Polymorphisms of DNA repair genes and risk of non-small cell lung cancer

Lung cancer is a leading cause of cancer mortality with an inter-individual difference in susceptibility to the disease. The inheritance of low-efficiency genotypes involved in DNA repair and replication may contribute to the difference in susceptibility. We investigated 44 single nucleotide polymorphisms (SNPs) in 20 DNA repair genes including nucleotide excision repair (NER) genes XPA, ERCC1, ERCC2/XPD, ERCC4/XPF and ERCC5/XPG; base excision repair (BER) genes APE1/APEX, OGG1, MPG, XRCC1, PCNA, POLB, POLiota, LIG3 and EXO1; double-strand break repair (DSB-R) genes XRCC2, XRCC3, XRCC9, NBS1 and ATR; and direct damage reversal (DR) gene MGMT/AGT. The study included 343 non-small cell lung cancer (NSCLC) cases and 413 controls from Norwegian general population. Our results indicate that SNPs in the NER genes ERCC1 (Asn118Asn, 15310G>C, 8902G>T), XPA (-4G>A), ERCC2/XPD (Lys751Gln) and ERCC5/XPD (His46His); the BER genes APE1/APEX (Ile64Val), OGG1 (Ser326Cys), PCNA (1876A>G) and XRCC1 (Arg194Trp, Arg280His, Arg399Gln); and the DSB-R genes ATR (Thr211Met), NBS1 (Glu185Gln), XRCC2 (Arg188His) and XRCC9 (Thr297Ile) modulate NSCLC risk. The level of polycyclic aromatic hydrocarbon-DNA (PAH-DNA) adducts in normal lung tissue from 211 patients was analysed. The variant alleles of XRCC1(Arg280His), XRCC1 (Arg399Gln), ERCC1(G8092T), ERCC5(His46His) and MGMT/AGT(Lys178Arg) were more frequent in patients with PAH-DNA adduct levels lower than the mean whereas the XRCC1(Arg194Trp) variant was more frequent in cases with higher adduct levels than the mean.     

ERCC1和XPD单核苷酸多态性与非小细胞肺癌铂类化疗敏感性的关系

目的：探讨DNA修复基因ERCC1 C118T和XPD Lys751Gln单核苷酸多态性与非小细胞肺癌（non-small-cell lung carcinoma,NSCLC）患者对含铂方案化疗敏感性的关系。方法：选择经病理确诊为NSCLC的患者73例,在实施化疗前采取静脉血,提取DNA,行DNA测序、用PCR-RFLP方法检测ERCC1 C118T和XPD Lys751Gln基因型。所有患者均经含铂方案化疗,观察疗效,统计临床获益率,分析NSCLC患者ERCC1和XPD单核苷酸多态性与含铂方案化疗敏感性的关系。结果：ERCC1 C118TC/C、C/T和T/T基因型临床获益率分别为94.9%、71.4%和83.8%。基因型C/C临床获益率明显高于C/T、T/T（P〈0.05）。XPD Lys751Gln基因型Lys/Lys、Lys/Gln临床获益率分别为80.3%和75.0%。基因型Lys/Lys与Lys/Gln临床获益率间的差异无统计学意义（P=0.702）。未检测到XPD Gln/Gln基因型。ERCC1 C118T、XPD Lys751Gln多态之间在对含铂方案的化疗敏感性方面无协同作用（P=0.134和P=0.236）。结论：DNA修复基因ERCC1 C118T单核苷酸多态性与NSCLC含铂方案化疗的敏感性有关,可作为预测NSCLC患者铂类药物化疗敏感性的参考指标之一。     

