XPD、XRCC1基因多态性预测晚期NSCLC对铂类药物的化疗敏感性

采用PCR-RFLP方法检测162例接受铂类药物化疗的晚期非小细胞肺癌（NSCLC）患者的DNA修复基因XPD和XRCC1的基因多态性，比较不同基因型对化疗敏感性的影响。携带Asn／Asn基因型患者的化疗失败风险是至少携带一个Asp等位基因（Asp／Asp和Asp／Asn基因型）个体的3倍（P〈O．05），而携带Arg／Arg基因型患者的化疗失败风险是至少携带一个Trp等位基因（Arg／Trp和Trp／Trp基因型）个体的2倍（P〈0．05），二者联合多态性分析发现，携带Asp／Asp和Arg／Trp基因型的患者化疗有效率最高，提示DNA修复基因多态性可以预测晚期NSCLC患者对铂类药物的化疗敏感性。     

XPD基因遗传多态与晚期结直肠癌患者化疗后生存期的关系

采用聚合酶链反应-限制性长度片段分析法检测96例晚期结直肠癌患者化疗前的XPD Asp312Asn和XPD Lys751Gin基因多态性分型，比较不同基因型患者化疗后的中位生存时间（MST）。结果XPD 751Lys／Lys基因型患者MST17．3个月，显著高于XPD 751Lys／Gln或Gin／Gin基因型患者（12．5个月）。XPD 312Asp／Asp基因型患者MST与XPD 312Asp／Ash或Asn／Asn基因型患者相比较无统计学差异。提示XPD Lys751GIn基因多态性与晚期结直肠癌患者化疗后的预后有关。     

XRCC1和XPD单核苷酸多态性预测晚期NSCLC铂类化疗敏感性的研究

目的探讨DNA损伤修复基因XRCC1和XPD单核苷酸多态性与晚期非小细胞肺癌(NSCLC)对铂类药物化疗敏感性的关系。方法以聚合酶链反应结合限制性片段长度多态性(PCR-RFLP)方法,检测166例以顺铂(DDP)为基础药物化疗的晚期NSCLC患者XRCC1 Arg194Trp和XPD Asp312Asn多态基因型,并比较不同基因型与化疗敏感性的关系。结果化疗总有效率(CR PR)为31.3%,其中CR2例,PR50例,SD70例,PD44例。携带至少1个XRCC1第194位密码子Trp等位基因患者化疗敏感性是携带Arg/Arg基因型患者的4.3倍(OR=4.32,95%CI=2.10~8.87,P=0.000);携带XPD第312位密码子Asp/Asp基因型患者化疗敏感性是携带至少1个Asn基因型患者的3.5倍(OR=3.49,95%CI=1.76~6.96,P=0.000)。联合分析这两个遗传多态性发现,尚不能认为XRCC1 Arg194Trp和XPD Asp312Asn多态性在NSCLC对铂类药物敏感性中存在联合作用(P>0.05)。结论XRCC1 Arg194Trp和XPD Asp312Asn单核苷酸多态性可能与NSCLC铂类药物敏感性有关。     

XPD基因遗传多态性与晚期结直肠癌患者对铂类药物敏感性关系的研究

目的 探讨核苷酸切除修复系统基因XPD遗传多态性与晚期结直肠癌(CRC)患者对铂类药物化疗敏感性的关系.方法 对晚期CRC患者96例进行含奥沙利铂的联合化疗,以影像学方法判定其疗效.在治疗前抽血检测XPD Asp312Asn和XPD Lys751Gln基因多态性,比较不同基因型患者的化疗敏感性.结果 患者化疗后部分缓解(PR)20例,稳定(SD)59例,进展(PD)17例,有效率(RR)为20.8%.多因素分析表明,携带Gln/Gln基因型患者的疾病进展风险是至少携带一个Lys等位基因(Lys/Lys和Lys/Gln基因型)个体的7.8倍(OR＝7.813,95%CI=1.834～33.277,P＜0.05),但未观察到XPD Asp312Asn多态与化疗敏感性相关,未发现XPD基因多态在影响铂类药敏感性中存在联合作用.结论 XPD基因遗传多态与晚期CRC对铂类化疗的敏感性相关.     

