中国四川人群DNA修复基因X射线修复交叉互补基因1-Arg399Gln多态性与鼻咽癌风险的关系

目的:观察中国四川人群X射线修复交叉互补基因1-Arg399Gln多态性,分析其与鼻咽癌发病风险的关系。方法:实验于2005-11/2006-04在泸州医学院分子生物学实验室完成。采用病例-对照研究方法,病例组和对照组均不采取任何干预措施,聚合酶链反应-限制性片段长度多态性检测220例鼻咽癌患者及性别、年龄(50±4)岁相匹配的250例正常人群X射线修复交叉互补基因1-Arg399Gln基因型频率分布。通过χ2检验、非条件Logistic回归分析相对危险度近似估计值比值比,以估计各研究因素与鼻咽癌发病风险的关系,及基因多态性与环境是否存在交互作用,采用SPSS12.0软件包完成。结果:①病例组和对照组Arg399Gln基因型Arg/Arg,Arg/Gln和Gln/Gln频率分布差异无显著性意义。②Arg399Gln多态性未增加个体患鼻咽癌的风险(P>0.05,OR=0.814,95%CI=0.325～2.037和OR=0.830,95%CI=0.254～2.710)。③EB病毒感染和X射线修复交叉互补基因1-Arg399Gln多态性存在交互作用(Wald=4.391,P=0.036),基因型为Arg/Gln和Gln/Gln同时伴有EB病毒感染的个体患鼻咽癌的风险增加。结论:X射线修复交叉互补基因1-Arg399Gln多态性与鼻咽癌的发生无相关性,但与EB病毒感染存在交互作用,基因型为Arg/Gln和Gln/Gln同时伴有EB病毒感染的个体患鼻咽癌的风险增加。     

XRCC1、XPD单核苷酸多态性与肺癌铂类化疗的临床预后研究

目的DNA修复基因XRCC1和XPD是参与铂-DNA加合物修复中的关键因子。探讨肿瘤石蜡组织中XR- CC1、XPD单核苷酸多态性与接受铂类药物化疗非小细胞肺癌(NSCLC)患者临床预后之间的关系。方法采用TaqMan探针Real-time PER方法评价53例石蜡包埋NSCLC组织中DNA修复基因XRCC1第399位密码子、XPD第751位密码子的多态性,并比较不同基因型与NSCLC肿瘤组织临床病理及铂类化疗预后之间的关系。结果XRCC1 Arg399Gln、XPD Lys751Gln基因多态性与NSCLC患者临床及肿瘤病理特征均未见相关性。携带XRCC1 Arg/Arg或Arg/Gln基因型NSCLC患者经铂类化疗后的平均总生存时间为24.0月,而携带Gln/Gln基因型患者仅为8.0月,两者有统计学差异(P=0.02)。XPD Lys751Gln与NSCLC患者无进展生存期和总生存时间均未见显著性差异(P>0.05)。XPD和XRCC1的多态性联合分析显示变异型等位基因的个数增加与总生存时间(P=0.015)相关。Cox比例风险模型显示XRCC1 Arg399Gln可以独立预测NSCLC患者的总生存时间(P=0.011)。结论XRCC1 Arg399Gln、XPD Lys751Gln基因多态性与NSCLC肿瘤临床病理特征无关。XRCC1 Arg399Gln基因多态性与NSCLC患者的总生存时间有关,在一定程度上可以作为判断NSCLC患者铂类药物化疗的预后指标。XRCC1和XPD SNP在铂类药物化疗预后方面可能存在一定的联合作用。     