ERCC1和XRCC1多态性与进展期非小细胞肺癌对铂类化疗的敏感性

目的探讨DNA修复基因ERCC1 118C/T和XRCC1 Arg194Trp多态性与进展期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者铂类药物化疗敏感性的关系。方法采用PCR-RFLP技术检测149例经病理确诊的接受含铂两药方案化疗的NSCLC患者外周血ERCC1 118和XRCC1 194位点的基因型,并分析其与化疗疗效的关系。结果经2个周期化疗后,149例进展期NSCLC患者化疗有效率为32.9%。携带至少1个ERCC1 118T突变基因患者的化疗有效率至少是C/C野生型基因携带者的3倍(49.1%vs 23.4%,OR=3.156,95%CI:1.548～6.334,P=0.001)。携带至少1个XRCC1 194Trp突变基因患者的化疗有效率显著高于Arg/Arg基因型携带者(41.3%vs 23.2%,OR=2.326,95%CI:1.138～4.753,P=0.019)。ERCC1 118C/T和XRCC1 Arg194Trp 2个基因多态之间存在一定的联合作用,携带至少1个ERCC1 118 T突变基因同时又携带至少1个XRCC1 194Trp突变基因型者的化疗有效率明显高于同时携带ERCC1 118C/C和XRCC1 194Arg/Arg野生型基因者(66.7%vs 17.1%,OR=9.714,95%CI:3.104～30.406,P<0.001)。结论与单基因检测比较,2个基因的联合检测在预测铂类药物化疗敏感性中的价值更大。ERCC1 118和XRCC1 194基因多态联合与NSCLC患者对铂类药物化疗敏感性相关,ERCC1和XRCC1基因型的联合检测有可能成为预测铂类药物化疗敏感性的指标。     

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.     

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.     

The association between the ERCC1/2 polymorphisms and the clinical outcomes of the platinum-based chemotherapy in non-small cell lung cancer (NSCLC): a systematic review and meta-analysis

The relationship between the ERCC1/2 single nucleotide polymorphisms (SNPs) and the clinical outcomes of the platinum-based chemotherapy in the non-small cell lung cancer (NSCLC) is still inconsistent and inconclusive despite extensive investigations have been conducted to address this question. In this meta-analysis, we aim to further explore the prognostic value of the ERCC1/2 SNPs in NSCLC by analyzing all currently available evidences. Relevant studies were searched in PubMed, Embase, and China National Knowledge Infrastructure. The inclusion criteria were platinum-based chemotherapy in NSCLC patients and evaluation of clinical outcomes in relation to the ERCC1 C118T, ERCC1 C8092A, ERCC2 Asp312Asn, and ERCC2 Lys751Gln. Clinical outcomes analyzed in this study included the overall response rate, overall survival (OS), and progression-free survival (PFS). Odds ratio (OR) or hazard ratio (HR) with 95 % confidence interval (CI) were calculated to examine the risk or hazard associated with each SNP. A total of 46 studies including 9,407 NSCLC patients were qualified for this meta-analysis. For ERCC1 C118T, the T allele was associated with a poor OS (HR?=?1.35, 95 % CI?=?1.04–1.75); for ERCC2 Asp312Asn, the Asn variant was linked to an unfavorable OS (HR?=?2.07, 95 % CI?=?1.11–3.88); and for ERCC2 Lys751Gln, patients with the Gln variant have a worse OS (HR?=?1.22, 95 % CI?=?1.05–1.41) and PFS (HR?=?1.35, 95 % CI?=?1.07–1.71). In addition, the main findings of the ERCC1/2 SNPs on chemotherapy toxicity were also summarized. This meta-analysis suggested that the ERCC1 C118T, ERCC2 Asp312Asn, and Lys751Gln may be useful biomarkers to predict the clinical outcomes of the platinum-based chemotherapy in NSCLC patients.     

