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.     

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.     

Association of DNA base excision repair genes (OGG1, APE1 and XRCC1) polymorphisms with outcome to platinum‐based chemotherapy in advanced nonsmall‐cell lung cancer patients

Polymorphism of DNA base excision repair (BER) genes affects DNA repair capacity and may alter sensitivity to platinum‐based chemotherapy regimens. This study investigated polymorphisms of OGG1 Ser326Cys, APE1 Asp148Glu APE1‐141T/G and XRCC1 Arg399Gln for association with clinical outcome in 235 advanced inoperable nonsmall‐cell lung cancer (NSCLC) patients after treatment with platinum‐based chemotherapy. The multivariate analysis showed that OGG1 326 GC was associated with poor PFS [hazard ratio (HR) 1.730, p = 0.005], while XRCC1 399 GA, or GA+AA, was associated with poor OS in short‐term period (HR 1.718, p = 0.003; HR 1.691, p = 0.003, respectively). Patients with OGG1 326/XRCC1 399 variant alleles had a higher risk to die early in short‐term period (HR 1.929, p < 0.001). Furthermore, patients with XRCC1 399 variant allele (GA+AA) had higher risk of hematologic toxicity (p = 0.009), whereas patients carrying the OGG1 326 variant (GG), or the APE1‐141 GG variant, had reduced risk of gastrointestinal toxicity (p = 0.015 and p = 0.023, respectively). The data from the current study provide evidence that OGG1 Ser326Cys, XRCC1 Arg399Gln, APE1 Asp148Glu, and APE1‐141T/G polymorphisms may be useful in predicting clinical outcomes in patients with advanced inoperable NSCLC that will undergo platinum‐based chemotherapy.     

The combination of ERCC1 and XRCC1 gene polymorphisms better predicts clinical outcome to oxaliplatin-based chemotherapy in metastatic colorectal cancer

Purpose

To evaluate the effect of excision repair cross-complementing group 1 (ERCC1) and X-ray cross-complementing group 1 (XRCC1) gene polymorphisms on treatment outcome in patients receiving oxaliplatin-based regimens for metastatic colorectal cancer.

Methods

Hundred and thirteen patients with a diagnosis of metastatic colorectal cancer were treated with oxaliplatin-based chemotherapy. ERCC1 codon 118C/T and XRCC1 codon 399A/G polymorphisms were tested by real-time polymerase chain reaction (RT-PCR) method in peripheral blood lymphocytes of these patients. Disease control rates and survivals were compared by types of genotypes.

Results

Analyses of the patterns of the polymorphism located at ERCC1 codon 118 showed that 55 (48.67%) patients were homozygous for C/C genotype, 15 (13.27%) were homozygous for the T/T genotype, and 43 (38.06%) were heterozygous for C/T genotype. Analyses of the polymorphism located at XRCC1 codon 399 showed that 61 (53.98%) patients were homozygous for A/A genotype, 13 (11.50%) were homozygous for the G/G genotype, and 39 (34.52%) were heterozygous for A/G genotype. After two cycles of chemotherapy, there was complete response (CR) in 1 patient, partial response (PR) in 24 patients, and stable disease (SD) in 56 patients. Altogether in 81 (71.68%) patients the disease was controlled after chemotherapy. Thirty-two (28.32%) patients showed disease progression. After adjusting for some clinical factors, both the ERCC1 polymorphism and the XRCC1 polymorphism lost their roles in predicting DCR (P = 0.662, P = 0.631) and MST (P = 0.692, P = 0.572). But the combination of ERCC1 and XRCC1 polymorphisms was significantly associated with DCR (P = 0.01) and MST (P = 0.000) independently.

Conclusions

This is the first study which showed that polymorphisms of ERCC1 and XRCC1, in combination not individually, were independent predictors for DCR and OS. This may contribute to the selection of patients who would benefit from oxaliplatin-based chemotherapy for metastatic colorectal cancer.     

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.     

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.     

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.     