XRCC1、XPD单核苷酸多态性与肺癌铂类化疗的临床预后研究

目的DNA修复基因XRCC1和XPD是参与铂-DNA加合物修复中的关键因子。探讨肿瘤石蜡组织中XR-（321、XPD单核苷酸多态性与接受铂类药物化疗非小细胞肺癌（NSCLC）患者临床预后之间的关系。方法采用TaqMan探针Real-time PCR方法评价53例石蜡包埋NSCLC组织中DNA修复基因XRCC1第399位密码子、XPD第751位密码子的多态性，并比较不同基因型与NSCLC肿瘤组织临床病理及铂类化疗预后之间的关系。结果XRCC1 Arg399Gin、XPD Lys751Gln基因多态性与NSCLC患者临床及肿瘤病理特征均未见相关性。携带XRC1 Arg／Arg或Arg／Gln基因型NSCLC患者经铂类化疗后的平均总生存时间为24．0月，而携带Gln／Gln基因型患者仅为8．0月，两者有统计学差异（P=0．02）。XPD Lys751Gln与NSCLC患者无进展生存期和总生存时闯均未见显著性差异（P〉0．05）。XPD和XROC1的多态性联合分析显示变异型等位基因的个数增加与总生存时间（P=0．015）相关。Cox比例风险模型显示XRCC1 Arg399Gln可以独立预测NSCLC患者的总生存时间（P=0．011）。结论XRCC1 Arg399Gln、XPD Lys751Gln基因多态性与NSCLC肿瘤临床病理特征无关。XRCC1 Arg399GIn基因多态性与NSCLC患者的总生存时间有关，在一定程度上可以作为判断NSCLC患者铂类药物化疗的预后指标。XRCC1和XPD SNP在铂类药物化疗预后方面可能存在一定的联合作用。     

XRCC1基因多态性与膀胱癌发病风险和临床预后的关系

目的 探讨X-射线交错互补修复基因1(XRCCI)的单核苷酸多态性(SNP)与膀胱癌发病风险和预后的关系.方法 采用聚合酶链式-限制性片段长度多态性技术(PCR-RFLP)检测230例膀胱癌患者和280例健康对照组的个体血液标本的XRCC1Arg194Trp、Arg399Gln两个SNP的基因型频率分布,分析与膀胱癌遗传易感性、病理分期及分级、复发和生存率的关系.结果 对于XRCCIArg194Trp和Arg399Gln位点,膀胱组和对照组间,Arg194CC、CT、TT基因型分布差异有统计学意义(P＜0.05),Arg399GlnAA、AG、GG基因型分布差异无统计学意义(P＞0.05).与CC基因型膀胱癌组相比较,携带TT基因型组差异有统计学意义(P＜0.05),与AA基因型组相比较,携带GG基因型组差异无统计学意义(P＞0.05).不同的临床分期和病理分级膀胱癌中,Arg194Trp的CC、CT、TT基因型频率有明显差异(P＜0.05),Arg399Gln的AA、AG、GG基因型频率无明显差异(P＞0 05).XRCCIArg194Trp位点CC、CT、TT基因型频率,复发(分别为41.0％ 、36.9％,22.1％)与未复发(分别为49.1％,45.4％,5.6％),死亡(分别为48.6％ 、38.9％、12.6％)与存活(分别为52.6％、45.2％、2.2％)患者分别比较,差异均有统计学意义(P＜0.05);Cox比例风险回归模型分析表明,与携带CC基因型的膀胱癌患者相比,携带TT基因型患者的疾病无进展生存时间(分别为32.5、16 5个月;HR=2.27,95％CI:1.22～ 4.36,P＜0.01)和总生存时间(分别为48.6、24.9个月;HR2.86,95 ％CI:1.75～3.96,P＜0.05)均明显缩短.未发现Arg399Gln点的基因型分布与预后的相关性(P＞0.05).结论 XRCC1Arg194Trp多态性可能与膀胱癌的发病风险、临床分期、分级和预后相关.     

EB病毒感染与XRCC1-Arg399Gln基因多态性在鼻咽癌发生中的交互作用

目的评估XRCCl-Arg399 Gln单核苷酸多态性在鼻咽癌发病中的风险,研究XRCCl-Arg399 Gln单核苷酸多态性与EB病毒感染的交互作用。方法采用病例对照研究,收集90名经病理确诊的鼻咽癌患者作为病例组和75名在我院进行健康体检的病人作为对照,并按照性别和年龄1∶1配对,提取全血基因组DNA进行PCR扩增,对扩增产物再进行测序PCR反应,最后分析得出XRCC1 Arg399Gln的基因型。结果 EB病毒感染能增加鼻咽癌发病风险,VCA-IgA、EA-IgA和Rta-IgG抗体三项阳性时可以增加鼻咽癌发病风险,但单项VCA-IgA阳性是鼻咽癌发病的最强危险因素(OR=26.526,95%CI:11.190~62.884),单因素条件Logistic回归分析显示,与携带XRCC-1 Arg399Gln的AA基因型相比,携带XRCC-1 Arg399Gln的GG基因型可增加鼻咽癌发病风险(OR=4.3,95%CI:1.184~15.618);XRCC-1 Arg399Gln的GA基因型与VCAIgA存在交互作用(OR=20.755,95%CI:5.312~81.094)。结论 XRCC-1基因的Arg399Gln基因多态性能够增加患鼻咽癌的风险,且Arg399Gln的GA基因型与EB病毒感染具有一定的交互作用。     

