NQO1基因多态性与子宫内膜癌发病风险的关联研究
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摘要
目的:醌氧化还原酶1(NQO1)是真核细胞内普遍存在的一类黄素蛋白酶,定位于人类染色体16p22。该酶催化醌双电子还原反应,对醌及其衍生物有解毒作用,能够解除醌类物质对细胞的毒害,从而起到保护细胞的作用,是人体内一种重要的化学致癌物代谢酶。NQO1第六位外显子(C609T),第四位外显子(C465T)为非同义编码单核苷酸多态(ns-cSNP),可引起蛋白质编码氨基酸序列改变从而导致蛋白质功能的改变,进而影响肿瘤的发生发展。因此,雌激素代谢过程中NQO1酶的活性可能与子宫内膜癌发生有密切关系。本研究旨在探讨NQO1单核苷酸多态性与中国北方妇女子宫内膜癌发病风险的关系。
方法:本研究采用病例-对照研究方法,209例病例来源于河北医科大学第四医院妇产科住院手术治疗的子宫内膜癌患者,所有病例均经病理学确诊。209例健康对照来自同期在同一医院进行健康体检的无关个体。均采集外周静脉血5ml,采用蛋白酶K消化-饱和氯化钠盐析法提取外周血白细胞DNA。采用蛋白酶K消化-饱和氯化钠盐析法提取外周血白细胞DNA,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)分析方法检测NQO1 C609T、C465T基因多态位点的基因型频率分布。
数据统计分析采用SPSS11.5版软件包(SPSS Company,Chicago,Illinois,USA)进行,P<0.05认为有统计学意义。对照组基因型频率进行Hardy-Weinberg平衡分析。病例组与对照组的基因型、等位基因型分布比较均采用行×列表卡方检验。以非条件Logistic回归法计算相对风险度的比值比(odds ratio,OR)及其95%可信区间(confidence interval,CI)。
结果:
1.初潮年龄及是否绝经与子宫内膜癌发病风险的关联分析
1.1初潮年龄在病例组和对照组的平均值分别为15.48、15.03岁,病例组初潮年龄≥15岁比例(47.4%)明显高于对照组(36.8%)。经统计分析发现,初潮年龄≥15岁的个体其子宫内膜癌的患病风险是初潮年龄<15岁个体的1.543倍,说明初潮年龄晚可能是子宫内膜癌的易感因素。
1.2根据是否绝经将病例组和对照组分为已绝经组和未绝经组,病例组所占频率分别为67.9%和32.1%,对照组为61.7%和38.3%。两组比较结果无显著性差异(P>0.05)。
2. NQO1 C609T与子宫内膜癌的关系
2.1统计学处理显示对照组的基因型频率分布均符合Hardy-Weinberg平衡(X2=0.445,P=0.505)。NQO1 C609T SNP的3种基因型频率(野生型C/C、杂交型C/T、突变型T/T)在病例组和对照组中分别是15.8%、65.1%、19.1%和29.7%、51.7%、18.7%,两组比较有显著性差异(X2=12,078,P=0,002)(Table 3)。病例组的T等位基因频率(51.7%)明显高于对照组(44.5%),两组比较有统计学意义(X2=4.313,P=0.038)。与C/C基因型比较,携带C/T+T/T基因型显著增加子宫内膜癌的发病风险(OR=2.249,95% CI=1.398-3.620)。
2.2根据初潮年龄进行分层分析,发现NQO1 C609T多态基因型在初潮年龄<15岁的病例组中的分布与对照组相比具有统计学意义(P<0.05),而初潮年龄≥15岁无统计学意义。C/C, T/T和C/T基因型在初潮年龄<15岁病例组中的分布与对照组相比,差异有统计学意义(P=0.001,OR=3.089,95%CI=1.579~6.044)。结果表明与C/C基因型相比,携带T/T和C/T基因增加初潮年龄<15岁个体患子宫内膜癌的发病风险。
2.3根据是否绝经进行分层分析,发现NQO1 C609T多态基因型在未绝经病例组的分布与对照组相比均有统计学意义(P<0.05)而在已绝经组无统计学意义。与C/C基因型比较,携带T/T和C/T的基因型在未绝经病例组的分布与对照组相比,病例组中基因型频率明显高于对照组,两组比较有统计学意义(P=0.007,OR=3.757,95%CI=1.571~8.984)。结果表明与C/C基因型相比,携带T/T和C/T基因增加未绝经个体患子宫内膜癌的发病风险。
3. NQO1 C465T SNPs与子宫内膜癌的关系
3.1统计学处理显示对照组NQO1 C465T SNPs的基因型频率分布均符合Hardy-Weinberg平衡(X2=0.14,P=0.71)。NQO1 C465T SNP的3种基因型频率(野生型C/C、杂交型C/T、突变型T/T )在病例组和对照组中分别是49.3%、46.9%、3.8%和55.5%、37.3%、7.2%,两组比较无显著性差异(X 2=1.661,P=0.436)。与C/C基因型比较,携带C/T+T/T基因型尚不能增加子宫内膜癌的发病风险(OR=1.284 , 95% CI=0.874-1.866)。
3.2根据初潮年龄进行分层分析,发现NQO1 C465T多态基因型在初潮年龄<15岁和初潮年龄≥15岁的病例组与对照组相比均无统计学意义(P>0.05)。与C/C比较,T/T和C/T基因型在初潮年龄<15岁和初潮年龄≥15岁的病例组与对照组中,两组比较均无统计学意义。
3.3根据是否绝经进行分层分析,发现NQO1 C465T多态基因型在未绝经和已绝经的病例组的分布与对照组相比均无统计学意义(P>0.05)。与C/C基因型比较,T/T和C/T基因型在初潮年龄<15岁和初潮年龄≥15岁的病例组与对照组中,两组比较均无统计学意义。
4. NQO1 C609T与NQO1 C465T连锁不平衡分析
采用2LD软件分析发现NQO1 C609T和NQO1 C465T SNPs间不存在连锁不平衡关系(D’=0.117157)。
结论:
1初潮年龄≥15岁的个体其子宫内膜癌的患病风险是初潮年龄<15岁个体的1.543倍,表明初潮年龄晚可能是子宫内膜癌的易感因素之一。
2 NQO1C609T多态性中,C/T、T/T、C/T+T/T基因型均显著增加子宫内膜癌的发病风险。根据是否绝经和初潮年龄分层分析发现,携带C/T、T/T基因型可增加未绝经和初潮年龄早的个体子宫内膜癌的患病风险。
3 NQO1C465T基因多态中突变的基因型及等位基因型与子宫内膜癌的发病风险无相关性。根据是否绝经和初潮年龄分层分析也未发现明显关联。
4 NQO1C465T和NQO1C609T基因多态性之间联合突变在子宫内膜癌发病风险中不具有协同作用。
Objective: Quinone oxidoreductase 1 (NQO1) is a kind of flavoprotein enzyme existing in the eukaryotic cell, which locate at the humankind chromosome 16p22. It is an important chemical carcinogen metabolic enzyme, which catalyzes quinone-electron reduction reaction and protects the cells from toxic effect of quinone and it’s derivate, by reducing their effects. Exons(C609T)and(C465T)are non-synonymous coding mononucleotide polymorphism, which may cause the change of protein coding amino acid sequence and the change of the protein function, then influence the occurrence and development of tumor. Therefore, the activity of NQO1 enzyme may have a close relationship with the occurrence of endometrial cancer in the process of estrogen metabolism. The research is to explore the relationship of NQO1 mononucleotide polymorphism with the risk of endometrial cancer in northern chinese women.
