DNA修复基因单核苷酸多态性在肿瘤化疗敏感性预测的应用进展

恶性肿瘤严重威胁着人类的健康,化学药物治疗在肿瘤的三大治疗方法中占有重要的地位。同一药物在不同个体产生的效果不完全相同,这种不同是由人类基因组中的遗传多态性即遗传差异决定的。人类基因组中一类普遍的遗传多态性是基因组中散在的单个碱基的不同,即单核苷酸多态性（single nucleotide polymorphims,SNPs）,是继第一代限制性片断长度多态性（restriction fragment length polymorphisms,RFLP）和第二代微卫星多态性（micwsmellite polymorphisms）之后的新一代遗传标记。     

DNA修复基因单核苷酸多态性预测铂类药物敏感性和预后

铂类药物是治疗实体肿瘤常用的药物之一,但是肿瘤细胞对铂类药物耐药导致化疗失败,成为临床治疗的一大难题。DNA修复能力是影响疗效的重要原因。DNA修复基因单核苷酸多态性(SNP)可改变DNA修复能力,因此,检测这些基因的单核苷酸多态性可以预测疗效。现综述DNA修复基因单核苷酸多态性预测铂类药物敏感性和预后的研究进展。     

DNA修复基因预测非小细胞肺癌化疗敏感性研究进展

人类细胞具有一系列DNA修复系统，以防御体内和体外因素引起的不同类型的DNA损伤，保持基因组的完整性。研究表明DNA修复能力低可能与个体肿瘤易感性密切相关，然而在肿瘤的治疗过程中，DNA损伤修复能力的增加却阻碍了疗效的发挥。肿瘤细胞DNA修复能力与化疗敏感性密切相关。近来许多研究表明，DNA修复基因单核苷酸多态性（single nueleotide polymorphism，SNP）、甲基化状态以及基因的过表达均可改变DNA修复的能力，因此检测DNA修复基因的分子状态可以预测个体肿瘤化疗的敏感性。     

DNA修复基因多态性与肺癌顺铂化疗敏感性的研究

目的:研究切除修复交叉互补基因1(excision repair cross-complementing gene 1,ERCC1)Asn118Asn、切除修复交叉互补基因2(excision repair cross-complementing gene 2,ERCC2)Lys751Gln和X线修复交叉互补基因1(X-ray repair cross complementing group 1,XRCC1)Arg399Gln单核苷酸多态性与非小细胞肺癌(non-small cell lung cancer,NSCLC)对铂类药物化疗敏感性的相关性。方法:采用基因测序的方法,检测89例以铂类药物为主要化疗方案的NSCLC患者外周血DNA中ERCC1基因Asn118Asn、ERCC2基因Lys751Gln和XRCC1基因Arg399Gln的基因型;采用统计学方法分析不同基因型与化疗疗效的相关性。结果:89例NSCLC患者采用铂类药物化疗总有效率为29.2%;ERCC1基因Asn118Asn和ERCC2基因Lys751Gln基因型在化疗有效组和无效组之间的分布,差异无统计学意义(P>0.05);而携带XRCC1基因Arg399Arg与携带至少1个Gln等位基因(Arg399Gln和Gln399Gln)基因型患者的有效率分别为76.9%和23.1%(χ2=11.1,P=0.001)。携带XRCC1基因Arg399Arg基因型患者对化疗的敏感性明显高于携带至少1个Gln等位基因型的患者(比值比为5.228,95%可信区间为1.776～15.387,P=0.003)。ERCC1、ERCC2和XRCC1基因型的联合可以提高化疗的有效率。结论:ERCC1、ERCC2和XRCC1基因的单核苷酸多态性的联合可能与NSCLC对铂类药物化疗敏感性具有相关性。     

DNA修复基因单核苷酸多态性与铂类药物抵抗研究进展

目前,肿瘤的标准化疗仍然是以解剖部位为基础选择化疗药物,但由于肿瘤本身以及患者个体之间异质性的存在,同一部位的肿瘤对标准化疗的敏感性及化疗产生的毒副反应差异很大。以肿瘤自身药物敏感性为指导开展个体化的药物治疗成为多年来临床研究的热点。随着人类基因组计划的完成,恶性肿瘤的分子亚分类成为可能,以药物敏感相关基因为检测目标的药物基因组学、药物遗传学获得快速发展,使个体化的药物治疗成为可能。     

XRCC1基因多态性与放射性损伤

X线修复交叉互补基因1(XRCC1)是一种重要的DNA修复基因,该基因的多态性会导致其编码蛋白相应的氨基酸改变,影响DNA修复,进而造成肿瘤患者的放射性损伤.目前研究发现,XRCC1单核苷酸多态性与肿瘤患者放射性损伤相关,但其相关性需进一步深入研究.     