XPD基因单核苷酸多态性与晚期非小细胞肺癌对铂类药物敏感性的关系

目的 研究DNA修复基因着色性干皮病基因(XPD) Lys751Gln和XPD Asp312Asn基因多态性与非小细胞肺癌化疗铂类敏感性的关系.方法 收集经病理学确诊的晚期非小细胞肺癌87例,所有病例化疗前抽静脉血,提取DNA,用多聚酶链反应-限制性片段长度多态性(PCR-RFLP)分析技术检测XPD Lys751Gln和XPD Asp312Asn基因型,比较不同基因型与铂类化疗疗效的关系及与无进展生存时间的关系.结果 总有效率43.7%,CR 3例(3.45%),PR 35例(40.23%),SD 20例(22.99%),PD 29例(33.33%),携带XPD751Lys/Lys、Lys/GIn基因型的患者,客观有效(CR+PR)分别为36例(48.6%)、2例(15.4%)二者相比差异有统计学意义(P=0.026).携带XPD 312Asp/Asp、Asp/Asn基因型的患者,客观有效(CR+PR)分别为35例(40.23%)、3例(30.0%)二者相比差异无统计学意义(P=0.556).携带XPD751 Lys/Lys、Lys/Gln与XPD312 Asp/Asp、Asp/Asn基因型的患者无进展生存时间(PFS)分别为6.7和5.9个月、6.5和6.4个月,无统计学意义(P=0.170、P=0.674).Cox回归模型分析显示XPD751位点基因型为Lys/Gln的患者疾病进展风险是基因型为Lys/Lys的患者的2.383倍(P=0.006).XPD751位点基因型为Lys/Gln可能是疾病进展较早的因素.结论 XPD Lys751Gln单核苷酸多态性与晚期非小细胞肺癌铂类药物耐药有关.未发现XPD基因单核苷酸多态性与无进展生存时间相关,但XPD751位点基因型为Lys/Gln可能是疾病进展较早的危险因素.     

核苷酸切除修复基因ERCC1、XPD和XPC多态性与燃煤污染型地方性砷中毒的关系研究

目的 探讨核苷酸切除修复基因ERCCI、XPD、XPC不同基因型与燃煤污染型砷中毒发病风险的关系.方法 以贵州省兴仁县交乐村燃煤污染型砷中毒病区229例砷中毒患者作为病例组,以有相似生活习惯、无燃用高砷煤史的非砷暴露村大果朵村198名居民作为对照组,每人抽取外周静脉血约2 ml提取DNA,采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术进行ERCC1 C8092A 、XPD Lys751 Gln、XPD Asp312Asn、XPD Arg156Arg、XPC P(AT+/-)多态位点检测.结果 病例组ERCC1 C8092A位点CA/AA基因型分布频率[ CA:29.78％ (67/225)、AA:10.67％ (24/225)]显著高于对照组[CA:23.08％( 45/195)、AA:5.13％ (10/195),x2=8.116,P＜0.05];其余各基因多态位点的基因型分布频率差异无统计学意义(x2值分别为5.649、4.394、0.865、1.490,P均＞0.05).携带ERCCI 8092CA+ AA、XPD Lys751Gln+ Gln751Gln 、XPD Asp312Asn+ Asn312Asn基因型个体分别较携带ERCC1 8092CC、XPD Lys751Lys、XPD Asp312Asp基因型个体发生砷中毒的风险升高1.780、1.681、1.790倍(95％CI分别为1.174～2.698、1.081～2.615和1.014～3.158,P均＜0.05);单一的XPD 基因Arg156Arg位点、XPC基因P(AT+/-)位点对砷中毒的发病风险没有影响(P均＞0.05).结论 核苷酸切除修复基因ERCC1 C8092A、XPD Lys751 Gln和Asp312Asn位点的多态性与燃煤污染型砷中毒的发病风险有关.     