Methods: The population-based case-control study included 209 endometrial cancer patients, who were done operations in the fourth hospital of Hebei Medical University, and were proven by pathology. And 209 healthy controls were from the same hospital for physical examination. Genomic DNA was extracted by using proteinase K digestion followed by a salting out procedure. Polymorphisms of NQO1 C609 T, C465T gene were analyzed by PCR-restriction fragment length polymorphism (RFLP) analysis.
Statistical analysis was performed using SPSS11.5 software package. P<0.05 was considered significant. Hardy-Weinberg analysis was performed by comparing the observed and expected genotype frequencies in the control group using Chi-square test. Comparison of the C609T and C465T genotypes and allelotypes distributions in cancer patients and healthy controls were performed by means of two-sided contingency tables using Chi-square test. The odds ratio (OR) and 95% confidence interval (CI) were calculated using an unconditional logistic regression model.
Results:
1 The correlation of menarche age and menopause with the risk of endometrial cancer
1.1 The menarche age is 15. 48 years old in case, and 15.03 in control group. The percentage of women whose menarche age were older than 15 in case, was obviously greater than that in control. By statistical analysis, the individuals with menarche age≥15 had 1.543 times risk to get endometrial cancer than those under 15, indicating the older menarche age is one of the predisposing factor of endometrial cancer.
1.2 According to menopause condition, the case group and control group were divided into pre-menopause and post-menopause group. The percentage of two groups were 32.1% and 67.9% in case, 38.3% and 61.7% in control. The difference was not significant between case and control groups (P>0.05).
2 Gene NQO1 C609T polymorphism with the risk of endometrial cancer
2.1 The distributions of NQO1 C609T genotypes among healthy controls did not significantly deviate from that expected by Hardy-Weinberg equilibrium (X2= 0.445, P= 0.505). The frequency of wild genotype (C/C), heterozygous genotype (C/T), and homozygous genotype (T/T) were 15.8%, 65.1%, 19.1% in case, 29.7%, 51.7%, 18.7% in control. The frequency of the T allele in patients (51.7%) was significantly higher than that in the controls (44.5%) (X2=4.313, P=0.038). Compared with C/C the genotype, merging T/T and C/T genotype, significantly increased the risk of endometrial cancer ( OR= 2.249).
2.2 According to menarche age, there was significant difference between the distribution of NQO1 C609T gene polymorphism in case group and that in control group while menarch age <15 (P<0.05). But there was no significant difference while menarche age≥15. The genotype distribution of C/C, C/T and T/T in case group was significantly different from that in control group while menarch age <15 (P=0.001, OR=3.089, 95%CI =1.579~6.044). Contrast with C/C genotype, merging T/T and C/T genotypes, the risk of developing endometrial cancer was increased while menarch age <15 (P=0.001, OR=3.089, 95%CI=1.579~6.044).