DNA Repair Gene Associated with Clinical Outcome ofEpithelial Ovarian Cancer Treated with Platinum-basedChemotherapy

Objective: The nucleotide excision repair (NER) and base excision repair (BER) pathways, two DNA repairpathways, are related to platinum resistance in cancer treatment. In this paper, we studied the association betweensingle nucleotide polymorphisms (SNPs) of involved genes and response to platinum-based chemotherapy inepithelial ovarian cancer. Method: Eight SNPs in XRCC1 (BER), XPC and XPD (NER) were assessed in 213patients with epithelial ovarian cancer using polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) and primer-introduced restriction analysis-polymerase chain reaction (PIRA-PCR) techniques.Results: The median progression-free survival (PFS) of patients carrying the Lys/Lys and Lys/Gln+Gln/Glngenotype of the XPC Lys/Gln polymorphism were 25 and 12 months, respectively (P=0.039); and the mean overallsurvival (OS) of patients was 31.1 and 27.8 months, respectively (P=0.048). Cox’s multivariate analysis suggestedthat patients with epithelial ovarian cancer with the Gln allele had an increased risk of death (HR=1.75; 95%CI=1.06-2.91) compared to those with the Lys/Lys genotype. There are no associations between the XPC PAT+/-,XRCC1 Arg194Trp, Arg280His, Arg399Gln, and XPD Asp312Asn, Lys751Gln polymorphisms and the survivalof patients with epithelial ovarian cancer when treated with platinum-based chemotherapy. Conclusion: Ourresults indicated that the XPC Lys939Gln polymorphism may correlate with clinical outcome of patients withepithelial ovarian cancer when treated with platinum-based chemotherapy in Northern China.     

Single nucleotide polymorphisms in DNA repair genes might be prognostic factors in muscle-invasive bladder cancer patients treated with chemoradiotherapy

DNA repair enzymes repair DNA damaged by platinum agents and ionising radiation. Single nucleotide polymorphisms (SNPs) in DNA repair genes modulate the repair capacity and might affect response and prognosis following platinum-based chemoradiotherapy (CRT). We investigated associations between the functional SNPs in DNA repair genes and response and survival in muscle-invasive bladder cancer patients treated with CRT to determine the predictive value of the SNPs in patient selection for bladder conservation therapy. The study group comprised 78 patients who underwent CRT for transitional cell carcinoma of the bladder. Single nucleotide polymorphisms in xeroderma pigmentosum complementation groups C (Lys939Gln, A/C), D (XPD; Lys751Gln, A/C), and G (Asp1104His, G/C), and X-ray repair cross-complementing groups 1 (XRCC1; Arg399Gln, G/A) and 3 (Thr241Met, T/C) genes were genotyped. Combined genotypes with at least one variant allele in XPD or XRCC1 were significantly associated with improved cancer-specific survival compared with remaining groups (P=0.009). In multivariate analysis, only the combined XPD and XRCC1 genotypes were independently associated with cancer-specific survival (P=0.04). The association was stronger in stage T3/T4 patients (P=0.0008). These results suggest that combined XPD and XRCC1 genotypes might be prognostic factors in muscle-invasive bladder cancer patients treated with CRT.     

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

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

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.     

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

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

Prospective assessment of XPD Lys751Gln and XRCC1 Arg399Gln single nucleotide polymorphisms in lung cancer.

