FEN1基因的遗传学和表观遗传学调控及其与多种肿瘤发生发展的关系
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摘要
背景和目的:FEN1(Flap endonuclease 1)通过参与多种DNA代谢途径在维护基因组稳定性和防止细胞恶性转化过程中发挥重要作用。FEN1基因的遗传学和表观遗传学改变可能影响其表达水平,从而与宿主的肿瘤易感性和肿瘤进展相关。本研究筛查了汉族人群FEN1基因功能性遗传变异及其启动子甲基化状态的改变并探讨其与肿瘤发生发展的关系。
方法:以全基因策略分析FEN1遗传变异;用一系列生物化学实验研究遗传变异对基因功能的影响。以彗星实验(Comet test)测定携带不同基因型焦炉作业工人白细胞DNA损伤修复程度。以重亚硫酸盐-DNA测序法分析FEN1启动子甲基化改变,实时定量PCR检测FEN1 mRNA表达量。以cDNA芯片和组织芯片技术检测FEN1在多种肿瘤标本中的表达情况。以病例-对照研究方法分析遗传变异与肿瘤易感性的关系,相关程度以多因素logistic回归计算的比值比(odds ratio,OR)及其95%可信区限(confidence interval,CI)表示。所有统计检验均为双侧检验。
结果:DNA测序发现FEN1基因存在两个高度连锁的单核苷酸多态,即-69G/A和4150G/T多态。位于启动子区的-69A→G改变可能增加抑制性转录因子结合从而降低FEN1转录活性,而4150G→T改变增加FEN1表达。在焦炉作业工人中,携带FEN1-69G或4150G等位基因者DNA损伤程度显著高于携带-69A或4150T者。含1,013例肺癌和1,131例对照的病例-对照分析显示,-69GG或4150GG基因型单独或与吸烟有相乘的联合作用增加肺癌发病风险。与相应的正常组织相比,多种肿瘤中FEN1 mRNA的表达显著上调。在伴有不典型增生的良性乳腺疾病和各种乳腺癌组织中皆有FEN1表达,且其表达量随肿瘤的进展而逐渐升高。FEN1启动子含两个CpG岛。其中CpG岛2在肿瘤组织中的去甲基化可能是导致FEN1在多种肿瘤组织中表达增高的主要原因。
结论:FEN1在肿瘤发生和发展的不同阶段通过相应的遗传学和表观遗传学改变分别与个体的肿瘤易感性和肿瘤进展相关。
Background & Aims: Flap endonuclease 1 (FEN1), involved in many DNA metabolic pathways, plays an essential role in maintaining genome integrity and cancer development. The genetic and epigenetic changes of FEN1 gene might contribute to differential FEN1 expression and, thus, be associated with individual susceptibility to cancer development and poor prognosis. This study sought to identify single nucleotide polymorphisms (SNPs) in the FEN1 gene and aberrant methylation of its promoter CpG islands and evaluated their effects on tumor development and progression.
Methods: DNA samples from 30 individuals were sequenced to search for SNPs in FEN1, and the function of the SNPs was investigated by a series of biochemical assays. The association between the FEN1 genotypes and the In-transformed Olive tail moment (Olive TM) values were tested in coke-oven workers, and the association between the genotypes and lung cancer susceptibility were examined in a case-control panel consisting of 1,013 lung cancer patients and 1,131 controls. The odds ratios and their 95% confidence intervals were estimated by logistic regression. The promoter methylation was identified by sequencing of sodium bisulfite-treated DNA and mRNA levels were determined by quantitative real-time RT-PCR. FEN1 expression was detected in BD Clontech~(TM) Cancer Profiling Array I and a Cybrdi~(TM) Breast Carcinoma Progression Tissue Array.
Results: Two SNPs (-69G/A and 4150G/T) were identified and the -69G and 4150G alleles were associated with reduced expression of FEN1 in vitro and in vivo. The higher In-transformed Olive TM values of coke-oven workers and significantly increased risks for developing lung cancer were associated with the FEN1 -69G or 4150G allele compared with the -69A or 4150T allele, respectively. A multiplicative joint effect between smoking and FEN1 polymorphisms in intensifying lung cancer risk was detected. FEN1 mRNA was overexpressed in multiple cancers compared with matched normal tissue. In breast cancer, FEN1 expression was inversively correlated with the degree of tumor differentiation. Moreover, we identified two CpG islands in the FEN1 promoter region and showed that hypomethylation of CpG island2 is important in regulating overexpression of the FEN1 gene in tumors.