XRCC1和hOGG1基因多态性与子宫内膜癌相关性的Meta分析

目的系统评价X线修复交叉互补基因1(XRCC1) Arg399Gln和人8-羟基鸟嘌呤DNA糖苷酶基因(h OGG1) Ser326Cys的多态性与子宫内膜癌的相关性。方法系统检索以下电子数据库:Pubmed、Medline、Excerpta Medica Database(Embase)、EBM、Cochrance library、中国知网、万方数据库和中国生物医学数据库。收集有关XRCC1基因Arg399Gln位点以及h OGG1基因Ser326Cys位点的多态性与子宫内膜癌相关性的病例对照试验,利用Rev Man5. 3软件对纳入文献进行Meta分析,计算合并OR值及其95%可信区间。结果最终纳入7篇病例对照试验,涉及1 033例试验组研究对象及1 123例对照组研究对象。在总人群的XRCC1基因Arg399Gln位点多态性与增加子宫内膜癌的易感性相关(显性模型OR=1. 45,95%CI:1. 03～2. 04;纯合模型OR=2. 28,95%CI:1. 23～4. 22,P=0. 09),在对高加索人的亚组分析中也显示了相同的结果(显性模型OR=1. 69,95%CI:1. 32～2. 15;隐性模型OR=2. 77,95%CI:1. 25～6. 11;纯合模型OR=3. 05,95%CI:2. 23～4. 17)。在高加索人h OGG1基因Ser326Cys多态性与也会使患子宫内膜癌的风险增加(杂合模型OR=1. 43; 95%CI:1. 05～1. 95)。结论 XRCC1基因Arg399Gln多态性与子宫内膜癌的易感性相关,399Gln等位基因可能是女性尤其是高加索人种女性患子宫内膜癌的危险因素。h OGG1基因Ser326Cys位点多态性与子宫内膜癌的易感性相关,在高加索人种326Cys等位基因可能会增加子宫内膜癌的发病风险。     

DNA修复基因XRCC1和XRCC3多态性与膀胱癌风险关联研究

目的：探讨DNA修复基因多态性与膀胱癌易感性的关系。方法：采用病例-对照研究,以PCR-RFLP技术检测膀胱癌组和对照组的基因多态,比较不同基因型与膀胱癌风险的关系。结果：XRCC1三种基因型在两组间的分布无统计学差异;XRCC3三种基因型在两组之间的分布有统计学差异。结论：XRCC1 Arg194Trp多态与膀胱癌易感性无关;携带XRCC3 241Met基因型的个体患膀胱癌的风险显著增加。     

XRCC1多态性与胰腺癌发病风险的meta分析

目的本文旨在系统评价X线修复交叉互补基因1(X-ray repair cross-complementating group 1,XRCC1)的单核苷酸多态性(single nucleotide polymorphisms,SNP)与胰腺癌发病风险的相关性。方法计算机检索数据库PubMed、Embase、the Cochrane Library、Web of Science、中国生物医学文献数据库(CBM)、万方数据库、中国期刊全文数据库(CNKI),按照纳入与排除标准筛选文献,对研究结果进行meta分析,评价发表偏倚并进行敏感性分析。结果共纳入8篇病例-对照研究,合并结果显示:XRCC1上的Arg399Gln(rs25487GA)突变和Arg194Trp(rs1799782CT)突变与胰腺癌发病风险之间的关联差异无统计学意义;XRCC1上的Arg280His(rs25489GA)突变与胰腺癌的发病风险密切相关(A vs G:OR=0.743,95%CI=0.576~0.958,P=0.022;GA vs GG:OR=0.701,95%CI=0.525~0.936,P=0.016;AA+GA vs GG:OR=0.710,95%CI=0.537~0.939,P=0.016);Egger检验显示不存在发表偏倚(P0.05);敏感分析逐个剔除研究后meta分析结果受单个研究的影响较小。结论本研究表明XRCC1上的Arg399Gln(rs25487GA)突变和Arg194Trp(rs1799782CT)突变与胰腺癌的发病风险无明显相关性;XRCC1上的Arg280His(rs25489GA)突变可能与胰腺癌的发病风险有关联。     