碱基切除修复基因单核苷酸多态性和晚期非小细胞肺癌治疗疗效研究

  目的 探讨碱基切除修复交叉互补基因（XRCC1）和脱嘌呤／脱嘧啶核酸内切酶（APE1）单核苷酸多态性与非小细胞肺癌（NSCLC）放化疗疗效的关系。方法 230例晚期不能手术治疗的NSCLC患者为试验对象。取患者治疗前抗凝外周血，提取有核细胞DNA，采用Taqman探针基因分型技术检测XRCC1 Arg194Trp，XRCC1 Arg399Gln 和APE1 Asn148Glu单核苷酸多态性。结果 在单纯化疗或放疗的患者中，治疗敏感和不敏感的患者XRCC1、 APE1基因型差异无统计学意义。在放化疗联合治疗组中，XRCC1基因型与疗效无显著性相关，但APE1（Asn148Glu，T／G）位点与疗效有一定的相关性。在Ⅲa和 Ⅲb无胸膜浸润组，携带有G／G或G／T基因型的患者对放化疗不敏感的可能性是携带有T／T基因型患者3.25倍（P = 0.043）。结论 APE1 Asn148Glu位点可能是一个依赖于临床分期的放化疗疗效预测的指标，APE1野生纯合型148 T／T（Asn148Asn）可能是Ⅲa期和Ⅲb期无胸膜浸润NSCLC放化疗敏感的标志。     

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.     

Gene-environment interactions between the smoking habit and polymorphisms in the DNA repair genes, APE1 Asp148Glu and XRCC1 Arg399Gln, in Japanese lung cancer risk

APE1 (apurinic/apyrimidinic endonuclease 1) and XRCC1 (X-ray cross-complementing group 1) are DNA repair proteins that play important roles in the base excision repair (BER) pathway. Polymorphisms in their encoding genes are associated with altered DNA repair capacity and thus may impact on cancer risk. In the present case-control study with 178 Japanese incident lung cancer cases and 449 age- and sex-matched controls, we investigated the gene-environment interaction among APE1 Asp148Glu, XRCC1 Arg399Gln and smoking habit in lung cancer risk. The results were analyzed by using conditional logistic regression models, adjusted for age, sex and smoking status. The adjusted odds ratio for the current smokers with APE1 148Asp/Asp, Asp/Glu and Glu/Glu genotype as compared with the never smokers with the Asp/Asp genotype were 3.01 (95% CI 1.39-6.51, P = 0.005), 2.73 (95% CI 1.29-5.77, P = 0.008) and 7.33 (95% CI 2.93-18.3, P < 0.001), respectively. The gene-environment interaction between current smoking and APE1 148Glu/Glu genotype was statistically significant (OR 3.59, 95% CI 1.28-10.1, P = 0.015). When APE1 Asp148Glu and XRCC1 Arg399Gln polymorphisms were evaluated together, the adjusted odds ratios for the current smokers with 0-1, 2 and 3-4 of APE1 148Glu or XRCC1 399Gln alleles as compared with never smokers with the 0 of these alleles were 2.96 (95% CI 1.57-5.58, P = 0.001), 3.86 (95% CI 1.85-8.05, P < 0.001) and 6.01 (95% CI 2.25-16.1, P < 0.001), respectively. The gene-environment interaction between current smoking and three or more APE1 148Glu or XRCC1 399Gln alleles was statistically significant (OR 2.44, 95% CI 1.00-9.22, P = 0.049). The OR for the gene-environment interaction of Glu/Glu genotype of APE1 codon 148 with heavy smoking was 1.04 (95% CI 0.38-2.90, P = 0.936) and that with light smoking was 2.67 (95% CI 1.00-7.68, P = 0.049). These results suggest that APE1 Asp148Glu and XRCC1 Arg399Gln polymorphisms might modify the risk of lung cancer attributable to cigarette smoking exposure.     