DNA修复基因预测非小细胞肺癌放化疗敏感性

化学药物和辐射所诱导的DNA损伤修复通路在肿瘤治疗疗效反应上扮演了重要的角色。肿瘤细胞DNA修复能力增强是肿瘤耐受放化疗的主要机制。DNA修复过程涉及许多基因，这些基因在遗传学及表遗传学上的改变可影响DNA修复的能力，因此通过检测这些基因的单核苷酸多态性、甲基化状态以及基因的过表达来预测疗效。现综述近年来碱基切除修复基因、核苷酸剪切修复基因及双链断裂修复基因预测非小细胞肺癌放化疗疗效的研究进展。     

DNA修复基因单核苷酸多态性与肺癌易感性关系的研究进展

肺癌是人类最常见的恶性肿瘤，在工业化国家和我国许多城市(如上海、北京)已位居全部恶性肿瘤死因的首位。我国多数地区的肺癌发病率和死亡率在过去的20-30年间迅速增长，并继续保持这一增长趋势，成为严重危害我国人民身体健康的主要疾病之一。肺癌的发病机制尚未完全阐明，但许多研究证明其形成是一个多因素、多阶段的过程，是由于环境危险因素和个体遗传因素复杂交互作用的结果。     

非小细胞肺癌NP方案化疗敏感性与DNA修复基因XRCC1多态性的关系

背景与目的:基因多态预测肿瘤化疗药物敏感性对肿瘤个体化治疗具有重要意义。本研究旨在探讨DNA修复基因XRCC1 codon194及399位点基因多态性与非小细胞肺癌长春瑞滨加顺铂(vinorelbine and cisplatin,NVB and DDP,NP)方案化疗敏感性的关系。方法:采用聚合酶链反应-限制性片段长度多态性技术检测164例非小细胞肺癌患者外周血DNAXRCC1194和399位点的多态性。选择NP方案化疗,化疗两周期后评价疗效,并分析化疗敏感性与基因多态性的关系。结果:携带XRCC1基因Codon194C/T+T/T基因型者化疗有效率(41.8%)是C/C基因型者(26.0%)的2.038倍(P=0.036,95%CI=1.044-3.976)。携带XRCC1基因Codon399G/G、A/G、A/A型的患者化疗有效率(37.1%,34.6%,14.3%)之间的差异无统计学意义(P>0.05)。应用分析软件SHEsis发现以     

应用DNA损伤与修复测定法研究肿瘤细胞的放射敏感性

 应用硷洗脱法研究了⁶⁰Cor射线及其联合高温对L(5178Y)细胞的DNA链断裂与修复的影响。 结果表明, 43℃加温30min能显著抑制r射线引起DNA断裂后的修复, 照前加温的增敏效果更好。 又应用羟基磷灰石层析法分析HL-60细胞和HL-60(VCR)细胞受照后两者DNA单链断裂程度无显著差异, 而DNA断链的修复能力有非常显著差异, 反映HL-60(VCR)细胞的重接修复能力高, 提示耐药的白血病细胞对辐射的敏感性较低。     

基因多态性预测结直肠癌化疗效果和不良反应

肿瘤患者个体之间存在化疗效果和不良反应的差异,如果仅仅根据个体的临床特征和病理特征指导治疗,已无法满足优化肿瘤治疗的要求.根据个体基因特征进行个体化治疗正日益受到关注.基因多态性是导致个体之间化疗反应差异的重要物质基础.基因多态性可以通过影响其相应蛋白的表达或活性,降低化疗药物的疗效或加重不良反应.近年来,在结直肠癌化疗方面的研究发现,参与药物代谢、转运和失活的多种蛋白,其相应基因的多态性位点可能会影响化疗效果和不良反应.因此,明确这些基因多态性位点对于实现肿瘤的个体化治疗具有重要意义.     