DNA修复基因XRCC1单核苷酸多态性与晚期非小细胞肺癌铂类药物化疗后生存期的关系

目的 研究DNA修复基因XRCC1单核苷酸多态性与晚期非小细胞肺癌（NSCLC）患者对顺铂或卡铂为主的方案化疗后生存期的关系。方法 经病理学确诊的晚期NSCLC患者135例，采用顺铂或卡铂为主的方案进行化疗。化疗前采集患者外周血，以聚合酶链反应-限制性长度片段分析（PCR—RFLP）方法进行XRCC1 Arg194Trp和XRCC1 Arg399Gln基因多态性的分型。比较不同基因型患者化疗后的中位生存时间（MST）和1、2年生存率。结果 中位随访12个月，135例患者的MST和1、2年生存率分别为12个月和48．1％、13．1％。携带XRCC1 399Arg／Arg的NSCLC患者化疗后MST和1、2年生存率分别为14．0个月和56．3％、20．8％；携带XRCC1 399Arg／Gin或Gin／Gln基因型的NSCLC患者化疗后MST和1、2年生存率分别为10．0个月和39．0％、7．6％，差异均有显著性（P〈0．05）。携带XRCC1 194Arg／Arg的NSCLC患者的MST和1、2年生存率分别为11．0个月和43、6％、13．2％；携带XRCC1 194Arg／Gln或Gln／Gln基因型的NSCLC患者MST和1、2年生存率分别为13．0个月和49．6％、11．3％，两组之间差异无显著性（P〉0．05）。结论 XRCC1 Arg399Gln基因多态性与晚期NSCLC患者铂类药物化疗后的生存期有关。XRCC1 Arg3 99Gln基因多态性可以在一定程度上判断晚期NSCLC患者铂类药物化疗后的预后。     

着色性干皮病基因D和X线交叉互补修复基因1的多态性与肺癌的相关性分析

目的:探讨着色性干皮病基因D(Xeroderma pigmentosum gene D,XPD)和X线交叉互补修复基因1(X-ray repair cross complementing gene 1,XRCC1)的多态性与肺癌之间的相关性。方法:采用聚合酶链反应—限制性片段长度多态性(polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP)技术,对150例肺癌患者(肺癌组)以及150例健康志愿者(健康对照组)的XPD-751、XRCC1-399两个多态位点进行基因型分析。结果:肺癌组及健康对照组XPD-751的基因型频率及突变等位基因频率差异有统计学意义(P分别为0.046、0.003);肺癌组及健康对照组的XRCC1-399基因型频率及突变等位基因频率则差异无统计学意义(P分别为0.395、0.105)。非小细胞肺癌组和小细胞肺癌组XPD-751的突变等位基因频率差异有统计学意义(P=0.012),鳞癌组、腺癌组及其他类型非小细胞肺癌组XPD-751的突变等位基因频率差异亦有统计学意义(P=0.023)。吸烟和XPD-751多态性两个危险因素共同存在时,罹患肺癌的相对危险度为2.812(95%CI:0.956~6.415),P=0.336。结论:XPD-751基因多态性与肺癌的发生相关,尤其与非小细胞肺癌中的鳞癌关系密切;而XRCC1-399基因多态性则与肺癌的发生无关;吸烟和XPD-751多态性在肺癌的发生中无交互作用。     