Association of DNA Base-excision Repair XRCC1, OGG1 and APE1 Gene Polymorphisms with Nasopharyngeal Carcinoma Susceptibility in a Chinese Population

Background: Numerous carcinogens and reactive oxygen species (ROS) may cause DNA damage includingoxidative base lesions that lead to risk of nasopharyngeal carcinoma. Genetic susceptibility has been reported toplay a key role in the development of this disease. The base excision repair (BER) pathway can effectively removeoxidative lesions, maintaining genomic stability and normal expression, with X-ray repair crosscomplementing1(XRCC1), 8-oxoguanine glycosylase-1 (OGG1) and apurinic/apyimidinic endonuclease 1 (APE1) playingimportant roles. Aims: To analyze polymorphisms of DNA BER genes (OOG1, XRCC1 and APE1) and exploretheir associations, and the combined effects of these variants, with risk of nasopharyngeal carcinoma. Materialsand Methods: We detected SNPs of XRCC1 (Arg399Gln), OGG1 (Ser326Cys), APE1 (Asp148Glu and -141T/G)using the polymerase chain reaction (PCR) with peripheral blood samples from 231 patients with NPC and 300healthy people, furtherly analyzing their relations with the risk of NPC in multivariate logistic regression models.Results: After adjustment for sex and age, individuals with the XRCC1 399Gln/Gln (OR=1.96; 95%CI:1.02-3.78; p=0.04) and Arg/Gln (OR=1.87; 95%CI:1.29-2.71; p=0.001) genotype variants demonstrated a significantlyincreased risk of nasopharyngeal carcinoma compared with those having the wild-type Arg/Arg genotype. APE1-141G/G was associated with a significantly reduced risk of NPC (OR=0.40;95%CI:0.18–0.89) in the smokinggroup. The OR calculated for the combination of XRCC1 399Gln and APE1 148Gln, two homozygous variants,was significantly additive for all cases (OR=2.09; 95% CI: 1.27-3.47; p=0.004). Conclusion: This is the first studyto focus on the association between DNA base-excision repair genes (XRCC1, OGG1 and APE1) polymorphismand NPC risk. The XRCC1 Arg399Gln variant genotype is associated with an increased risk of NPC. APE1-141G/G may decrease risk of NPC in current smokers. The combined effects of polymorphisms within BERgenes of XRCC1 399Gln and APE1 148Gln may contribute to a high risk of nasopharyngeal carcinoma.     

Susceptibility to arsenic-induced skin lesions from polymorphisms in base excision repair genes

Genetic polymorphisms in the base excision DNA repair pathway may influence individual susceptibility to arsenic and the development of arsenic-induced skin lesions. Data from a case-control study of 792 cases and 792 matched controls conducted in Bangladesh from 2001 to 2003 were analyzed using conditional logistic regression to assess the associations between four common base excision repair (BER) genetic polymorphisms X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln, XRCC1 Arg194Trp, human 8-oxoguanine DNA glycosylase (hOGG1) Ser326Cys and apurinic/apyrimidinic endonuclease (APE1) Asp148Glu and arsenic-induced skin lesions including melanosis and keratosis. Adjusted for toenail arsenic, body mass index, education, smoking and betel nut use, individuals with the APE1 148Glu/Glu polymorphism had a 2-fold increased odds of skin lesions compared with individuals with the 148Asp/Asp genotype (1.93; 95% confidence interval 1.15, 3.19). Gene-environment interactions between toenail arsenic and XRCC1 Arg194Trp and APE1 Asp148Glu were observed. Within the lowest arsenic tertile, APE1 148Glu/Glu had 2.5 times the odds ratio compared with wild-type, whereas within the highest tertile of arsenic the odds ratios for skin lesions did not differ. In contrast, at low arsenic levels, the odds ratios for skin lesions did not differ much by XRCC1 Arg194Trp genotype. However, at the highest tertile of arsenic, the XRCC1 194Arg/Arg polymorphism conferred a 3-fold larger odds ratio for skin lesions compared with XRCC1 194Trp/Trp. Individuals may have different odds for developing skin lesions based in part on their genetic profile for BER and their arsenic exposure history. Future research on arsenic-induced skin lesions should consider the impact of genetic variation to individual susceptibility to arsenic toxicity.     