XRCC1单核苷酸多态性对非小细胞肺癌患者顺铂疗效的影响

目的探讨人类X射线交错互补修复基因1(XRCC1)单核苷酸多态性(SNP)与非小细胞肺癌(NSCLC)铂类药物化疗后预后的关系。方法采用MALDI-TOF-MS法检测204例经病理学确诊的接受铂类药物化疗的晚期NSCLC患者XRCC1(399)的基因型,并随机抽取5%的样本进行基因测序来验证该方法的准确性。比较不同基因型与铂类药物化疗后生存期的关系。结果 204例NSCLC患者中,部分缓解61例,疾病稳定116例,疾病进展27例;治疗有效率为29.9%,无效率为70.1%。携带XRCC1(399)G/G、G/A+A/A基因型的NSCLC患者铂类化疗后有效率分别为36.9%(38/103)和22.8%(23/101),两者比较差异有统计学意义(P<0.05)。XRCC1(399)G/G基因型患者对顺铂类药物的敏感性是G/A+A/A基因型患者的1.983倍(95%可信区间(CI):1.073~3.662,P=0.028)。携带XRCC1(399)G/G、G/A+A/A基因型的NSCLC患者铂类化疗后中位生存期(MST)、1年生存率及2年生存率分别为12.0月、52.4%、11.7%和10.0月、37.6%、3.0%,两者比较差异均有统计学意义(P<0.05)。结论 XRCC1(399)基因多态性与晚期NSCLC患者铂类药物化疗后的生存期有显著相关性,有可能成为铂类药物化疗后生存期的预测指标。     

东北地区汉族人群DNA修复基因XPD单核苷酸多态性与胃癌的相关性

目的:研究核苷酸切除修复基因XPD单核苷酸多态性与东北地区汉族人群胃癌风险的关系.方法:以聚合酶链反应-限制性片段长度多态性方法分析了238例胃癌患者标本XPD基因Asp312Asn和Lys751Gln多态性,比较不同基因型与胃癌风险的关系.结果:Lys751Gln多态在胃癌患者中的分布和正常对照组差异不显著,与胃癌风险无关.胃癌患者中Asp/Asn和Asn/Asn基因型频率明显高于正常对照组(P=0.041);与携带312Asp/Asp基因型者比较,携带至少1个312Asn等位基因者(即Asp/Asn和Asn/Asn基因型)罹患胃癌的风险增加1.901倍(95%CI:1.119-3.229).结论:XPD基因Asp312Asn多态是东北地区汉族人群胃癌遗传易感因素.     

DNA修复基因多态性与非小细胞肺癌患者含铂方案化疗预后的关系

目的探讨DNA修复基因ERCC1 C118T和XPD Lys751Gln单核苷酸多态性与含铂方案化疗非小细胞肺癌(NSCLC)患者临床预后的关系。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,分析NSCLC患者ERCC1和XPD单核苷酸多态性与铂类化疗预后之间的关系。结果所有NSCLC患者中位生存期为18.0个月。ERCC1 CC型的中位总生存时间为19.803个月,CT型为15.993个月,TT型为16.233个月,CC型与CT、TT型间比较差异均有统计学意义(χ2=12.855,P=0.000;χ2=8.602,P=0.003)。XPD Lys751Gln只检测到A/A型、A/C型,A/A型的中位总生存时间为18.044个月,A/C型的中位总生存时间为18.075个月,两组间比较差异无统计学意义(χ2=0.034,P=0.854)。结论 DNA修复基因ERCC1C118T单核苷酸多态性与NSCLC患者铂类药物化疗后的生存期有关,在一定程度上可作为铂类药物化疗后生存期的预测指标。     

DNA切除修复基因XPD在肝癌中遗传易感性的荟萃分析

目的 探讨DNA切除修复基因XPD基因多态性在中国人群原发性肝癌中的遗传易感性. 方法 检索中外数据库,获得有关XPD基因多态性与肝癌发病风险的病例对照研究资料进行Meta分析,得到合并的优势比(OR)和95％可信区间(95％CI). 结果 共纳入XPD基因多态位点相关文献6篇,累计病例3424例,对照3636例;在XPD基因多态位点751和312位点等位基因的OR (95％CI)分别为1.25 (0.70～ 2.24)和0.85 (0.58～ 1.25);在XPD基因多态位点751,与野生基因型Lys/Lys相比,(Lys/Gln+Gln/Gln)合并的OR(95％CI)为1.31(0.71 ～ 2.42);在XPD基因多态位点312位点,与野生基因型Asp/Asp相比,(Asp/Asn+Asn/Asn)合并的OR值(95％CI)为1.19 (0.73～ 1.95). 结论 XPD多态性遗传位点751和312不是中国人群原发性肝癌发病的风险因素.     