XRCC1 polymorphism and lung cancer risk

DNA repair plays a critical role in protecting the genome of the cell from the insults of carcinogens or ionizing radiation. Reduced DNA repair capacity can increase the susceptibility to environmental- or occupational-induced cancers. Three coding polymorphisms at codon 194, codon 280 and codon 399 in the x-ray cross complementing group 1 (XRCC1) DNA repair gene have been identified, and it is possible that these polymorphisms may affect DNA repair capacity and thus modulate cancer susceptibility. In this review, we summarize the literature and discuss the relevance of XRCC1 polymorphisms and lung cancer risk. The frequency of genetic polymorphisms is dependent on the ethnic origins of a population. The frequency of the variant allele of codon 194 among Asians is on average 31.2% (95% confidence interval [CI]: 29.6-32.8), which is significantly higher than among Caucasians (6.6%; 95% CI: 5.9-7.4) or Africans (7.3%; 95% CI: 5.7-9.2). The variant allele in codon 399 occurs among Africans at a frequency of 15.5% (95% CI: 13.5-17.7), 34.7% in Caucasians (95% CI: 33.8-35.6) and 26.5% in Asians (95% CI: 25.6-27.4). Results regarding lung cancer risk are inconsistent. The lung cancer risk associated with polymorphisms of the XRCC1 codon 194 demonstrate an odds ratio (OR) of around 1.0. For the XRCC1 codon 280, lung cancer risk varied between ORs of 0.26 and 1.8; and for the XRCC1 codon 399 between 0.32 and 3.25. Only two studies showed significantly elevated risks (OR: 3.25; 95% CI: 1.2-10.7; OR: 1.3; 95% CI: 1.0-1.8, respectively), whereas one study showed a decreased lung cancer risk (OR: 0.60; 95% CI: 0.46-40.80). Lung cancer risk increased with cigarette smoking. A significant association was not observed between the single-nucleotide polymorphisms and tobacco-related cancers. Lung cancer risk increased significantly for the variant XRCC1 -77 genotypes (TC and CC) compared with the TT genotype (OR: 1.46; 95% CI: 1.18-1.82). The risk was more pronounced in smokers (OR: 1.63; 95% CI: 1.20-2.21) than in nonsmokers (OR: 1.28; 95% CI: 0.94-1.76). No association with polymorphisms were found for various histological tumor types. The XRCC1 399 Gln/Gln variant genotype was associated with a higher median survival time.     

Multiplex pyrosequencing of two polymorphisms in DNA repair gene XRCC1

DNA repair enzymes play a pivotal role in platinum-based chemotherapy. Within the gene encoding for the base excision repair enzyme XRCC1, several nonsynonymous polymorphisms have been identified. It has been shown that the Arg399Gln single-nucleotide polymorphism results in a polymorphic enzyme that is less capable of initiating DNA repair. We developed a multiplex pyrosequence assay to simultaneously detect two nonsynonymous polymorphisms within the XRCC1 gene. Both of these polymorphisms resulted in amino acid changes: G/A in codon 399 changes Arg into Gln, and deletion of A in the second position of codon 576 results in a stopcodon. We established the frequency of these mutations in 270 patients suffering from colorectal cancer. Allele frequencies of G in second position of codon 399 and A in the second position codon 576 are 61.1 and 99.6%, respectively, in these patients. This fast and reliable method allows for simultaneous detection of the infrequent mutant C or CT alleles instead of the A deletion at codon 576. The method may be used in pharmacogenetic studies of platinum-based chemotherapy.     

DNA修复基因XRCC1单核苷酸多态性与SLE的相关性

目的 分析中国汉族人群SLE患者与健康对照人群中DNA修复基因X线修复交叉互补基因1(XRCC1)的单核苷酸多态性(SNP)分布,探讨其对SLE易感性的影响及与临床表现、实验室指标的关联程度。 方法 用等位基因特异性PCR(AS-PCR)检测39例中国汉族SLE患者和40例中国汉族健康人的XRCC1基因多态位点Arg194Trp、Arg280His和Arg399G1n的SNP型别。 结果 SLE组XRCC1多态位点Arg399G1n等位基因和基因型频率分布与健康人对照组比较具有显著性差异(P<0.05)。XRCC1多态位点Arg194Trp与SLE患者的血液系统损害及抗SS-A抗体的存在相关(P<0.05)。 结论 XRCC1基因SNP与SLE发生及临床表现和自身抗体可能相关。     