PURPOSE: XRCC1 and XPD play key roles in the repair of DNA lesions and adducts. Contrasting findings have been reported on the effect of polymorphisms of these genes on the response to platinum-based chemotherapy in advanced non-small-cell lung cancer (NSCLC). This study aimed to investigate the relationship between the XPD Lys751Gln and XRCC1 Arg399Gln genotypes and outcome in lung cancer patients. EXPERIMENTAL DESIGN: We genotyped 203 NSCLC and 45 small-cell lung carcinoma (SCLC) patients for the two polymorphisms. Most of the patients (81%) received a platinum-based chemotherapy. RESULTS: The patients' genotype frequencies did not significantly differ from controls and both groups were in Hardy-Weinberg equilibrium for the two polymorphisms. The XRCC1399 Gln/Gln variant genotype was associated with a higher median survival time (80 weeks versus 54.6 weeks for the Arg/Gln heterozygous and 55.6 weeks for the wild-type Arg/Arg genotype; P=0.09). At the multivariable analysis adjusted for histology, stage of the disease, performance status, age, and gender, the Gln/Gln genotype was associated with a better survival of borderline significance in the subgroup of patients treated with cisplatin (hazard ratio, 0.55; 95% CI, 0.30-1.00); this association became significant for those with grade 3-4 clinical toxicity (hazard ratio, 0.46; 95% CI, 0.22-0.98). No association between XPD Lys751Gln genotype and clinical outcome was found. CONCLUSION: This prospective investigation provides suggestive evidence of a favorable effect of the XRCC1399 Gln/Gln genotype on survival in platinum-treated NSCLC and, for the first time, in SCLC patients also. This contrasts with other authors who did not include non-platinum-treated patients, but it does fit the expectation for a suboptimal ability to remove DNA adducts.     

核苷酸切除修复系统基因遗传多态与晚期非小细胞肺癌患者铂类药物敏感性关系

背景与目的:肿瘤细胞对铂类药物的化疗敏感性与个体的DNA损伤修复能力关系密切,本研究探讨核苷酸切除修复系统(nucleotideexcisionrepair,NER)的重要成员XPC、XPD和ERCC1基因的遗传多态与晚期非小细胞肺癌(non-smallcelllungcancer,NSCLC)患者对铂类药物敏感性的关系。方法:对接受含铂类药物化疗的200例晚期NSCLC患者进行临床疗效评价。以聚合酶链-扩增片段长度多态性(PCR-AFLP)和限制性片段长度多态性(RFLP)的方法检测XPC-PAT、XPDLys751Gln(rs1052559)和ERCC1C8092A(rs1052559)多态的基因型,比较不同基因型与化疗敏感性的关系。结果:结合疗效情况,XPC-PAT遗传多态各基因型在化疗有效组(CR PR)和无效组(SD PD)中的分布频率差异有显著性(!2检验,P=0.023),携带XPCLL基因型个体的化疗敏感性是XPCSS基因型携带者的3.04倍(95%CI为1.25～7.41,P=0.015)。没有发现XPDLys751Gln和ERCC1C8092A多态与化疗敏感性的相关性。但联合分析后发现,核苷酸切除修复系统的这三个遗传多态在晚期NSCLC患者对铂类药物敏感性中存在一定的联合作用(趋势检验,P=0.021)。结论:核苷酸切除修复系统中XPC-PAT、XPDLys751Gln和ERCC1C8092A遗传多态可能与NSCLC患者对铂类药物敏感性相关。     

Association of the DNA repair gene XPD Asp312Asn polymorphism with p53 gene mutations in tobacco-related non-small cell lung cancer

Lung cancer, a disease related mostly to tobacco smoke exposure and a leading cause of cancer-related death in industrialized countries, is frequently associated with mutations in the p53 tumor suppressor gene. Genetic differences resulting in inter-individual variation in DNA repair capacity may in part account for susceptibility of a cell to genotoxic agents leading to somatic mutations, including p53 mutations, and eventual transformation of a normal cell into a malignant phenotype. The objective of this study is to investigate the relationship between the polymorphisms of two DNA repair genes, the nucleotide excision repair xeroderma pigmentosum group D (XPD) gene (codons 312 and 751) and the base excision repair X-ray repair cross-complementing group 1 (XRCC1) gene (codon 399), and p53 mutations among lung cancer patients. Lung tumors from 204 smokers with non-small cell lung cancer (NSCLC) were analyzed for mutations in exons 5-8 of the p53 gene and genotypes of XPD and XRCC1. p53 mutations were found in 20% (40/204) of the patients. Patients with the XPD codon 312 Asn allele were less likely to have p53 mutations (13.8%) than XPD 312 Asp/Asp (27.3%) [odds ratio (OR) 0.43, 95% confidence interval (CI) 0.20-0.89, P = 0.023]. No association was found between p53 mutations and either XPD Lys751Gln or XRCC1 Arg399Gln. However, the p53 mutation frequency increased with the increased number of the combined genotypes among XPD 312WT (Asp/Asp), XPD 751VT (Lys/Gln or Gln/Gln) or XRCC1 399VT (Arg/Gln or Gln/Gln) (P = 0.01, trend test). These results suggest that individuals who smoke and have the XPD codon 312 Asp/Asp genotype may be at a greater risk of p53 mutations, especially if combined with other polymorphisms that may result in deficient DNA repair.     

