DNA修复基因多态性与胶质瘤发病相关关系研究
发布时间：2018-09-18 11:36
【摘要】：第一部分 目的：神经系统肿瘤占所有肿瘤类型的2%,据统计全球每年神经系统肿瘤发病率大约为4.2/105-5.4/105,胶质瘤占神经系统肿瘤的80%。目前胶质瘤的发病原因尚不清楚,唯一确定的环境暴露因素只有辐射暴露,同时遗传因素也在胶质瘤的发病中起到了重要的作用。单核苷酸多态性可以影响到基因表达产物发生改变或出现数量的变化,从而使得基因的表达出现不同,出现遗传特征的差异。人体内众多DNA修复基因的单核苷酸多态性就使得相应的修复酶具有多样性,个体间对DNA修复的能力就具有差异。BER和NER是最重要的DNA损伤修复途径,本研究采用PCR-RFLP的方法,检测DNA修复基因中NER途径中ERCC1, ERCC2的三个主要SNP与胶质瘤的发病的相关关系。本研究拟采用病例对照研究,收集集312名由病理确诊的胶质瘤作为病例和312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。 方法：采用Qiagen Blood Kit血基因组DNA试剂盒提取DNA,应用Sequenom MassARRAY(?)技术平台和基质辅助激光解吸电离飞行时间质谱技术(Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry, MALDI-TOF-MS)检测ERCC1Asn118Asn、ERCC2Lys751Gln和ERCC2Asp312Asn基因多态性。并采用条件logistic regression建立胶质瘤危险性与ERCC1Asn118Asn、ERCC2Lys751Gln和ERCC2Asp312Asn基因多态性相关关系。 结果：胶质瘤家族史和电离辐射暴露均能增加患者患胶质瘤的风险。ERCC1Asn118Asn、ERCC2Lys751Gln和ERCC2Asp312Asn在对照组中的基因型频率分布符合Hardy-Weinberg遗传平衡定律。多因素条件Logistic回归分析,与携带ERCC2751AA基因型相比,发现携带ERCC2751CC基因型可以增加患胶质瘤的风险,相应的OR (95%CI)值为2.47(1.46,3.74)。与ERCC2751A等位基因型相比,携带ERCC2751C等位基因可以增加患胶质瘤的风险,相应的OR (95%CI)为1.58(1.29,2.15)。在交互作用的模型当中,ERCC2751AC+CC基因型电离辐射暴露史的交互作用系数为γ=2.15,可见携带ERCC2751AC+CC基因对电离辐射的效应有放大作用,属于正向交互。 结论：ERCC2Lys751Gln基因多态性能够增加患者患胶质瘤的风险,并与电离辐射暴露史有一定交互作用。但未发现ERCC1Asn118Asn和ERCC2Asp312Asn基因多态性与胶质瘤的相关关系。 第二部分 目的：肿瘤的发生被认为是一种多因素、多环节的综合性疾病,不仅涉及到人体本身,人体基因组而且还与外部环境的改变息息相关。X线修复交叉互补基因1(X-ray repair cross-complementing group1, XRCC1)是1990年从转染的中国仓鼠卵巢细胞株CHO突变体的EM9细胞的基因文库中克隆得到筛选得到的。XRCC1基因的前期研究已经证实,XRCC1基因的缺失后会引起细胞对电离辐射、DNA交联剂等物质更加敏感,从而导致各种各样的基因损伤作用。本研究选取了XRCC1基因的三个多态性位点作为研究对象,以患者外周血为目标,提取基因组DNA,采用SNP分型技术进行多态性与胶质瘤相关性分析。 方法：采用Qiagen Blood Kit血基因组DNA试剂盒提取DNA,应用Sequenom MassARRAY(?)技术平台和基质辅助激光解吸电离飞行时间质谱技术(Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry, MALDI-TOF-MS)检测XRCC1Arg194Trp、Arg399G1n和Arg280His基因多态性。并采用条件logistic regression建立胶质瘤危险性与XRCCl Arg194Trp、 Arg399G1n和Arg280His基因多态性相关关系。 结果：XRCC1Arg194Trp、XRCC1Arg399G1n和XRCC1Arg280His在对照组中的基因型频率分布符合Hardy-Weinberg平衡。多因素logistic回归分析结果显示,对于XRCC1Arg194Trp等位基因而言,携带TT基因型可以增加患者患胶质瘤的风险,相应的OR值为1.66,95%的置信区间为1.49-1.89之间。对于XRCC1Arg399G1n基因型,携带AA基因型可以增加患者患胶质瘤的风险,相应的OR值为1.48,95%的置信区间为1.27-1.85之间。在交互作用的模型当中,XRCC1194CT+CC和XRCC1399GA+AA与电离辐射均有交互作用。电离辐射能够增加患胶质瘤的风险和概率,二者具有协同效应。 结论：XRCC1Arg194Trp和XRCC1Arg399G1n基因多态性能够增加患者患胶质瘤的风险,并与电离辐射暴露史有一定交互作用。但未发现XRCC1Arg280His基因多态性与胶质瘤的相关关系。
[Abstract]:Part one
Objective: Nervous system tumors account for 2% of all tumor types. According to statistics, the annual incidence of nervous system tumors is about 4.2/105-5.4/105 in the world, and gliomas account for 80% of all nervous system tumors. Mononucleotide polymorphisms can affect the change of gene expression products or the quantity of gene expression products, thus making the gene expression different and the genetic characteristics different. BER and NER are the most important DNA repair pathways. In this study, three major SNPs of ERCC1 and ERCC2 in the NER pathway of DNA repair genes were detected by PCR-RFLP. A case-control study was conducted to collect 312 pathologically confirmed gliomas. The control group consisted of 312 patients undergoing physical examination in our hospital and matched by sex and age 1:1.