DNA repair gene XRCC1 and XPD polymorphisms and their association with coronary artery disease risks and micronucleus frequency

Coronary artery disease (CAD) is a multifactorial process that appears to be caused by the interaction of environmental risk factors with multiple predisposing genes. In this study, we investigated the effects of the XPD Lys751Gln and XRCC1 Arg399Gln polymorphisms on the presence and the severity of CAD. We also investigated the presence of DNA damage in the peripheral lymphocytes of patients with CAD by using the micronucleus (MN) test and the effect of XPD Lys751Gln and XRCC1 Arg399Gln polymorphisms on this damage. The study population consisted of 147 patients with angiographically documented CAD and 48 healthy controls. No association between XPD Lys751Gln or XRCC1 Arg399Gln polymorphisms and the presence or the severity of CAD was observed. On the other hand, a significantly higher frequency of MN was observed in CAD patients compared with controls (5.7 ± 1.9 vs 5.0 ± 2.1, respectively, P = 0.018). We found an elevated frequency of MN in CAD patients with the XPD 751Gln allele (Gln/Gln genotype) or the XRCC1 399Gln (Arg/Gln or Gln/Gln genotypes) allele compared with the XPD 751Lys (Lys/Lys genotype) allele or XRCC1 399 Arg (Arg /Arg genotype) allele, respectively. These preliminary results suggest that XPD Lys751Gln and XRCC1 Arg399Gln polymorphisms may not be a significant risk factor for developing CAD. In addition, our results indicate that the MN frequency is associated with presence, but not severity, of CAD and is related to the XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms, suggesting an elevated frequency of MN in CAD patients with the XPD 751Gln or XRCC1 399Gln alleles.     

Prognostic importance of DNA repair gene polymorphisms of <Emphasis Type="Italic">XRCC1</Emphasis> Arg399Gln and <Emphasis Type="Italic">XPD</Emphasis> Lys751Gln in lung cancer patients from India

Purpose Inter individual variation in lung cancer susceptibility may be modulated in part through genetic polymorphisms in the DNA repair genes, especially the genes involved in the Base Excision Repair (BER) and nucleotide excision repair (NER) pathway. Two of the genetic polymorphisms, XRCC1Arg399Gln and XPD Lys751Gln have been extensively studied in the association with lung cancer risk, although published studies have been inconclusive. Methods In order to verify the role of the common variant alleles in the XPD gene, we have genotyped 211 lung cancer patients and 211 healthy controls using PCR-RFLP assays in a hospital based, case-control study in an Indian population. Logistic regression models were fit to examine the relationship between the log odds of lung cancer and each covariate. Overall Survival in relation to various genotypes and clinicopathological factors were analyzed using Kaplan Meier estimates and hazard ratios were calculated using Cox Regression analysis. Results The carriers of XRCC1 399 AA genotypes were at higher risk of lung cancer (OR = 2.1, 95% CI:1.224–3.669, P = 0.007) than carriers of GG genotype. Subjects carrying 751 AC genotype were at an increased risk of carcinoma of the lung (OR = 1.8; 95% CI:1.233–2.807, P = 0.003) than subjects with AA genotypes. Compared to the XRCC1 399 GG/ XPD 751 AA reference genotype, the combined variants, XRCC1 399 GG/ XPD 751 AC+CC (OR = 1.9, 95% CI: 1.037–3.481), P = 0.03), XRCC1 399 GA+AA/ XPD 751 AA (OR = 1.7, 95% CI: 1.020–2.833, P = 0.04), XRCC1 399 GA+AA/XPD 751 AC+CC (OR = 2.7, 95% CI: 1.582–4.864, P = 0.01), had significantly higher odds ratios. Increasing numbers of either XPD or XRCC1 variant alleles were associated with shorter overall survival, the risk being significant for the XRCC1 gene polymorphism (P = 0.01 by log-rank test). The hazard of dying was significant for the XRCC1 399 AA genotype (HR = 3.04, 95%CI: 1.393–6.670, P = 0.005). Higher tumour stage also came out as significant predictors of patient death. Conclusions These findings suggest that genetic polymorphisms in the DNA repair genes may modulate overall lung cancer susceptibility and that pathological stage and XRCC1 Arg399Gln independently predicted overall survival among Indian lung cancer patients.     