Association of Four ERCC1 and ERCC2 SNPs with Survival of Bone Tumour Patients

Aim: SNPs of ERCC1 and ERCC2 genes have been found to be associated with response to platinum therapyin different clinical settings. In the current study, we investigated the relationship of SNPs in ERCC1 and ERCC2to cisplain response and survival in osteosarcoma patients. Methods: 267 consecutive patients diagnosed withosteosarcoma between January 2003 to January 2005 were followed up until the end of January 2010. ERCC1Asn118Asn, ERCC1 Gln504Lys, ERCC2 Asp312Asn and ERCC2 Lys751Gln polymorphisms were detectedbased upon the Sequenom MassARRAY platform. Results: For ERCC1 Asn118Asn, the variant genotype T/Twas strongly significantly associated with a higher event free survival when compared with the wild-type C/C,with an adjusted OR (95% CI) of 0.39 (0.14-0.95). ERCC2 751 A/A genotype showed increased event free survivalof osteosarcoma (HR=0.44; 95%CI=0.10-0.87). However, we did not find significant association of ERCC1Gln504Lys and ERCC2 Asp312Asn polymorphisms with prognosis of osteosarcoma. Conclusion: We first reportassociations of four SNPs, ERCC1 Asn118Asn, ERCC1 Gln504Lys, ERCC2 Asp312Asn and ERCC2 Lys751Gln,with risk of death from osteosarcoma in a Chinese population, indicating ERCC1 118T/T and ERCC2 A/A maybe used as surrogate markers for clinical outcome of osteosarcoma treatmetn with cisplain.     

Polymorphisms in the DNA repair genes XRCC1 and ERCC2, smoking, and lung cancer risk.

XRCC1 (X-ray cross-complementing group 1) and ERCC2 (excision repair cross-complementing group 2) are two major DNA repair proteins. Polymorphisms of these two genes have been associated with altered DNA repair capacity and cancer risk. We have described statistically significant interactions between the ERCC2 polymorphisms (Asp312Asn and Lys751Gln) and smoking in lung cancer risk. In this case-control study of 1091 Caucasian lung cancer patients and 1240 controls, we explored the gene-environment interactions between the XRCC1 Arg399Gln polymorphism, alone or in combination with the two ERCC2 polymorphisms, and cumulative smoking exposure in the development of lung cancer. The results were analyzed using logistic regression models, adjusting for relevant covariates. Overall, the adjusted odds ratio (OR) of XRCC1 Arg399Gln polymorphism (Gln/Gln versus Arg/Arg) was 1.3 [95% confidence interval (CI), 1.0-1.8]. Stratified analyses revealed that the ORs decreased as pack-years increased. For nonsmokers, the adjusted OR was 2.4 (95% CI, 1.2-5.0), whereas for heavy smokers (>/=55 pack-years), the OR decreased to 0.5 (95% CI, 0.3-1.0). When the three polymorphisms were evaluated together, the adjusted ORs of the extreme genotype combinations of variant alleles (individuals with 5 or 6 variant alleles) versus wild genotype (individuals with 0 variant alleles) were 5.2 (95% CI, 1.7-16.6) for nonsmokers and 0.3 (95% CI, 0.1-0.8) for heavy smokers, respectively. Similar gene-smoking interaction associations were found when pack-years of smoking (or smoking duration and smoking intensity) was fitted as a continuous variable. In conclusion, cumulative cigarette smoking plays an important role in altering the direction and magnitude of the associations between the XRCC1 and ERCC2 polymorphisms and lung cancer risk.     