2.3 According to whether or not menopause, the gene polymorphisms of NQO1 C609T were different between the case and control group while premenopause (P<0.05), but no difference while post-menopause (P>0.05). Contrast with C/C the genotype, merging T/T and C/T genotypes, the risk of developing endometrial cancer was increased while premenopause (P=0.007, OR=3.757, 95%CI=1.571~8.984).
3 Gene NQO1 C465T polymorphism with the risk of endometrial cancer
3.1 The distributions of NQO1 C465T genotypes among healthy controls did not significantly deviate from that expected by Hardy-Weinberg equilibrium (X2=0.14,P=0.71). The frequency of C/C, C/T and T/T genotypes were 49.3%、46.9%、3.8% in case and 55.5%、37.3%、7.2% in control. The frequency of the T allele in patients (27.3%) was not significantly different from that in the controls (25.8%) (X2=4.313, P=0.038). No significant difference was found either when the distribution of C/C genotype was compared with the T/T+C/T genotypes (P=0.436, OR= 1.284, 95% CI =0.874-1.866).
3.2 According to menarche age, there was no significant difference between the case and control group while menarche age <15 (P>0.05), and either while menarche age≥15. No significant difference was found either when the distribution of C/C genotype was compared with the T/T+C/T genotype (P=0.436, OR= 1.284, 95% CI=0.874-1.866).
3.3 According to whether or not menopause, the polymorphisms of NQO1 C465T were not different between the case and control group while premenopause (P>0.05), and while post-menopause either (P>0.05). No significant difference was found either when the distribution of C/C genotype was compared with the T/T+C/T genotypes (P=0.436, OR=1.284, 95% CI=0.874-1.866).
4. Linkage disequilibrium analysis of NQO1 C609T and NQO1 C465T
There was no unification in genetic polymorphism of NQO1 C609T and NQO1 C465T on the risk of endometrial cancer by 2LD software.
Conclusions:
1 The individual with menarche age≥15 has 1.543 times of risk to get endometrial cancer, indicating the older menarche age is one of the predisposing factors in endometrial cancer.
2 Among the NQO1 C609T gene polymorphism, the C/C and T/T genotypes increase the risk of endometrial cancer. Stratified by menarch age and menopause condition, the individual with C/C or T/T genotypes is susceptible to the endometrial cancer while premenopause or early menarche age.
3 The NQO1 C465T polymorphism has no association with the risk of endometrial cancer. According to menarche age and menopause condition, there were no relationships with the endometrial cancer as well.
4 There was no unification between NQO1 C609T gene polymorphism and NQO1 C465T on the risk of endometrial cancer.
方法:本研究采用病例-对照研究方法,209例病例来源于河北医科大学第四医院妇产科住院手术治疗的子宫内膜癌患者,所有病例均经病理学确诊。209例健康对照来自同期在同一医院进行健康体检的无关个体。均采集外周静脉血5ml,采用蛋白酶K消化-饱和氯化钠盐析法提取外周血白细胞DNA。采用蛋白酶K消化-饱和氯化钠盐析法提取外周血白细胞DNA,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)分析方法检测NQO1 C609T、C465T基因多态位点的基因型频率分布。
数据统计分析采用SPSS11.5版软件包(SPSS Company,Chicago,Illinois,USA)进行,P<0.05认为有统计学意义。对照组基因型频率进行Hardy-Weinberg平衡分析。病例组与对照组的基因型、等位基因型分布比较均采用行×列表卡方检验。以非条件Logistic回归法计算相对风险度的比值比(odds ratio,OR)及其95%可信区间(confidence interval,CI)。
结果:
1.初潮年龄及是否绝经与子宫内膜癌发病风险的关联分析
1.1初潮年龄在病例组和对照组的平均值分别为15.48、15.03岁,病例组初潮年龄≥15岁比例(47.4%)明显高于对照组(36.8%)。经统计分析发现,初潮年龄≥15岁的个体其子宫内膜癌的患病风险是初潮年龄<15岁个体的1.543倍,说明初潮年龄晚可能是子宫内膜癌的易感因素。
1.2根据是否绝经将病例组和对照组分为已绝经组和未绝经组,病例组所占频率分别为67.9%和32.1%,对照组为61.7%和38.3%。两组比较结果无显著性差异(P>0.05)。
2. NQO1 C609T与子宫内膜癌的关系
