotide excision repair pathway genes (XPD [Lys751Gln], XPC [Lys939Gln], and XPG [Asp1104His]), the base excision repair XRCC1 (Arg399Gln), and double‐strand break repair XRCC3 (Thr241Met) in a population of 200 HD cases and 220 matched controls. Variants were investigated independently and in combination; odd ratios (OR) were calculated.

RESULTS:

A positive association was found for XRCC1 gene polymorphism Arg399Gln (OR, 1.77; 95% confidence interval [95% CI], 1.16‐2.71) and risk of HD. The combined analysis demonstrated that XRCC1/XRCC3 and XRCC1/XPC polymorphisms were associated with a significant increase in HD risk. XRCC1 Arg/Arg and XRCC3 Thr/Met genotypes combined were associated with an OR of 2.38 (95% CI, 1.24‐4.55). The XRCC1 Arg/Gln and XRCC3 Thr/Thr, Thr/Met, and Met/Met genotypes had ORs of 1.88 (95% CI, 1.02‐4.10), 1.97 (95% CI, 1.05‐3.73), and 4.13 (95% CI, 1.50‐11.33), respectively. XRCC1 Gln/Gln and XRCC3 Thr/Thr variant led to a significant increase in risk, with ORs of 3.00 (95% CI, 1.15‐7.80). Similarly, XRCC1 Arg/Gln together with XPC Lys/Lys was found to significantly increase the risk of HD (OR, 2.14; 95% CI, 1.09‐4.23).

CONCLUSIONS:

These data suggest that genetic polymorphisms in DNA repair genes may modify the risk of HD, especially when interactions between the pathways are considered. Cancer 2009. © 2009 American Cancer Society.     

Polymorphisms of the <Emphasis Type="Italic">XRCC1</Emphasis>, <Emphasis Type="Italic">XRCC3</Emphasis>, &; <Emphasis Type="Italic">XPD</Emphasis>genes,and colorectal cancer risk: a case-control study in Taiwan

Background  

Recent studies relating to the association between DNA repair-gene polymorphisms and colorectal cancer risk would, to the best of our knowledge, appear to be very limited. This study was designed to examine the polymorphisms associated with three DNA repair genes, namely: XRCC1 Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln, and investigate their role as susceptibility markers for colorectal cancer.     

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.     

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.     

No association between XRCC1 and XRCC3 gene polymorphisms and breast cancer risk: Iowa Women's Health Study

BACKGROUND: Genetic variation in DNA repair may contribute to differences in the susceptibility of several cancers. We evaluated two polymorphisms in the base excision repair pathway (BER) (XRCC1; Arg194Trp and Arg399Gln) and one polymorphism in the double strand DNA repair pathway (XRCC3; Thr241Met) for their association with breast cancer risk. METHODS: The association was analyzed in a nested case control study of 460 breast cancer cases and 324 cancer-free controls within the Iowa Women's Health Cohort. DNA was obtained from blood samples or paraffin embedded tissues (PET) and all samples were genotyped by one of three genotyping platforms-PCR-RFLP, PCR-INVADER, or Sequenom. RESULTS: None of the three polymorphisms studied were significantly associated with breast cancer risk (XRCC1: Arg194Trp (OR=1.21, 95% CI: 0.78-1.88); Arg399Gln (OR=1.20, 95% CI: 0.80-1.79); XRCC3: Thr241Met (OR=1.04, 95% CI: 0.76-1.41). CONCLUSIONS: These results suggest that independently these polymorphisms of XRCC1 and XRCC3 genes do not contribute significantly to the genetic susceptibility of breast cancer.     