The APE1 Asp148Glu polymorphism and colorectal cancer susceptibility: a meta-analysis

Background

Published data regarding the association between the APE1 Asp148Glu polymorphism and colorectal cancer susceptibility remained controversial. This meta-analysis of literatures was performed to draw a more precise estimation of the relationship.

Materials and methods

We systematically searched PubMed, Embase, and Web of Science with a time limit of August 19, 2013. Summary odds ratios (ORs) with 95 % CIs were used to assess the strength of association between the APE1 Asp148Glu polymorphism and colorectal cancer susceptibility using random-effects model.

Results

A total of eight case–control studies including 2,597 cases and 3,063 controls were included for analysis. Overall, no significant associations were found between the APE1 Asp148Glu polymorphism and colorectal cancer susceptibility for GG vs TT (OR?=?1.00, 95 % CI?=?0.73–1.36, p?=?0.00 for heterogeneity), TG vs TT (OR?=?1.17, 95 % CI?=?0.88–1.55, p?=?0.00 for heterogeneity), the dominant model GG + TG vs TT (OR?=?1.21, 95 % CI?=?0.91–1.60, p?=?0.00 for heterogeneity) nor the recessive model GG vs TG + TT(OR?=?0.95, 95 % CI?=?0.75–1.20, p?=?0.02 for heterogeneity). In subgroup analysis, no significant associations were found in the Asian or Caucasian populations.

Conclusion

This meta-analysis suggested that the APE1 Asp148Glu polymorphism was not associated with colorectal cancer susceptibility among Asians or Caucasians.     

DNA repair gene polymorphism associated with sensitivity of lung cancer to therapy

This study aimed to investigate association between single-nucleotide polymorphisms (SNPs) of excision repair cross-complementing gene 1 (ERCC1), excision repair cross-complementing gene 2 (ERCC2), and X-ray repair cross-complementing group 1 (XRCC1) with sensitivity of advanced non-small cell lung cancer (NSCLC) patients to platinum-based chemotherapy. A total of 89 NSCLC patients were recruited and treated with two cycles of platinum-based chemotherapy. DNA was extracted from peripheral lymphocytes for detection of SNPs of ERCC1 Asn118Asn, ERCC2 Lys751Gln, and XRCC1 Arg399Gln. The overall response rate of these patients was 29.2%. There was no statistically significant difference of treatment response between the wild genotypes and the variant genotypes for the ERCC1 Asn118Asn and ERCC2 Lys751Gln gene. The distributions of genotypes XRCC1 Arg399Gln differed significantly between the response and non-response groups (76.9 vs. 23.1%, P = 0.001). The XRCC1 399Arg/Arg genotype carriers had a higher response rate than that of the Gln genotype carriers (OR = 4.81, 95%CI = 1.778-13.013, P = 0.002). The combination of the favorable genotypes of ERCC1, ERCC2, and XRCC1 had a higher response rate compared to that of patients with other genotypes. The combined polymorphisms of ERCC1, ERCC2, and XRCC1 may be associated with sensitivity of NSCLC to platinum-based chemotherapy. Further studies will verify these SNPs as biomarkers for prediction of platinum-based chemotherapy responses of NSCLC patients.     

Differential toxicity biomarkers for irinotecan- and oxaliplatin-containing chemotherapy in colorectal cancer

Purpose

Oxaliplatin or irinotecan is usually administered jointly with fluoropyrimidines in colorectal cancer patients treated with chemotherapy. Both drugs have different toxicity patterns. Biomarkers for predicting high-risk severe adverse reactions can help select the best treatment.

Methods

A retrospective analysis of 106 colorectal cancer patients receiving an oxaliplatin-based treatment and 56 receiving an irinotecan-based treatment was performed. One copy number variant (GSTT1) and nine polymorphisms in irinotecan and oxaliplatin metabolism, transport or DNA repair genes (ABCB1, UGT1A1, XRCC1, ERCC1, ERCC2, GSTP1) were genotyped by SNaPshot, polymerase chain reactions’ length fragments, or copy number assays.