2.1统计学处理显示对照组的基因型频率分布均符合Hardy-Weinberg平衡(X2=0.445,P=0.505)。NQO1 C609T SNP的3种基因型频率(野生型C/C、杂交型C/T、突变型T/T)在病例组和对照组中分别是15.8%、65.1%、19.1%和29.7%、51.7%、18.7%,两组比较有显著性差异(X2=12,078,P=0,002)(Table 3)。病例组的T等位基因频率(51.7%)明显高于对照组(44.5%),两组比较有统计学意义(X2=4.313,P=0.038)。与C/C基因型比较,携带C/T+T/T基因型显著增加子宫内膜癌的发病风险(OR=2.249,95% CI=1.398-3.620)。
2.2根据初潮年龄进行分层分析,发现NQO1 C609T多态基因型在初潮年龄<15岁的病例组中的分布与对照组相比具有统计学意义(P<0.05),而初潮年龄≥15岁无统计学意义。C/C, T/T和C/T基因型在初潮年龄<15岁病例组中的分布与对照组相比,差异有统计学意义(P=0.001,OR=3.089,95%CI=1.579~6.044)。结果表明与C/C基因型相比,携带T/T和C/T基因增加初潮年龄<15岁个体患子宫内膜癌的发病风险。
2.3根据是否绝经进行分层分析,发现NQO1 C609T多态基因型在未绝经病例组的分布与对照组相比均有统计学意义(P<0.05)而在已绝经组无统计学意义。与C/C基因型比较,携带T/T和C/T的基因型在未绝经病例组的分布与对照组相比,病例组中基因型频率明显高于对照组,两组比较有统计学意义(P=0.007,OR=3.757,95%CI=1.571~8.984)。结果表明与C/C基因型相比,携带T/T和C/T基因增加未绝经个体患子宫内膜癌的发病风险。
3. NQO1 C465T SNPs与子宫内膜癌的关系
3.1统计学处理显示对照组NQO1 C465T SNPs的基因型频率分布均符合Hardy-Weinberg平衡(X2=0.14,P=0.71)。NQO1 C465T SNP的3种基因型频率(野生型C/C、杂交型C/T、突变型T/T )在病例组和对照组中分别是49.3%、46.9%、3.8%和55.5%、37.3%、7.2%,两组比较无显著性差异(X 2=1.661,P=0.436)。与C/C基因型比较,携带C/T+T/T基因型尚不能增加子宫内膜癌的发病风险(OR=1.284 , 95% CI=0.874-1.866)。
3.2根据初潮年龄进行分层分析,发现NQO1 C465T多态基因型在初潮年龄<15岁和初潮年龄≥15岁的病例组与对照组相比均无统计学意义(P>0.05)。与C/C比较,T/T和C/T基因型在初潮年龄<15岁和初潮年龄≥15岁的病例组与对照组中,两组比较均无统计学意义。
3.3根据是否绝经进行分层分析,发现NQO1 C465T多态基因型在未绝经和已绝经的病例组的分布与对照组相比均无统计学意义(P>0.05)。与C/C基因型比较,T/T和C/T基因型在初潮年龄<15岁和初潮年龄≥15岁的病例组与对照组中,两组比较均无统计学意义。
4. NQO1 C609T与NQO1 C465T连锁不平衡分析
采用2LD软件分析发现NQO1 C609T和NQO1 C465T SNPs间不存在连锁不平衡关系(D’=0.117157)。
结论:
1初潮年龄≥15岁的个体其子宫内膜癌的患病风险是初潮年龄<15岁个体的1.543倍,表明初潮年龄晚可能是子宫内膜癌的易感因素之一。
2 NQO1C609T多态性中,C/T、T/T、C/T+T/T基因型均显著增加子宫内膜癌的发病风险。根据是否绝经和初潮年龄分层分析发现,携带C/T、T/T基因型可增加未绝经和初潮年龄早的个体子宫内膜癌的患病风险。
3 NQO1C465T基因多态中突变的基因型及等位基因型与子宫内膜癌的发病风险无相关性。根据是否绝经和初潮年龄分层分析也未发现明显关联。
4 NQO1C465T和NQO1C609T基因多态性之间联合突变在子宫内膜癌发病风险中不具有协同作用。
Objective: Quinone oxidoreductase 1 (NQO1) is a kind of flavoprotein enzyme existing in the eukaryotic cell, which locate at the humankind chromosome 16p22. It is an important chemical carcinogen metabolic enzyme, which catalyzes quinone-electron reduction reaction and protects the cells from toxic effect of quinone and it’s derivate, by reducing their effects. Exons(C609T)and(C465T)are non-synonymous coding mononucleotide polymorphism, which may cause the change of protein coding amino acid sequence and the change of the protein function, then influence the occurrence and development of tumor. Therefore, the activity of NQO1 enzyme may have a close relationship with the occurrence of endometrial cancer in the process of estrogen metabolism. The research is to explore the relationship of NQO1 mononucleotide polymorphism with the risk of endometrial cancer in northern chinese women.
Methods: The population-based case-control study included 209 endometrial cancer patients, who were done operations in the fourth hospital of Hebei Medical University, and were proven by pathology. And 209 healthy controls were from the same hospital for physical examination. Genomic DNA was extracted by using proteinase K digestion followed by a salting out procedure. Polymorphisms of NQO1 C609 T, C465T gene were analyzed by PCR-restriction fragment length polymorphism (RFLP) analysis.
Statistical analysis was performed using SPSS11.5 software package. P<0.05 was considered significant. Hardy-Weinberg analysis was performed by comparing the observed and expected genotype frequencies in the control group using Chi-square test. Comparison of the C609T and C465T genotypes and allelotypes distributions in cancer patients and healthy controls were performed by means of two-sided contingency tables using Chi-square test. The odds ratio (OR) and 95% confidence interval (CI) were calculated using an unconditional logistic regression model.