Single nucleotide polymorphisms for DNA repair genes in breast cancer patients

BACKGROUND: The incidence rate for breast cancer (BC) has been increasing in many countries and BC still remains the most common form of cancer in female and continues to be a major health problem worldwide. We explored the association of single nucleotide polymorphisms (SNPs) in DNA repair genes with breast cancer. METHODS: SSCP and RFLP were used to analyze genotypes of DNA repair genes for NBS1, XPC, XPD and XRCC3. RESULTS: T/C in XRCC3 exon 7 had a somewhat deviation from HWE in BC group (P=0.08). The genotype frequency for heterozygote A/C in XPC exon 15 and T/C in XRCC3 exon 7, homozygote A/A in XPD exon 10 were significantly different between BC group and control group in Chinese population (P<0.05, OR=1.47, 95% CI, 1.00-2.16 for A/C in XPC exon 15; P<0.05, OR=1.79, 95% CI, 0.98-3.26 for T/C in XRCC3 exon 7; P<0.05, OR=0.51, 95% CI, 0.27-0.94 for G/A in XPD exon 10). For the SNPs in NBS1 exon 5 (Glu185Gln, G/C) and XPD exon 23 (Lys751Gln, A/C), no remarkable difference for genotype distributions and allele frequencies was observed between BC group and control group in the study. CONCLUSIONS: The genotypes of A/C in XPC exon 15, T/C in XRCC3 exon 7 and A/A in XPD exon 10 studied were significantly different between BC group and control group in Chinese population.     

Rapid analysis of XRCC1 polymorphisms using real-time polymerase chain reaction

DNA repair plays a critical role in protecting the genome from carcinogens or ionizing radiation. Three coding polymorphisms at codons 194, 280, and 399 in X-ray cross-complementing group 1 (XRCC1) DNA repair gene have been identified that may affect DNA repair and alter cancer susceptibility. In order to study their role in molecular-epidemiology studies we developed a single-step procedure for genotyping these polymorphisms using real-time polymerase chain reaction (rt-PCR) and subsequent melting curve analysis. Genotypes of 622 unrelated Caucasians without prior history of cancer were determined by real-time PCR and compared to genotypes obtained by restriction fragment length polymorphism PCR. In the population studied, the allele frequency of the XRCC1 26304 site (C-->T) of codon 194 in exon 6 was 0.065, the allele frequency of the XRCC1 27466 site (G-->A) of codon 280 in exon 9 was 0.048 and of the XRCC1 28152 site (G-->A) of codon 399 in exon 10 was 0.35. There was no disagreement between the two methods. These findings confirm the real-time fluorescence PCR method as a rapid and reliable assay for the analysis of large numbers of samples.     

Polymorphisms in genes involved in DNA repair and metabolism of xenobiotics in individual susceptibility to sporadic diffuse gastric cancer.

BACKGROUND: Gastric cancer is the second highest cause of cancer mortality in the world, despite declining rates of incidence in many industrialized countries. We carried out a case-control study to evaluate whether polymorphisms of DNA repair and glutathione S-transferase (GST) genes modulate the risk of developing diffuse gastric cancer. METHODS: ERCC1 118 T/C, XRCC1 399 G/A, XPD 312 G/A, XPD 751 A/C, XRCC3 241 C/T, MS 919 A/G, GSTP1 105 A/G, GSTM1-null/positive and GSTT1-null/positive genotypes were obtained for a series of 126 Helicobacter pylori-negative diffuse gastric cancer patients and 144 Helicobacter pylori-negative controls sampled from the population of Marche, an area with high gastric cancer risk in central Italy. RESULTS: GSTP1 105 A/G and GSTP1 105 G/G genotypes were identified as protective factors, with odds ratio (OR) of 0.4 (95% CI 0.17-0.81, p=0.01) and OR=0.58 (95% CI 0.33-1, p=0.05), respectively. GSTT1-null genotype was identified as a protective factor, with OR=0.48 (95% CI 0.22-0.99, p=0.04). There was no significant difference between cases and controls for XPD 751 A/C, ERCC1 118 T/C, XRCC3 241 C/T, XRCC1 399 G/A, XPD 312 G/A, GSTM1-null/positive and MS 919 A/G polymorphisms. CONCLUSIONS: This study suggests that GSTP1 105A/G and GSTT1-null/positive genotypes might be associated with a reduced risk for sporadic diffuse gastric cancer. Clin Chem Lab Med 2007;45:822-8.