XRCC1 and XRCC3 variants and risk of glioma and meningioma

Several single nucleotide polymorphisms (SNPs) affecting DNA repair capacity and modifying cancer susceptibility have been described. We evaluated the association of SNPs Arg194Trp, Arg280His, and Arg399Gln in the X-ray cross-complementing group 1 (XRCC1) and Thr241Met in the X-ray cross-complementing group 3 (XRCC3) DNA repair genes with the risk of brain tumors. The Caucasian study population consisted of 701 glioma (including 320 glioblastoma) cases, 524 meningioma cases, and 1,560 controls in a prospective population-based case–control study conducted in Denmark, Finland, Sweden, and the UK. The studied SNPs were not significantly associated with the risk of brain tumors. The highest odds ratios (ORs) for the associations were observed between the homozygous variant genotype XRCC1 Gln399Gln and the risk of glioma (OR = 1.32; 95% confidence interval, CI, 0.97–1.81), glioblastoma (OR = 1.48; 95% CI, 0.98–2.24), and meningioma (OR = 1.34; 95% CI, 0.96–1.86). However, in pair-wise comparisons a few SNP combinations were associated with the risk of brain tumors: Among others, carriers of both homozygous variant genotypes, i.e., XRCC1 Gln399Gln and XRCC3 Met241Met, were associated with a three-fold increased risk of glioma (OR = 3.18; 95% CI, 1.26–8.04) and meningioma (OR = 2.99; 95% CI, 1.16–7.72). In conclusion, no significant association with brain tumors was found for any of the polymorphisms, when examined one by one. Our results indicated possible associations between combinations of XRCC1 and XRCC3 SNPs and the risk of brain tumors.     

The association of XRCC1 gene single nucleotide polymorphisms with response to neoadjuvant chemotherapy in locally advanced cervical carcinoma

Background

Platinum-based neoadjuvant chemotherapy (NAC) is new therapeutic strategy for locally advanced cervical carcinoma, but the variables used to predict NAC response are still infrequently reported. The aim of our study was to investigate the association between XRCC1 gene single nucleotide polymorphisms (SNPs) and NAC response.

Methods

Seventy patients with locally advanced cervical carcinoma who underwent NAC were collected. SNPs of XRCC1 (at codon 194 and 399) and XRCC1 protein expression were detected. The association of XRCC1 gene SNPs and protein expression with NAC response were analyzed.

Results

Response to NAC was not statistically significant in three genotypes, Arg/Arg, Arg/Trp, Trp/Trp of XRCC1 at codon 194(X² = 1.243, P = 0.07), while responses were significantly different in genotypes Arg/Arg, Arg/Gln, Gln/Gln of XRCC1 at codon 399 (X² = 2.283, P = 0.020). The risk of failure to chemotherapy in the patients with a Gln allele(Arg/Gln+Gln/Gln) was significantly greater than that with Arg/Arg(OR = 3.254, 95%CI 1.708 ~ 14.951). The expression level of XRCC1 protein was significantly associated with response to NAC. Moreover, the genotype with the Gln allele(Arg/Gln+Gln/Gln) at codon 399, but not codon at 194, presented a significantly higher level of XRCC1 protein expression than that with Arg/Arg genotype (F = 2.699, p = 0.009).

Conclusion

SNP of XRCC1 gene at codon 399 influences the response of cervical carcinoma to platinum-based NAC. This is probably due to changes in expression of XRCC1 protein, affecting response to chemotherapy.     

XRCC1, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy subjects

DNA repair genes have an important role in protecting individuals from cancer-causing agents. Polymorphisms in several DNA repair genes have been identified and individuals with non-dramatic reductions in the capacity to repair DNA damage are observed in the population, but the impact of specific genetic variants on repair phenotype and cancer risk has not yet been clarified. In 308 healthy Italian individuals belonging to the prospective European project EPIC, we have investigated the relationship between DNA damage, as measured by (32)P-DNA adduct levels, and three genetic polymorphisms in different repair genes: XRCC1-Arg399Gln (exon 10), XRCC3-Thr241Met (exon 7) and XPD-Lys751Gln (exon 23). DNA adduct levels were measured as relative adduct level (RAL) per 10(9) normal nucleotides by DNA (32)P-post-labelling assay in white blood cells from peripheral blood. Genotyping was performed by PCR-RFLP analysis. The XRCC3-241Met variant was significantly associated with higher DNA adduct levels, whereas XRCC1-399Gln and XPD-751Gln were associated with higher DNA adduct levels only in never-smokers. XRCC3-241Met homozygotes had an average DNA adduct level of 11.44 +/- 1.48 (+/-SE) compared with 7.69 +/- 0.88 in Thr/Met heterozygotes and 6.94 +/- 1.11 in Thr/Thr homozygotes (F = 3.206, P = 0.042). Never-smoking XRCC1-399Gln homozygotes had an average DNA adduct level of 15.60 +/- 5.42 compared with 6.16 +/- 0.97 in Gln/Arg heterozygotes and 6.78 +/- 1.10 in Arg/Arg homozygotes (F = 5.237, P = 0.007). A significant odds ratio (3.81, 95% CI 1.02-14.16) to have DNA adduct levels above median value was observed for XPD-751Gln versus XPD-751Lys never-smoking homozygotes after adjustment for several confounders. These data show that all the analysed polymorphisms could result in deficient DNA repair and suggest a need for further investigation into the possible interactions between these polymorphisms, smoking and other risk factors.     