Results:
1 The correlation of menarche age and menopause with the risk of endometrial cancer
1.1 The menarche age is 15. 48 years old in case, and 15.03 in control group. The percentage of women whose menarche age were older than 15 in case, was obviously greater than that in control. By statistical analysis, the individuals with menarche age≥15 had 1.543 times risk to get endometrial cancer than those under 15, indicating the older menarche age is one of the predisposing factor of endometrial cancer.
1.2 According to menopause condition, the case group and control group were divided into pre-menopause and post-menopause group. The percentage of two groups were 32.1% and 67.9% in case, 38.3% and 61.7% in control. The difference was not significant between case and control groups (P>0.05).
2 Gene NQO1 C609T polymorphism with the risk of endometrial cancer
2.1 The distributions of NQO1 C609T genotypes among healthy controls did not significantly deviate from that expected by Hardy-Weinberg equilibrium (X2= 0.445, P= 0.505). The frequency of wild genotype (C/C), heterozygous genotype (C/T), and homozygous genotype (T/T) were 15.8%, 65.1%, 19.1% in case, 29.7%, 51.7%, 18.7% in control. The frequency of the T allele in patients (51.7%) was significantly higher than that in the controls (44.5%) (X2=4.313, P=0.038). Compared with C/C the genotype, merging T/T and C/T genotype, significantly increased the risk of endometrial cancer ( OR= 2.249).
2.2 According to menarche age, there was significant difference between the distribution of NQO1 C609T gene polymorphism in case group and that in control group while menarch age <15 (P<0.05). But there was no significant difference while menarche age≥15. The genotype distribution of C/C, C/T and T/T in case group was significantly different from that in control group while menarch age <15 (P=0.001, OR=3.089, 95%CI =1.579~6.044). Contrast with C/C genotype, merging T/T and C/T genotypes, the risk of developing endometrial cancer was increased while menarch age <15 (P=0.001, OR=3.089, 95%CI=1.579~6.044).
2.3 According to whether or not menopause, the gene polymorphisms of NQO1 C609T were different between the case and control group while premenopause (P<0.05), but no difference while post-menopause (P>0.05). Contrast with C/C the genotype, merging T/T and C/T genotypes, the risk of developing endometrial cancer was increased while premenopause (P=0.007, OR=3.757, 95%CI=1.571~8.984).
3 Gene NQO1 C465T polymorphism with the risk of endometrial cancer
3.1 The distributions of NQO1 C465T genotypes among healthy controls did not significantly deviate from that expected by Hardy-Weinberg equilibrium (X2=0.14,P=0.71). The frequency of C/C, C/T and T/T genotypes were 49.3%、46.9%、3.8% in case and 55.5%、37.3%、7.2% in control. The frequency of the T allele in patients (27.3%) was not significantly different from that in the controls (25.8%) (X2=4.313, P=0.038). No significant difference was found either when the distribution of C/C genotype was compared with the T/T+C/T genotypes (P=0.436, OR= 1.284, 95% CI =0.874-1.866).
3.2 According to menarche age, there was no significant difference between the case and control group while menarche age <15 (P>0.05), and either while menarche age≥15. No significant difference was found either when the distribution of C/C genotype was compared with the T/T+C/T genotype (P=0.436, OR= 1.284, 95% CI=0.874-1.866).
3.3 According to whether or not menopause, the polymorphisms of NQO1 C465T were not different between the case and control group while premenopause (P>0.05), and while post-menopause either (P>0.05). No significant difference was found either when the distribution of C/C genotype was compared with the T/T+C/T genotypes (P=0.436, OR=1.284, 95% CI=0.874-1.866).
4. Linkage disequilibrium analysis of NQO1 C609T and NQO1 C465T
There was no unification in genetic polymorphism of NQO1 C609T and NQO1 C465T on the risk of endometrial cancer by 2LD software.
Conclusions:
1 The individual with menarche age≥15 has 1.543 times of risk to get endometrial cancer, indicating the older menarche age is one of the predisposing factors in endometrial cancer.
2 Among the NQO1 C609T gene polymorphism, the C/C and T/T genotypes increase the risk of endometrial cancer. Stratified by menarch age and menopause condition, the individual with C/C or T/T genotypes is susceptible to the endometrial cancer while premenopause or early menarche age.
3 The NQO1 C465T polymorphism has no association with the risk of endometrial cancer. According to menarche age and menopause condition, there were no relationships with the endometrial cancer as well.