DNA损伤修复调控因子与肿瘤耐药的研究进展

DNA分子是生物细胞中易受辐射损伤的敏感分子,亦称靶分子.多种理化因素如紫外线、电离辐射、化学诱变剂等导致细胞DNA损伤,同时生物体内本身又存在修复体系.肿瘤细胞DNA修复能力与化疗药物敏感性密切相关.本文综述DNA损伤修复机制-碱基切除修复、核苷酸切除修复、错配修复、DNA双链断裂修复等研究进展以及与肿瘤耐药之间的联系.     

The association of genetic variations in DNA repair pathways with severe toxicities in NSCLC patients undergoing platinum‐based chemotherapy

Genetic variations in genes involved in repairing platinum‐induced DNA lesions may contribute to the toxicity of platinum‐based chemotherapy. The role of single‐nucleotide polymorphisms (SNPs) within DNA repair pathways in the occurrence of severe toxicity is not yet understood. Current studies prefer to do original works rather than analyze previously published data. Our study aimed to replicate associations between previously investigated SNPs and toxicities and to identify new genetic makers. We systematically examined the relevance of 97 SNPs in 54 candidate genes responsible for repairing DNA interstrand and intrastrand cross‐links to severe toxicity in a discovery cohort of 437 NSCLC patients receiving platinum‐based chemotherapy. Statistically significant SNPs were then assessed for replication in an independent validation cohort of 781 NSCLC patients. We found that 7 SNPs were significant at p < 0.01 (RRM1 rs12806698, XPC rs2228000, XPF rs1799801, hMLH1 rs1800734, PMS2 rs1062372, REV3L rs462779 and FANCC rs4647554) in the discovery cohort. Among them, two SNPs (RRM1 rs12806698 and hMLH1 rs1800734) remained significant after Bonferroni correction. XPC rs2228000 showed a significant relationship with severe gastrointestinal toxicity in the validation cohort. When the two cohorts were combined, XPC rs2228000 presented better tolerance of severe hematologic toxicity, gastrointestinal toxicity and leukopenia (OR = 0.677, 95% CI: 0.510–0.899, p = 0.007; OR = 0.565, 95% CI: 0.368–0.869, p = 0.009; OR = 0.628, 95% CI: 0.439–0.899, p = 0.011, respectively). Our findings can offer comprehensive pharmacogenetic information for platinum‐induced toxicities.     

Polymorphisms in the DNA nucleotide excision repair genes and lung cancer risk in Xuan Wei, China

The lung cancer mortality rate in Xuan Wei County is among the highest in China and has been attributed to exposure to indoor smoky coal emissions that contain very high levels of polycyclic aromatic hydrocarbons (PAHs). Nucleotide excision repair (NER) plays a key role in reversing DNA damage from exposure to environmental carcinogens, such as PAHs, that form bulky DNA adducts. We studied single nucleotide polymorphisms (SNPs) and their corresponding haplotypes in 6 genes (ERCC1, ERCC2/XPD, ERCC4/XPF, ERCC5/XPG, RAD23B and XPC) involved in NER in a population-based case-control study of lung cancer in Xuan Wei. A total of 122 incident primary lung cancer cases and 122 individually matched controls were enrolled. Three linked SNPs in ERCC2 were associated with lung cancer with similar ORs; e.g., persons with the Gln allele at codon 751 had a 60% reduction of lung cancer (OR = 0.40, 95% CI 0.18-0.89). Moreover, one haplotype in ERCC2 was associated with a decreased risk of lung cancer (OR = 0.40, 95% CI 0.19-0.85) compared to the most common haplotype. In addition, subjects with one or 2 copies of the Val allele at codon 249 of RAD23B had a 2-fold increased risk of lung cancer (OR = 1.91, 95% CI 1.12-3.24). In summary, our results suggest that genetic variants in genes involved in the NER pathway may play a role in lung cancer susceptibility in Xuan Wei. However, due to the small sample size, additional studies are needed to evaluate these associations within Xuan Wei and in other populations with substantial environmental exposure to PAHs.     