Results

In irinotecan-treated patients, C allele of ABCB1 C1236T SNP was associated with a lower risk of asthenia (OR = 0.043; 96 % CI = 0.004–0.444; P = 0.008) and C allele of ABCB1 C3435T SNP was associated with a lower risk of diarrhea (OR = 0.162; 95 % CI = 0.031–0.844; P = 0.031); and individuals with two copies of GSTT1 gene had a lower risk for asthenia (OR = 0.074; 95 % CI = 0.009–0.617; P = 0.016). In oxaliplatin-treated patients, carriers of two C variants of Asn118Asn ERCC1 SNP had a lower risk for neutropenia (OR = 0.203; 95 % CI = 0.060–0.683; P = 0.01).

Conclusions

These biomarkers could help oncologists select the best treatment by reducing toxicity associated with irinotecan or oxaliplatin in colorectal cancer patients, thus increasing their quality of life.     

Pharmacogenetic analysis of adjuvant FOLFOX for Korean patients with colon cancer

Purpose

Ethnic diversity of genetic polymorphism can result in individual differences in the efficacy and toxicity of cancer chemotherapy.

Methods

We analyzed 20 germline polymorphisms in 10 genes (TS, MTHFR, ERCC1, XPD, XRCC1, ABCC2, AGXT, GSTP1, GSTT1 and GSTM1) from prospectively enrolled 292 Korean patients treated with adjuvant oxaliplatin plus leucovorin plus 5-fluorouracil (FOLFOX) for colon cancer.

Results

In contrast to previous studies in Caucasians, neutropenia (grade 3–4, 60.5 %) was frequently observed, whereas only 16.4 % experienced grade 2 or more sensory neuropathy. Neutropenia was more frequent in MTHFR 677TT [adjusted odds ratio (OR) 2.32, 95 % confidence interval (CI) 1.19–4.55] and ERCC1 19007TT (adjusted OR 4.58, 95 % CI 1.20–17.40) genotypes. Patients harboring XRCC1 23885GG experienced less grade 2–4 neuropathy [adjusted OR 0.52, 95 % CI 0.27–0.99]. MTHFR 677TT (p = 0.002) and XRCC1 23885GG (p = 0.146) genotypes were also more prevalent in Koreans compared to Caucasians. TS ‘low’ genotype (adjusted HR 1.83, 95 % CI 1.003–3.34) was significantly related to shorter disease-free survival. Overall survival was not significantly different according to the polymorphisms.

Conclusions

Polymorphisms in MTHFR, XRCC1 and TS are related to toxicities and disease-free survival in patients with colon cancer. The ethnic differences in frequencies of genotypes may explain the ethnic difference in toxicity profile following adjuvant FOLFOX 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.     

Predictive value of APE1, BRCA1, ERCC1 and TUBB3 expression in patients with advanced non-small cell lung cancer (NSCLC) receiving first-line platinum–paclitaxel chemotherapy

Purpose

Drug resistance is not only one of the major obstacles to treatment but also a poor prognosis in advanced non-small cell lung cancer (NSCLC) patients. The aim of this study was to evaluate the predictive value of APE1, BRCA1, ERCC1 and TUBB3 in advanced NSCLC patients who received platinum–paclitaxel treatment.

Methods

One hundred and thirty-six advanced NSCLC patients, who were treated with first-line platinum–paclitaxel chemotherapy, were enrolled in this study. The protein expression levels of APE1, BRCA1, ERCC1 and TUBB3 were assessed by immunohistochemistry and analyzed for the association with response to chemotherapy and progression-free survival (PFS) and overall survival (OS).

Results

Patients with negative expression of APE1, ERCC1 or TUBB3 benefited from platinum plus paclitaxel regimen chemotherapy. ERCC1-negative patients had better PFS (P = 0.016) and OS (P = 0.030) compared with positive patients. Similarly, the APE1-negative patients showed better PFS (P = 0.004) and longer OS though statistically insignificant. Multivariate analysis showed that APE1 and ERCC1 were independent predictor for PFS (HR 2.07; P = 0.004 and HR 1.66; P = 0.016) and OS (HR 1.99; P = 0.008 and HR 1.64; P = 0.040). Moreover, patients with both APE1- and ERCC1-negative or both APE1- and TUBB3-negative tumors had significantly higher response rate, longer median PFS and OS following treatment with platinum and paclitaxel (P < 0.05).