4 There was no unification between NQO1 C609T gene polymorphism and NQO1 C465T on the risk of endometrial cancer.
引文
1 1代恩勇,卢振霞. NQO1与肿瘤.国外医学遗传学分册, 2003, 26: 141-144
2 Cavaliri E, Rogan E, Chakravarti D. The role of endogenous catechol quinones in the initiation of cancer and neurodegenerative diseases. Methods Enzymol, 2004, 382: 293-319
3 Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acid Res, 1988, 16(3): 1215
4 Legro RS, Kunselman AR, Miler SA, etal. Role of androgens in the growth of endometrial carcinoma: an in vivo animal model. Am J Obstet Gynecol, 2001, 184(3): 303-308
5 Jaiswal AK, McBride OW, Adesnik M, etal. Human dioxin-inducible cytosolic NAD (P) H: menadione oxidoreductase. cDNA sequence and localization of gene to chromosome 16. J Biol Chem, 1988, 263(27): 13572-13578
6 Dinkova-Kostova AT, Talalay P. Persuasive evidence that quinone reductase type 1(DT diaphorase) protects cells against the toxicity of electrophiles and reactive forms of oxygen. Free Radic BioMed, 2000, 29(3-4): 231-240
7代恩勇,卢振霞,史洁坪,等. NQO1基因多态性与大肠癌遗传易感性中国肿瘤临床, 2004, 31: 09-91
8 Traver R D, Horikoshi T, Danenberg KD, etal. NAD (P) H: Quinone oxidoreductase gene expression in human colon carcinoma cells: characterization of mutation which modulates DT-diaphorase activity and mitomycin sensitivity. Cancer Res, 1992, 52(4): 797-802
9 Traver RD, Siegel D, Beall HD, etal. Characterization of a polymorphism in NAD (P) H: quinine oxidoreductase (DT-diaphorase). Br J Cancer, 1997, 75(1): 69-75
10 Nioi P, Hayes JD. Contribution of NAD (P) H: quinine oxidoreductase1 to protection against carcinogenesis, and regulation of its gene by the Nrf-2 basic-region leucine zipper and the arylhydrocarbon receptor basic heplix-loop-helix transcription factors. Mutat Res, 2004, 555: 149-171
11 Basil JB, Mutch DG. Role of hormone replacement therapy in cancer survivors. Clin Obstet Gynecol, 2001, 44(3): 464-77
12 Kuehl BL, Paterson JW, Peacock JW, etal. Presence of a heterozygous substitution and its relationship to DT-diaphorase activity. Br J Cancer, 1995 Sep, 72(3): 555-61
13吴春玲,陈艳,李桂兰,等. NQO1酶与苯中毒及相关疾病遗传易感性的关系.中华劳动卫生职业病杂志, 2003, 21: 137-138
14 Rudant J, Menegaux F, Leverger G, etal. Childhood hematopoietic malignancies and parental use of tobacco and alcohol: the ESCALE study (SFCE). Cancer Causes Control. 2008 Dec; 19(10): 1277-90
15 Lawson KA, Woodson K, Virtamo J, etal. Association of the NAD (P) H: quinine oxidoreductase (NQO1) 609C→T polymorphism with lung cancer risk among male smokers. Cancer Epidemiol biomarkers. Prev, 2005, 14(9): 2275-2276
16 Vander Logt EM, Bergevoet SM, Roelofs HM, etal. Role of epoxide hydrolase, NAD (P) H: quinine oxidoreductase, cytochrome P450 2E1 or alcohol dehydrogenase genetypes in susceptibility to colorectal cancer. Mutat Res, 2006, 593(1-2): 39-49
17 Zhang J, Schulz WA, Li Y, etal. Association of NAD (P) H: quinine oxidoreductase1 (NQO1) C609T polymorphism with esophageal squamous cell carcinomani a German Caucasian and a northern Chinese population. Carcinogenesis, 2003, 24(5): 905-9
18 Smith MT, Wang Y, Kane E, etal. Low NAD (P) H: quinone oxidoreductase 1 activity is associated with increased risk of acute leukemia in adults. Blood, 2001, 97(5): 1422-1426
19 Siegel D, Anwar A, Winski SL, etal. Rapid polyubiquitination and proteasomal degradation of a mutant form of NAD (P) H: quinoneoxidoreductase 1. Mol Pharmacol, 2001, 59(2): 263-8
20 Moran JL, Siegel D, Ross D. A potential mechanism underlying the increased susceptibility of individuals with a polymorphism in NAD (P) H: quinone oxidoreductase 1(NQO1) to benzene toxicity. Proc Natl Acad Sci USA, 1999, 96(14): 8150-8155
21 Hishida A, Terakura S, Emi N, etal. GSTT1 and GSTM1 deletions,NQO1 C609T polymorphism and risk of chronic myelogenous leukemia in Japanese. Asian Pac J Cancer Prev, 2005, 6(3): 251-255
22张战强,杨琳,张悦,杨艺红等. NQO1C609T, RAD51G135C和XRCC3C241T单核苷酸多态性与急性淋巴细胞白血病发病相关性研.中国实验血液学杂志, 2009, 17(3): 523-528
23吴玉霞,高怡瑾,赵金彩,等. GSTM1?GYP2E1和NQO1基因多态性与儿童白血病发病风险的初步研究.中华流行病学杂志, 2004, 25(9): 819
24 24周艳丽,陈华芳,史习舜,等. NQO1基因多态性与食管癌易感性的病例对照研究.中国肿瘤, 2006, 15(10): 659-663