METHODS: DNA was extracted by Qiagen Blood Kit blood genomic DNA kit, and ERCC1Asn118Asn, ERCC2Lys751Gln and ERCC2Asp were detected by Sequenom MassARRAY (?) platform and Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS). The association between the risk of glioma and the polymorphisms of ERCC1Asn118Asn, ERCC2Lys751Gln and ERCC2Asp312Asn was established by conditional logistic regression.
Results: Family history of gliomas and exposure to ionizing radiation increased the risk of gliomas. The genotype frequencies of ERCC1Asn118Asn, ERCC2Lys751Gln and ERCC2Asp312Asn in the control group were in accordance with Hardy-Weinberg's law of genetic balance. Multivariate conditional logistic regression analysis showed that ERCC-2751AA genotype was more likely to be carried than ERCC2751AA genotype. 2751CC genotype increased the risk of glioma with an OR (95% CI) of 2.47 (1.46, 3.74). Compared with ERCC2751A genotype, carrying ERCC2751C allele increased the risk of glioma with an OR (95% CI) of 1.58 (1.29, 2.15). In the interaction model, ERCC2751AC + CC genotype had a history of exposure to ionizing radiation. The interaction coefficient is gamma=2.15, which shows that carrying ERCC2751AC+CC gene amplifies the effect of ionizing radiation and belongs to positive interaction.
Conclusion: ERCC2Lys751Gln gene polymorphism can increase the risk of glioma and interact with the history of ionizing radiation exposure, but there is no correlation between ERCC1Asn118Asn and ERCC2Asp312Asn gene polymorphism and glioma.
The second part
Objective: Tumor genesis is considered to be a multifactorial, multilinking, complex disease involving not only the human body itself, but also the human genome. X-ray repair cross-complementing group 1 (XRCC1) is a Chinese hamster ovarian cell line CHO transfected in 1990. The mutant EM9 cells were cloned and screened. Previous studies of the XRCC1 gene have confirmed that the deletion of the XRCC1 gene will cause cells to be more sensitive to ionizing radiation, DNA crosslinking agents and other substances, resulting in a variety of gene damage. Subjects: Genomic DNA was extracted from peripheral blood of patients and the correlation between polymorphism and glioma was analyzed by SNP typing.
METHODS: DNA was extracted by Qiagen Blood Kit blood genomic DNA kit, and XRCC1Arg194Trp, Arg399G1n and Arg280 substrates were detected by Sequenom Mass ARRAY (?) platform and Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-HisTOF-MS). Conditional logistic regression was used to establish the association between the risk of glioma and the polymorphisms of XRCCl Arg194Trp, Arg399G1n and Arg280His genes.
Results: Genotype frequencies of XRCC1Arg194Trp, XRCC1Arg399G1n and XRCC1Arg280His in the control group were in accordance with Hardy-Weinberg equilibrium. Multivariate logistic regression analysis showed that TT genotype could increase the risk of glioma in patients with XRCC1Arg194Trp allele, and the corresponding OR value was 1.66,95% confidence interval. For the XRCC1Arg399G1n genotype, carrying the AA genotype increased the risk of glioma with an OR of 1.48 and a 95% confidence interval of 1.27-1.85. In the interaction model, both XRCC1194CT + CC and XRCC1399GA + AA interacted with ionizing radiation. Ionizing radiation increased the risk of glioma Risk and probability, the two have synergistic effect.