Conclusion

The data indicate that APE1, ERCC1 and TUBB3 could be a useful biomarker to predict clinical outcome in patients with advanced NSCLC receiving first-line platinum–paclitaxel chemotherapy.     

XRCC1 and XPD genetic polymorphisms and clinical outcomes of gastric cancer patients treated with oxaliplatin-based chemotherapy: a meta-analysis

This meta-analysis aimed to obtain a comprehensive and reliable assessment of the relationships between XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms and the clinical outcomes of gastric cancer (GC) patients treated with oxaliplatin-based chemotherapy. The PubMed, CINAHL, Web of Science, CISCOM, EBSCO, Google Scholar, Cochrane Library, and CBM databases were searched for relevant articles published before September 1, 2013 without language restrictions. Crude odd ratios (ORs) or hazard risk (HR) [95 % confidence intervals (CI)] were calculated. Twelve clinical cohort studies were assessed with a total 1,024 GC patients treated with oxaliplatin-based chemotherapy. Our meta-analysis findings revealed that GC patients with the GA?+?AA (A carrier) genotypes of XRCC1 Arg399Gln showed a lower effective clinical response (CR?+?PR) than those with the GG (A non-carrier) genotype (OR?=?0.41, 95 % CI 0.20～0.82, P?=?0.012). However, there was no statistically significant difference in effective clinical response between those with XPD AC?+?CC (C carrier) genotypes and CC (C non-carrier) genotype (OR?=?0.55, 95 % CI 0.28～1.07, P?=?0.076). Furthermore, the GA?+?AA genotypes of XRCC1 Arg399Gln was associated with a worse progression-free survival (PFS) and overall survival (OS) compared with the CC genotype (PFS, HR?=?1.90, 95 % CI 1.12～2.69, P?<?0.001; OS, HR?=?2.13, 95 % CI 0.79～3.47, P?=?0.002, respectively). No relationships were found between XPD Lys751Gln polymorphism and both PFS and OS (all P?>?0.05). No publication bias was detected in this meta-analysis. Results from the current meta-analysis indicate that XRCC1 Arg399Gln polymorphism may be associated with poor clinical outcomes in GC patients treated with oxaliplatin-based chemotherapy.     

Lack of Influence of XRCC1 and XPD Gene Polymorphisms on Outcome of Platinum-based Chemotherapy for Advanced Non Small Cell Lung Cancers

Purpose: Genetic polymorphisms of DNA repair genes are associated with differential enzyme activity andmay help explain interindividual differences in response rates after platinum-based chemotherapy for non smallcell lung cancers (NSCLCs). This study was conducted to assess relationships between X-ray repair crosscomplementing group1 (XRCC1) and xeroderma pigmentosum group D (XPD) genetic polymorphisms andoutcome in NSCLC patients. Methods: From March 1, 2005 to December 31, 2008, the polymerase chainreaction-restriction fragment length polymorphism method was applied to evaluate genetic polymorphisms ofthe XRCC1 codon399 (Arg/Gln) and XPD codon751 (Lys/Gln) DNA repair genes in 108 patients with stage IIIBand IV NSCLCs treated with platinum-based chemotherapy in the Department of Chemotherapy of JiangsuCancer Hospital and Research Institute. Results: Among the assessed NSCLC patients, the overall responserate of chemotherapy was 21.6%. No association was found with either of the genetic polymorphisms, althoughthe XRCC1 399Arg/Arg genotype was associated with a non-significant higher median survival time (29 monthsversus 21 months for the Arg/Gln genotype and 15 months for the Gln/Gln genotype, P=0.09). Conclusion: Ourresults suggested no influence of the XRCC1 codon399 (Arg/Gln) and XPD codon751 (Lys/Gln) geneticpolymorphisms on treatment response and survival in advanced NSCLC patients with platinum-basedchemotherapy.