25 Saldivar SJ, Wang Y, Zhao H, etal. An association between a NQO1 genetic polymorphism and risk of lung cancer. Mutation Res, 2005, 582: 71-78
26 Chan EC, Lam SY, Fu KH, etal. Polymorphisms of the GSTM1, GSTP1, MPO, XRCC1, and NQO1 genes in Chinese patients with non-small cell lung cancers: relationship with aberrant promoter methylation of the CDKN2A and RARB genes. Cancer Genetics and Cytogenetics, 2005, 162: 10-20
27 Alexandrie AK, Nyberg F, Warholm M, etal. Influence of CYP1A1, GSTM1, GSTT1, and NQO1 genotypes and cumulative smoking dose on lung cancer risk in a Swedish population. Cancer Epi Bio Prev, 2004, 13(6): 906-914
28 Sorensen M, Autrup H, Tjonneland A, etal. Genetic polymorphisms in CYP1B1, GSTA1, NQO1 and NAT2 and the risk of lung cancer. Cancer Letters, 2005, 221: 185-190
29 Yang M, Choi Y, Hwangbo B, etal. Combined effects of genetic polymorphisms in six selected genes on lung cancer suscep tibility. Lung Cancer, 2007, 57: 135-142
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12 Kuehl BL, Paterson JW, Peacock JW, etal. Presence of a heterozygous ubstitution and its relationship to DT-iaphorase activity. Br Jancer, 1995, 72(3): 555-561
13周艳丽,陈华芳,史习舜,等. NQO1基因多态性与食管癌易感性的病例对照研究.中国肿瘤, 2006, 15(10): 659-663
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16 Rudant J, Menegaux F, Leverger G, etal. Childhood hematopoietic malignancies and parental use of tobacco and alcohol: the ESCALE study (SFCE). Cancer Causes Control. 2008 Dec; 19(10): 1277-90
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32张战强,杨琳,张悦,杨艺红等. NQO1C609T, RAD51G135C和XRCC3C241T单核苷酸多态性与急性淋巴细胞白血病发病相关性研.中国实验血液学杂志, 2009, 17(3): 523-528
33周艳丽,陈华芳,史习舜,等. NQO1基因多态性与食管癌易感性的病例对照研究.中国肿瘤, 2006, 15(10): 659-663
34 Lafuente MJ, Casterad X, Trias M, etal. NAD (P) H: quinone oxidoreductase-dependent risk for colorectal cancer and its association with the presence of K-ras mutations in tumors. Carcinogenesis, 2000, 21(10): 1813-1819
35 Harth V, Donat S, Ko Y, etal. NAD (P) H quinone oxidoreductase1 codon 609 polymorphism and its association to colorectal cancer. Arch Toxicol, 2000, 73(10211): 528-531
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37 Smith MT, Wang Y, Kane E, etal. Low NAD (P) H: quinone oxidoreductase 1 activity is associated with increased risk of acute leukemia in adults. Blood, 2001, 97(5): 1422-1426
38 Larson RA, Wang Y, Banerjee M, etal. Prevalence of the inactivating 609C-->T polymorphism in the NAD (P) H: quinone oxidoreductase (NQO1) gene in patients with primary and therapy-related myeloid leukemia. Blood, 1999, 94(2): 803-807
39 Smart RC, Zannoni VG.. DT-diaphorase and peroxidase influence thecovalent binding of the metabolites of phenol, the major metabolite of benzene. Mol Pharmacol, 1984, 26(1): 105-114
40 David Siegel, John Ryder, David Ross, etal. NAD (P) H: quinone oxidoreductase 1 expression in human bone marrow endothelial cells. Toxicology Letters, 2001, 125(123): 93-98
41 Moran JL, Siegel D, Ross D. A potential mechanism underlying the increased susceptibility of individuals with a polymorphism in NAD (P) H: quinone oxidoreductase 1 (NQO1) to benzene toxicity. P roc Natl A cad Sci U SA, 1999, 96(14): 8150-8155
42 Smith M T. The mechanism of benzene-induced leukemia: a hypothesis and speculations on the causes of leukemia. Environ Health Perspect, 1996, 104 Suppl 6: 1219-1225
2 Cavaliri E, Rogan E, Chakravarti D. The role of endogenous catechol quinones in the initiation of cancer and neurodegenerative diseases. Methods Enzymol, 2004, 382: 293-319
3 Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acid Res, 1988, 16(3): 1215
4 Legro RS, Kunselman AR, Miler SA, etal. Role of androgens in the growth of endometrial carcinoma: an in vivo animal model. Am J Obstet Gynecol, 2001, 184(3): 303-308
5 Jaiswal AK, McBride OW, Adesnik M, etal. Human dioxin-inducible cytosolic NAD (P) H: menadione oxidoreductase. cDNA sequence and localization of gene to chromosome 16. J Biol Chem, 1988, 263(27): 13572-13578
6 Dinkova-Kostova AT, Talalay P. Persuasive evidence that quinone reductase type 1(DT diaphorase) protects cells against the toxicity of electrophiles and reactive forms of oxygen. Free Radic BioMed, 2000, 29(3-4): 231-240