The genotype distribution of the XRCC1 gene indicates a role for base excision repair in the development of therapy-related acute myeloblastic leukemia

Polymorphisms in several DNA repair genes have been described. These polymorphisms may affect DNA repair capacity and modulate cancer susceptibility by means of gene-environment interactions. We investigated DNA repair capacity and its association with acute myeloblastic leukemia (AML). We studied polymorphisms in 3 DNA repair genes: XRCC1, XRCC3, and XPD. We also assessed the incidence of a functional polymorphism in the NQO1 gene, which is involved in protection of cells from oxidative damage. We genotyped the polymorphisms by using polymerase chain reaction-restriction fragment-length polymorphism analysis in 134 patients with de novo AML, 34 with therapy-related AML (t-AML), and 178 controls. The distributions of the XRCC3 Thr241Met and NQO1 Pro187Ser genotypes were not significantly different in patients and controls. However, the distribution of the XRCC1 Arg399Gln genotypes was significantly different when comparing the t-AML and control groups (chi(2), P =.03). The presence of at least one XRCC1 399Gln allele indicated a protective effect for the allele in controls compared with patients with t-AML (odds ratio 0.44; 95% confidence interval, 0.20-0.93). We found no interactions between the XRCC1 or XRCC3 and NQO1 genotypes. We also found no differences in the distribution of the XPD Lys751Gln or XRCC1 Arg194Trp genotypes. Our data provide evidence of a protective effect against AML in individuals with at least one copy of the variant XRCC1 399Gln allele compared with those homozygous for the common allele.     

DNA修复基因XRCC1 Arg194Trp Arg280His和Arg399Gln多态性与前列腺癌相关性的Meta分析

目的探讨DNA修复基因X线修复交叉互补因子1（XRCC1）主要单核苷酸多态性与前列腺癌易感性的关系。方法在MEDLINE、EMBASE和OVID数据库上检索文献,收集及提取符合纳入标准的以XRCC1密码子194、280、399多态性与前列腺癌易感性为内容的病例对照研究文献,应用Stata统计软件进行Meta分析,比值比（ORs）及其95%可信区间（95%CI）评价关联强度;应用SPSS软件分析吸烟与前列腺癌关系,OR？评价其相对危险度。结果 XRCC1 399 Gln/Gln和XRCC1 280 Arg/His与前列腺癌的发病风险有关（Gln/Gln vs Arg/Arg：OR？=1.27,95%CI=1.02～1.59;Arg/His vs Arg/Arg：OR？=1.66,95%CI=1.09～2.52）,尤其在亚组分析中亚洲人的Gln/Gln明显增加了前列腺癌的发病风险（OR？=1.52,95%CI=1.18～1.96）;Arg194Trp与前列腺癌的发病风险无明显关联。吸烟是前列腺癌的危险因素（χ2=13.974,P=0.000,OR？=1.22）。结论 XRCC1 399 Gln/Gln和280 Arg/His可能与前列腺癌的易感性相关。     

DNA repair genes polymorphisms in multiple myeloma: no association with XRCC1 (Arg399Gln) polymorphism, but the XRCC4 (VNTR in intron 3 and G-1394T) and XPD (Lys751Gln) polymorphisms is associated with the disease in Turkish patients