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.     

Prognostic Significance of GSTP1, XRCC1 and XRCC3 Polymorphisms in Non-small Cell Lung Cancer Patients

Aim: Individual differences in chemosensitivity and clinical outcome in non-small cell lung cancer (NSCLC)patients treatment with platinum-based chemotherapy may be due to genetic factors. Our study aimed toinvestigate the prognostic role of GSTP1, XRCC1 and XRCC3 in NSCLC patients treated with chemotherapy.Methods: A total of 460 cases were consecutively selected from The Affiliated Hospital of Nantong Universitybetween Jan. 2003 to Nov. 2006, and all were followed-up until Nov. 2011. Genotyping of GSTP1 Ile105Val, XRCC1Arg194Trp, XRCC1 Arg399Gln and XRCC3 Thr241Met was conducted by duplex polymerase-chain-reactionwith confronting-two-pair primer methods. Results: Patients with GSTP Val/Val exhibited a shorter survivaltime, and had a 1.89 fold greater risk of death than did those with the IIe/IIe genotype. For XRCC1 Arg194Trp,the variant genotype Trp/Trp was significantly associated with a decreased risk of death from NSCLC whencompared with the Arg/Arg. Individuals carrying XRCC1 399Gln/Gln genotype had a longer survival time,with a lowered risk of death from NSCLC. Conclusion: This study indicated that GSTP1 Ile105Val, XRCC1Arg194Trp and XRCC1Arg399Gln genes have a role in modifying the effect of platinum-based chemotherapyfor NSCLC patients in a Chinese population. Our findings provide information for therapeutic decisions forindividualized therapy in NSCLC cases.     

Polymorphisms in ERCC1 C8092A predict progression-free survival in metastatic/recurrent nasopharyngeal carcinoma treated with cisplatin-based chemotherapy

Objectives

We evaluated whether DNA repair gene polymorphisms had an effect on clinical outcomes in metastatic/recurrent nasopharyngeal carcinoma (NPC) patients treated with cisplatin-based chemotherapy.

Materials and methods

Clinical data of 101 patients with metastatic/recurrent NPC between 2004 and 2011 were reviewed. Five potentially functional polymorphisms (ERCC1 Asn118Asn, ERCC1 C8092A, XPD Lys751Gln, XRCC1 Arg399Gln and XRCC1 Arg280His) were genotyped using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Results

The ERCC1 C8092A polymorphism was an independent predictor of PFS in Chinese NPC patients treated with cisplatin-based chemotherapy. Compared to the patients carrying the C/C genotype, the patients with the C/A or A/A genotype had an increased risk of disease progression on cisplatin-based chemotherapy (7.9 vs. 9.3 months; HR 1.61; 95 % CI 1.08–2.61; p = 0.047). However, no association between the other polymorphisms, response rate, disease progression and survival was detected in metastatic/recurrent NPC patients.

Conclusion

The ERCC1 C8092A polymorphism might be a useful predictive marker in metastatic/recurrent NPC patients treated with cisplatin-based chemotherapy. However, a large-scale prospective study is warranted to validate our findings.     

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.     

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.     