Conclusion: Functional SNPs in FEN1 are associated with susceptibility to DNA damage and lung cancer development, and elevated FEN 1 expression due to the aberrant promoter methylation may be associated with cancer progression.
方法:以全基因策略分析FEN1遗传变异;用一系列生物化学实验研究遗传变异对基因功能的影响。以彗星实验(Comet test)测定携带不同基因型焦炉作业工人白细胞DNA损伤修复程度。以重亚硫酸盐-DNA测序法分析FEN1启动子甲基化改变,实时定量PCR检测FEN1 mRNA表达量。以cDNA芯片和组织芯片技术检测FEN1在多种肿瘤标本中的表达情况。以病例-对照研究方法分析遗传变异与肿瘤易感性的关系,相关程度以多因素logistic回归计算的比值比(odds ratio,OR)及其95%可信区限(confidence interval,CI)表示。所有统计检验均为双侧检验。
结果:DNA测序发现FEN1基因存在两个高度连锁的单核苷酸多态,即-69G/A和4150G/T多态。位于启动子区的-69A→G改变可能增加抑制性转录因子结合从而降低FEN1转录活性,而4150G→T改变增加FEN1表达。在焦炉作业工人中,携带FEN1-69G或4150G等位基因者DNA损伤程度显著高于携带-69A或4150T者。含1,013例肺癌和1,131例对照的病例-对照分析显示,-69GG或4150GG基因型单独或与吸烟有相乘的联合作用增加肺癌发病风险。与相应的正常组织相比,多种肿瘤中FEN1 mRNA的表达显著上调。在伴有不典型增生的良性乳腺疾病和各种乳腺癌组织中皆有FEN1表达,且其表达量随肿瘤的进展而逐渐升高。FEN1启动子含两个CpG岛。其中CpG岛2在肿瘤组织中的去甲基化可能是导致FEN1在多种肿瘤组织中表达增高的主要原因。
结论:FEN1在肿瘤发生和发展的不同阶段通过相应的遗传学和表观遗传学改变分别与个体的肿瘤易感性和肿瘤进展相关。
Background & Aims: Flap endonuclease 1 (FEN1), involved in many DNA metabolic pathways, plays an essential role in maintaining genome integrity and cancer development. The genetic and epigenetic changes of FEN1 gene might contribute to differential FEN1 expression and, thus, be associated with individual susceptibility to cancer development and poor prognosis. This study sought to identify single nucleotide polymorphisms (SNPs) in the FEN1 gene and aberrant methylation of its promoter CpG islands and evaluated their effects on tumor development and progression.
Methods: DNA samples from 30 individuals were sequenced to search for SNPs in FEN1, and the function of the SNPs was investigated by a series of biochemical assays. The association between the FEN1 genotypes and the In-transformed Olive tail moment (Olive TM) values were tested in coke-oven workers, and the association between the genotypes and lung cancer susceptibility were examined in a case-control panel consisting of 1,013 lung cancer patients and 1,131 controls. The odds ratios and their 95% confidence intervals were estimated by logistic regression. The promoter methylation was identified by sequencing of sodium bisulfite-treated DNA and mRNA levels were determined by quantitative real-time RT-PCR. FEN1 expression was detected in BD Clontech~(TM) Cancer Profiling Array I and a Cybrdi~(TM) Breast Carcinoma Progression Tissue Array.
Results: Two SNPs (-69G/A and 4150G/T) were identified and the -69G and 4150G alleles were associated with reduced expression of FEN1 in vitro and in vivo. The higher In-transformed Olive TM values of coke-oven workers and significantly increased risks for developing lung cancer were associated with the FEN1 -69G or 4150G allele compared with the -69A or 4150T allele, respectively. A multiplicative joint effect between smoking and FEN1 polymorphisms in intensifying lung cancer risk was detected. FEN1 mRNA was overexpressed in multiple cancers compared with matched normal tissue. In breast cancer, FEN1 expression was inversively correlated with the degree of tumor differentiation. Moreover, we identified two CpG islands in the FEN1 promoter region and showed that hypomethylation of CpG island2 is important in regulating overexpression of the FEN1 gene in tumors.
Conclusion: Functional SNPs in FEN1 are associated with susceptibility to DNA damage and lung cancer development, and elevated FEN 1 expression due to the aberrant promoter methylation may be associated with cancer progression.
引文
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