7代恩勇,卢振霞,史洁坪,等. NQO1基因多态性与大肠癌遗传易感性中国肿瘤临床, 2004, 31: 09-91
8 Traver R D, Horikoshi T, Danenberg KD, etal. NAD (P) H: Quinone oxidoreductase gene expression in human colon carcinoma cells: characterization of mutation which modulates DT-diaphorase activity and mitomycin sensitivity. Cancer Res, 1992, 52(4): 797-802
9 Traver RD, Siegel D, Beall HD, etal. Characterization of a polymorphism in NAD (P) H: quinine oxidoreductase (DT-diaphorase). Br J Cancer, 1997, 75(1): 69-75
10 Nioi P, Hayes JD. Contribution of NAD (P) H: quinine oxidoreductase1 to protection against carcinogenesis, and regulation of its gene by the Nrf-2 basic-region leucine zipper and the arylhydrocarbon receptor basic heplix-loop-helix transcription factors. Mutat Res, 2004, 555: 149-171
11 Basil JB, Mutch DG. Role of hormone replacement therapy in cancer survivors. Clin Obstet Gynecol, 2001, 44(3): 464-77
12 Kuehl BL, Paterson JW, Peacock JW, etal. Presence of a heterozygous substitution and its relationship to DT-diaphorase activity. Br J Cancer, 1995 Sep, 72(3): 555-61
13吴春玲,陈艳,李桂兰,等. NQO1酶与苯中毒及相关疾病遗传易感性的关系.中华劳动卫生职业病杂志, 2003, 21: 137-138
14 Rudant J, Menegaux F, Leverger G, etal. Childhood hematopoietic malignancies and parental use of tobacco and alcohol: the ESCALE study (SFCE). Cancer Causes Control. 2008 Dec; 19(10): 1277-90
15 Lawson KA, Woodson K, Virtamo J, etal. Association of the NAD (P) H: quinine oxidoreductase (NQO1) 609C→T polymorphism with lung cancer risk among male smokers. Cancer Epidemiol biomarkers. Prev, 2005, 14(9): 2275-2276
16 Vander Logt EM, Bergevoet SM, Roelofs HM, etal. Role of epoxide hydrolase, NAD (P) H: quinine oxidoreductase, cytochrome P450 2E1 or alcohol dehydrogenase genetypes in susceptibility to colorectal cancer. Mutat Res, 2006, 593(1-2): 39-49
17 Zhang J, Schulz WA, Li Y, etal. Association of NAD (P) H: quinine oxidoreductase1 (NQO1) C609T polymorphism with esophageal squamous cell carcinomani a German Caucasian and a northern Chinese population. Carcinogenesis, 2003, 24(5): 905-9
18 Smith MT, Wang Y, Kane E, etal. Low NAD (P) H: quinone oxidoreductase 1 activity is associated with increased risk of acute leukemia in adults. Blood, 2001, 97(5): 1422-1426
19 Siegel D, Anwar A, Winski SL, etal. Rapid polyubiquitination and proteasomal degradation of a mutant form of NAD (P) H: quinoneoxidoreductase 1. Mol Pharmacol, 2001, 59(2): 263-8
20 Moran JL, Siegel D, Ross D. A potential mechanism underlying the increased susceptibility of individuals with a polymorphism in NAD (P) H: quinone oxidoreductase 1(NQO1) to benzene toxicity. Proc Natl Acad Sci USA, 1999, 96(14): 8150-8155
21 Hishida A, Terakura S, Emi N, etal. GSTT1 and GSTM1 deletions,NQO1 C609T polymorphism and risk of chronic myelogenous leukemia in Japanese. Asian Pac J Cancer Prev, 2005, 6(3): 251-255
22张战强,杨琳,张悦,杨艺红等. NQO1C609T, RAD51G135C和XRCC3C241T单核苷酸多态性与急性淋巴细胞白血病发病相关性研.中国实验血液学杂志, 2009, 17(3): 523-528
23吴玉霞,高怡瑾,赵金彩,等. GSTM1?GYP2E1和NQO1基因多态性与儿童白血病发病风险的初步研究.中华流行病学杂志, 2004, 25(9): 819
24 24周艳丽,陈华芳,史习舜,等. NQO1基因多态性与食管癌易感性的病例对照研究.中国肿瘤, 2006, 15(10): 659-663
25 Saldivar SJ, Wang Y, Zhao H, etal. An association between a NQO1 genetic polymorphism and risk of lung cancer. Mutation Res, 2005, 582: 71-78
26 Chan EC, Lam SY, Fu KH, etal. Polymorphisms of the GSTM1, GSTP1, MPO, XRCC1, and NQO1 genes in Chinese patients with non-small cell lung cancers: relationship with aberrant promoter methylation of the CDKN2A and RARB genes. Cancer Genetics and Cytogenetics, 2005, 162: 10-20
27 Alexandrie AK, Nyberg F, Warholm M, etal. Influence of CYP1A1, GSTM1, GSTT1, and NQO1 genotypes and cumulative smoking dose on lung cancer risk in a Swedish population. Cancer Epi Bio Prev, 2004, 13(6): 906-914
28 Sorensen M, Autrup H, Tjonneland A, etal. Genetic polymorphisms in CYP1B1, GSTA1, NQO1 and NAT2 and the risk of lung cancer. Cancer Letters, 2005, 221: 185-190
29 Yang M, Choi Y, Hwangbo B, etal. Combined effects of genetic polymorphisms in six selected genes on lung cancer suscep tibility. Lung Cancer, 2007, 57: 135-142
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