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

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

食管癌中ERCC2/XPD和XRCC1基因多态性的表达

目的:探讨DNA损伤修复基因ERCC2/XPD和XRCC1基因多态性与食管癌遗传易感性的关系。方法:采用病例对照研究设计,选取100例食管癌病例和80例正常对照。选取ERCC2/XPD Lys751Gln和XRCC1 Arg399Gln基因多态性为研究位点,以聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法进行多态性检测,应用Logistic回归计算OR值及95%CI,比较不同基因型与食管癌发病风险的关系。结果:病例组和对照组中变异型等位基因ERCC2/XPD Lys751Gln的频率分别是15.7%和13.0%。与野生基因型Lys/Lys相比,携带XPD Lys/Gln和Gln/Gln基因型者患食管癌的危险度比值比(odds ratio,OR)分别是1.94(95%CI:1.22～3.36)和0.56（95%CI:0.15～2.64)。变异型等位基因XRCC1 399Gln的频率在病例组和对照组中分别是29.8%和30.2%,与野生基因型XRCC1 Arg/Arg相比,带Arg/Gln和Gln/Gln基因型者患食管癌的OR分别是0.94(95%CI:0.69～1.31)和1.83(95%CI:0.84～3.89)。分析结果提示饮酒、酸泡菜与XPD Lys751Gln基因多态存在交互作用,交互效应OR值分别为2.24(95%CI:1.18～2.87)和2.53(95%CI:1.71～3.46),携带XPD Lys751Gln和XRCC Arg1399Gln突变基因者若同时暴露于酸泡菜或酒精,则患食管癌的危险显著增加,相较未暴露于上述因素者,OR值均增大。结论:DNA损伤修复基因ERCC2/XPD和XRCC1单核苷酸多态性可能与当地居民食管癌遗传易感性有关,与饮酒、酸泡菜存在交互作用。     

GSTP1, ERCC1 and ERCC2 Polymorphisms,Expression and Clinical Outcome of Oxaliplatin-based Adjuvant Chemotherapy in Colorectal Cancer in Chinese Population

Aim: Platinum agents have shown to be effective in the treatment of colorectal cancer. We assessed whethersingle nucleotide polymorphisms (SNPs) in GSTP1, ERCC1 Asn118Asn and ERCC2 Lys751Gln might predictthe overall survival in patients receiving oxaliplatin-based chemotherapy in a Chinese population. Methods:SNPs of GSTP1, ERCC1 Asn118Asn and ERCC2 Lys751Gln in 335 colorectal cancer patients were assessedusing TaqMan nuclease assays. Results: At the time of final analysis on Nov. 2011, the median follow-up periodwas 37.7 months (range from 1 to 60 months). A total of 229 patients died during follow-up. Our study showedGSTP1 Val/Val (HR=0.44, 95% CI=0.18-0.98), ERCC1 C/C (HR=0.20, 95% CI=0.10-0.79) and ERCC2 G/G(HR=0.48, 95% CI=0.19-0.97) to be significantly associated with better survival of colorectal cancer. GSTP1Val/Val, ERCC1 C/C and ERCC2 G/G were also related to longer survival among patients with colon cancer,with HRs (95% CIs) of 0.41 (0.16-0.91), 0.16 (0.09-0.74) and 0.34 (0.16-0.91), respectively. Conclusion: GSTP1,GSTP1, ERCC1 Asn118Asn and ERCC2 Lys751Gln genotyping might facilitate tailored oxaliplatin-basedchemotherapy for colorectal cancer patients.     

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.