CONCLUSION: XRCC1Arg194Trp and XRCC1Arg399G1n gene polymorphisms can increase the risk of glioma and interact with the history of ionizing radiation exposure.
【学位授予单位】：南方医科大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R739.41
本文编号：2247784
[Abstract]:Part one
Objective: Nervous system tumors account for 2% of all tumor types. According to statistics, the annual incidence of nervous system tumors is about 4.2/105-5.4/105 in the world, and gliomas account for 80% of all nervous system tumors. Mononucleotide polymorphisms can affect the change of gene expression products or the quantity of gene expression products, thus making the gene expression different and the genetic characteristics different. BER and NER are the most important DNA repair pathways. In this study, three major SNPs of ERCC1 and ERCC2 in the NER pathway of DNA repair genes were detected by PCR-RFLP. A case-control study was conducted to collect 312 pathologically confirmed gliomas. The control group consisted of 312 patients undergoing physical examination in our hospital and matched by sex and age 1:1.
METHODS: DNA was extracted by Qiagen Blood Kit blood genomic DNA kit, and ERCC1Asn118Asn, ERCC2Lys751Gln and ERCC2Asp were detected by Sequenom MassARRAY (?) platform and Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS). The association between the risk of glioma and the polymorphisms of ERCC1Asn118Asn, ERCC2Lys751Gln and ERCC2Asp312Asn was established by conditional logistic regression.
Results: Family history of gliomas and exposure to ionizing radiation increased the risk of gliomas. The genotype frequencies of ERCC1Asn118Asn, ERCC2Lys751Gln and ERCC2Asp312Asn in the control group were in accordance with Hardy-Weinberg's law of genetic balance. Multivariate conditional logistic regression analysis showed that ERCC-2751AA genotype was more likely to be carried than ERCC2751AA genotype. 2751CC genotype increased the risk of glioma with an OR (95% CI) of 2.47 (1.46, 3.74). Compared with ERCC2751A genotype, carrying ERCC2751C allele increased the risk of glioma with an OR (95% CI) of 1.58 (1.29, 2.15). In the interaction model, ERCC2751AC + CC genotype had a history of exposure to ionizing radiation. The interaction coefficient is gamma=2.15, which shows that carrying ERCC2751AC+CC gene amplifies the effect of ionizing radiation and belongs to positive interaction.
Conclusion: ERCC2Lys751Gln gene polymorphism can increase the risk of glioma and interact with the history of ionizing radiation exposure, but there is no correlation between ERCC1Asn118Asn and ERCC2Asp312Asn gene polymorphism and glioma.
The second part
Objective: Tumor genesis is considered to be a multifactorial, multilinking, complex disease involving not only the human body itself, but also the human genome. X-ray repair cross-complementing group 1 (XRCC1) is a Chinese hamster ovarian cell line CHO transfected in 1990. The mutant EM9 cells were cloned and screened. Previous studies of the XRCC1 gene have confirmed that the deletion of the XRCC1 gene will cause cells to be more sensitive to ionizing radiation, DNA crosslinking agents and other substances, resulting in a variety of gene damage. Subjects: Genomic DNA was extracted from peripheral blood of patients and the correlation between polymorphism and glioma was analyzed by SNP typing.
METHODS: DNA was extracted by Qiagen Blood Kit blood genomic DNA kit, and XRCC1Arg194Trp, Arg399G1n and Arg280 substrates were detected by Sequenom Mass ARRAY (?) platform and Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-HisTOF-MS). Conditional logistic regression was used to establish the association between the risk of glioma and the polymorphisms of XRCCl Arg194Trp, Arg399G1n and Arg280His genes.
Results: Genotype frequencies of XRCC1Arg194Trp, XRCC1Arg399G1n and XRCC1Arg280His in the control group were in accordance with Hardy-Weinberg equilibrium. Multivariate logistic regression analysis showed that TT genotype could increase the risk of glioma in patients with XRCC1Arg194Trp allele, and the corresponding OR value was 1.66,95% confidence interval. For the XRCC1Arg399G1n genotype, carrying the AA genotype increased the risk of glioma with an OR of 1.48 and a 95% confidence interval of 1.27-1.85. In the interaction model, both XRCC1194CT + CC and XRCC1399GA + AA interacted with ionizing radiation. Ionizing radiation increased the risk of glioma Risk and probability, the two have synergistic effect.
CONCLUSION: XRCC1Arg194Trp and XRCC1Arg399G1n gene polymorphisms can increase the risk of glioma and interact with the history of ionizing radiation exposure.
【学位授予单位】：南方医科大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R739.41
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