OBJECTIVE: This study aims to investigate the association between the polymorphisms in DNA repair genes (XPD, XRCC1, and XRCC4) and clinical parameters in patients with multiple myeloma (MM), their effects on prognosis and their roles in susceptibility to MM. Patients and methods: Sixty patients, diagnosed with MM and 70 individuals as the healthy control group were included in the study. Gene polymorphisms were detected with the polymerase chain reaction and/or polymerase chain reaction-restriction fragment length polymorphism method. When the genotype frequencies of XPD (Llys751Gln) and XRCC1 (Arg399Gln) genes were examined in the patient and control groups, no significant difference was detected, while a significant association was found in XRCC4 (VNTR in intron 3 and G-1394T) polymorphisms. A significant association was found in the MM patients group for AA genotype and event-free survival (EFS) in terms of XPD (751) gene polymorphism (P = 0.047). When VNTR intron 3 polymorphism was compared for genotype frequency, DD genotype was found to be significantly low (P = 0.012) in the patient group, whereas GG and TT genotypes were found to be significantly lower in the patient group for the genotype frequency XRCC4 (G-1394T) polymorphism when compared to the control group (P = 0.015, P = 0.010, respectively). RESULTS: These data provide support for the hypothesis that a common variation in the genes encoding XRCC4 DNA repair proteins may contribute to susceptibility to myeloma. These findings require further validation in independent populations.     

Polymorphisms in DNA repair genes XRCC1, XRCC3 and XPD, and colorectal cancer risk: a case–control study in an Indian population

Purpose

Genetic polymorphisms in DNA repair genes may influence variations in individual DNA repair capacity, which could be associated with the development of cancer. We detected the distributions of three single-nucleotide polymorphisms (XRCC1 Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln) in DNA repair genes, and assessed the associations of these genetic polymorphisms with colon and rectal cancer susceptibility as well as evaluated the interactions of gene–gene and gene–environment in a case–control study of an Indian population.

Methods

This case–control study was conducted with 302 cases (including 59 colon and 243 rectal cancer patients) and 291 cancer-free healthy controls. Genotypes were determined by PCR–RLFP assays. The effects [odds ratios (ORs) and 95% confidence intervals (95% CIs)] of genetic polymorphisms on colorectal cancer were estimated using unconditional logistic regression.

Results

The XRCC1 399Gln allele was found to be associated with a significantly increased rectal cancer risk among men (OR = 1.65, 95% CI 1.04–2.64). Whereas the XRCC3 241Met allele showed a protective tendency against rectal cancer (OR = 0.68, 95% CI 0.46–1.02) for both men and women. Furthermore, a combination of the XRCC1 399Gln allele with XRCC3 Thr/Thr genotype and the XPD 751Gln allele demonstrated the highest rectal cancer risk (OR = 3.52, 95% CI 1.43–9.44).

Conclusions

The combined effects of putative risk alleles/genotypes for different DNA repair pathways may strengthen the susceptibility to rectal cancer.     

Excision repair cross-complementing group 2/Xeroderma pigmentousm complementation group D (ERCC2/XPD) genetic variations and susceptibility to diffuse large B cell lymphoma in Egypt

Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous neoplasm. Although several genetic and environmental factors have been postulated, no obvious risk factors have been emerged for DLBCL in the general population. DNA repair systems are responsible for maintaining the integrity of the genome and protecting it against genetic alterations that can lead to malignant transformation. The current study aimed at investigating the possible role of ERCC2/XPD Arg156Arg, Asp312Asn and Lys751Gln genetic polymorphisms as risk factors for DLBCL in Egypt. The study included 81 DLBCL patients and 100 healthy controls. Genotyping of the studied genetic polymorphisms was performed by polymerase chain reaction–restriction fragment length polymorphism technique. Our results revealed that there was no statistical difference encountered in the distribution of ?Asp312Asn and ?Lys751Gln polymorphic genotypes between DLBCL cases and controls, thus it could not considered as molecular risk factors for DLBCL in Egyptians. However, Arg156Arg polymorphism at exon-6 conferred twofold increased risk of DLBCL (OR 2.034, 95 %CI 1.015–4.35, p = 0.43), and the risk increased when co-inherited with Lys751Gln at exon-23 (OR 3.304, 95 %CI 1.113–9.812, p = 0.038). In conclusion, ERCC2/XPD Arg156Arg polymorphism might be considered as a genetic risk factor for DLBCL in Egyptians, whether alone or conjoined with Lys751Gln.     

Xeroderma pigmentosum group D 751 polymorphism as a predictive factor in resected gastric cancer treated with chemo-radiotherapy

INTRODUCTION The xeroderma pigmentosum group D (XPD) gene en- codes a protein required for nucleotide excision repair (NER). This product recognizes and repairs a wide range of structurally unrelated lesions such as bulky adducts caused by UV light, envir…