Predictive value of XRCC1 and XRCC3 gene polymorphisms for risk of ovarian cancer death after chemotherapy

Objective: To investigate any association between XRCC1 and XRCC3 polymorphisms and outcome ofplatinum-based chemotherapy in ovarian cancer patients. Methods: With a prospective study design was caseswere consecutively collected from January 2005 to January 2007. All 310 included patients were followed-upuntil the end of January 2010. Genotyping of XRCC1 and XRCC3 polymorphisms was conducted by TaqManGene Expression assays. Results: A total of 191 patients died during follow-up. Our study showed a lowersurvival rate in XRCC1 399 Arg/Arg genotype than Gln/ Gln, with a significant increased risk of death (HR=1.69,95%CI=1.07-2.78). Similarly, those carrying XRCC3 Thr/ Thr genotype had a increased risk as compare tothe Met/Met genotype, with a HR (95% CI) of 1.90 (1.12-3.41). There was no significant association betweenXRCC1 Arg194Trp and XRCC1Arg280His gene polymorphisms and ovarian cancer death. Conclusion: Ourstudy demonstrates that polymorphisms in DNA repair genes have roles in the susceptibility and survival ofovarian cancer patients.     

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.     

Association between XRCC3 Thr241Met polymorphism and risk of brain tumors: a meta-analysis

X-ray repair cross-complementing group 3 (XRCC3) plays an important role in the process of homologous recombination repair for DNA double-strand breaks which further maintains the stability of the genome. XRCC3 Thr241Met polymorphism has been indicated in the development of cancers, but the association of the XRCC3 Thr241Met polymorphism with risk of brain tumors is still unclear owing to the conflicting findings from previous studies. We performed a meta-analysis to provide a better understanding on the association between the XRCC3 Thr241Met polymorphism and risk of brain tumors. The pooled odds ratio (OR) with corresponding 95 % confidence interval (95 % CI) was used to assess the association. Thirteen case–control studies involving a total of 4,984 cases and 7,472 controls were included. Overall, there was no statistically significant association between the XRCC3 Thr241Met polymorphism and risk of brain tumors under all contrast models. Subgroup analysis by race suggested that the XRCC3 Thr241Met polymorphism was associated with increased risk of brain tumors in Asians under all four contrast models (Met vs. Thr: OR?=?1.22, 95 % CI 1.09–1.36, P?<?0.01; MetMet vs. ThrThr: OR?=?1.89, 95 % CI 1.38–2.57, P?<?0.01; MetMet vs. ThrThr/ThrMet: OR?=?1.78, 95 % CI 1.31–2.40, P?<?0.01; and MetMet vs. ThrThr/ThrMet: OR?=?1.19, 95 % CI 1.04–1.36, P?=?0.01). However, there was no significant association between the XRCC3 Thr241Met polymorphism and risk of brain tumors in Caucasians. Therefore, the XRCC3 Thr241Met polymorphism is associated with increased risk of brain tumors, especially in Asians.     

XRCC3 Thr241Met polymorphism and ovarian cancer risk: a meta-analysis

Genetic polymorphism of X-ray repair crosscomplementing group 3 (XRCC3) Thr241Met has been implicated to alter the risk of ovarian cancer, but the results are controversial. In order to get a more precise result, a meta-analysis was performed. All eligible studies were identified through an extensive search in PubMed, Excerpta Medica Database (Embase), Chinese National Knowledge Infrastructure database, and Chinese Biomedical Literature Database before August 2013. The association between the XRCC3 Thr241Met polymorphism and ovarian cancer risk was conducted by odds ratios (ORs) and 95 % confidence intervals (95 % CIs). Finally, a total of four publications including seven studies with 3,635 cases and 5,473 controls were included in our meta-analysis. Overall, there was no association between XRCC3 Thr241Met polymorphism and risk of ovarian cancer under all five genetic models in overall population (T vs. C: OR?=?0.99, 95 % CI?=?0.960–1.03, P?=?0.752; TT vs. CC: OR?=?1.00, 95 % CI?=?0.91–1.10, P?=?0.943; TC vs. TT: OR?=?0.97, 95 % CI?=?0.92–1.04, P?=?0.396, Fig. 1; TT vs. TC/CC: OR?=?1.00, 95 % CI?=?0.91–1.12, P?=?0.874; TT/TC vs. CC: OR?=?0.98, 95 % CI?=?0.94–1.03, P?=?0.486). In the subgroup analysis according to ethnicity, the results suggested that XRCC3 Thr241Met polymorphism was not associated with the risk of ovarian cancer in Caucasians population. No significant association was found between the XRCC3 Thr241 Met polymorphism and the risk of ovarian cancer. Given the limited sample size and ethnicities included in the meta-analysis, further large scaled and well-designed studies are needed to confirm our results.