Enhanced repair of DNA interstrand crosslinking in ovarian cancer cells from patients following treatment with platinum-based chemotherapy

Despite high tumour response rates to platinum-based chemotherapy in ovarian cancer survival is poor due to the emergence of drug resistance. Mechanistic studies in clinical material have been hampered by the unavailability of sensitive methods to detect the critical drug-induced effects in individual cells. A modification of the single cell gel electrophoresis (comet) assay allows the sensitive detection of DNA interstrand crosslinking in both tumour and normal cells derived directly from clinical material. Tumour cells isolated from 50 ovarian cancer patients were treated ex vivo with 100 microM cisplatin for 1 h and crosslink formation and repair (unhooking) measured. No significant difference in the peak level of crosslinking in tumour cells was observed between patients who were either newly diagnosed or previously treated with platinum-based therapy, or between tumour and mesothelial cells from an individual patient. This indicates no difference in cellular mechanisms such as drug transport or detoxification. In contrast, the percentage repair (unhooking) of DNA interstrand crosslinks was much greater in the group of treated patients. At 24 h in the 36 newly diagnosed patient tumour samples, only one gave >50% repair and 23 gave <10% repair; however, 19 out of 22 treated patient samples gave >10% repair and 14 showed >50% repair. The estimated median difference (newly diagnosed minus treated) was -52 (95% CI -67 to -28), and the P-value from a Mann-Whitney test was <0.001. In eight patients, it was possible to obtain tumour samples prior to any chemotherapy, and also on relapse or at interval debulking surgery following platinum-based chemotherapy. In these patients, the mean % repair prior to therapy was 2.85 rising to 71.23 following treatment. These data demonstrate increased repair of DNA interstrand crosslinks in ovarian tumour cells following platinum therapy which may contribute to clinical acquired resistance.     

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。     

XRCC 1多态性与肿瘤化疗敏感性和预后的研究

化疗是恶性肿瘤最重要的治疗手段,对肿瘤化疗耐药机制以及化疗效果预测一直是肿瘤学研究的热点.DNA修复能力是影响化疗疗效的重要因素,修复基因的单核苷酸多态性可改变修复能力,X线修复交叉互补基因1(XRCC1)是参与DNA修复的重要成分,检测XRCC 1基因的单核苷酸多态性可以预测治疗疗效.     

Association between DNA repair gene polymorphisms and risk of glioma: A systematic review and meta-analysis

Background

Association studies of germline DNA repair single nucleotide polymorphisms (SNPs) and glioma risk have yielded inconclusive results. We therefore performed a systematic review and meta-analysis of studies investigating this association.

Methods

We identified 27 eligible studies investigating 105 SNPs in 42 DNA repair genes. Of these, 10 SNPs in 7 genes were analyzed in at least 4 studies and were therefore included in our meta-analysis. The meta-analysis was performed for homozygote comparison, heterozygote comparison, and dominant and recessive models by applying a fixed- or random-effects model. The funnel and forest plots were created using RevMan software.

Results

We found that SNPs rs3212986 (odds ratio [OR] = 1.35 (1.08–1.68), P = .008), rs13181 (OR = 1.18 (1.06–1.31), P = .002), and rs25487 (OR = 1.12 (1.03–1.22), P = .007) in DNA repair genes ERCC1, ERCC2 (XPD), and XRCC1 may increase the risk of glioma, while polymorphisms rs1136410 (OR = 0.78 (0.68–0.89), P = .0004) and rs12917 (OR = 0.84 (0.73–0.96), P = .01) in PARP1(ADPRT) and MGMT are associated with decreased susceptibility to glioma. No evidence of significant associations between ERCC2 rs1799793, OGG1 rs1052133, XRCC1 rs25489, XRCC1 rs1799782, or XRCC3 rs861539 and risk of glioma was observed.

Conclusion

This study provides evidence that DNA repair genes ERCC1, ERCC2, and XRCC1 might be low-penetrance glioma-risk genes, while MGMT and PARP1 polymorphisms may confer protection against glioma.