亚甲基四氢叶酸还原酶基因C677T多态性对癌基因C-erbB-2 CpG岛甲基化状态的影响及其与肿瘤的关系
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摘要
目的:研究肿瘤及其相对应的癌旁组织中C-erbB-2基因启动子区域CpG岛的甲基化状态、癌蛋白C-erbB-2表达水平以及肿瘤组织中C-erbB-2基因甲基化状态对癌蛋白表达水平的影响;探讨亚甲基四氢叶酸还原酶(MTHFR)基因C677T多态性对肿瘤组织C-erbB-2基因启动子区CpG岛甲基化的影响及其与肿瘤的关系。
方法:用甲基化特异性聚合酶链式反应(MSP)分析经病理证实的247例肿瘤及其肿瘤旁组织中C-erbB-2基因启动子区域CpG岛的甲基化状态,用聚合酶链式反应-限制性片段长度多态性法(PCR-RFLP)检测247例肿瘤患者及100例正常对照中MTHFR基因C677T多态性,并用免疫组织化学法(IHC)检测43例结直肠癌及癌旁组织中C-erbB-2蛋白的表达。
结果:在研究的所有肿瘤中,癌组织中的C-erbB-2基因启动子区CpG岛甲基化率明显低于癌旁组织(43.3%vs.69.2%,P=0.000),但未发现癌组织中C-erbB-2基因启动子区CpG岛甲基化与临床病理参数间的关联。肿瘤患者中MTHFR基因677位点T等位基因频率显著高于正常对照组,677 CT/TT基因型显著增加了肿瘤的风险(OR=1.619,95%CI:1.012-2.588,P=0.043)。肿瘤患者中,CT/TT基因型个体肿瘤组织中C-erbB-2甲基化率低于CC基因型个体(39.4%vs.50.O%),但差异不具有统计学意义(P=0.103);在肿瘤组织发生C-erbB-2甲基化与未甲基化的个体间C、T等位基因的分布差异也不具有显著性意义(P=0.078)。在乳腺癌C-erbB-2启动子区CpG岛发生甲基化的个体中CC基因型和C等位基因的频率显著高于未发生甲基化的个体(P值分别为0.008和0.007)。
所检测的43例结直肠癌组织和癌旁组织中,癌蛋白C-erbB-2过度表达率分别为67.4%和27.9%,差异具有统计学意义(P=0.000)。C-erbB-2癌蛋白表达水平与肿瘤分期相关(P=0.010),与年龄(P=0.586)、性别(P=0.739)、肿瘤部位(P=0.05)、组织学分级(P=0.815)、淋巴结转移(P=0.594)等参数均无明显相关。结直肠癌组织中C-erbB-2基因启动子区CpG岛甲基化状态与癌蛋白表达水平相关(P=0.03,r=0.331)。
结论:在癌组织中C-erbB-2基因启动子区CpG岛呈低甲基化状态,MTHFR基因677 CT/TT基因型显著增加了肿瘤的风险;在乳腺癌中,MTHFR基因C677T多态性对C-erbB-2基因启动子区CpG岛的甲基化有明显影响。
C-erbB-2基因启动子区CpG岛的低甲基化可能是结直肠癌组织C-erbB-2癌蛋白过度表达的重要因素之一,有望成为有用的肿瘤分子诊断标记和治疗靶点。
Objective To explore the methylation status of CpG island in the promoter region of C-erbB-2 gene in tumor and matched adjacent tissues and the expression of C-erbB-2 oncoprotein and to realize the effect of methylation status in C-erbB-2 gene promoter region on the oncoprotein expression.To investigate the effect of methylenetetrahydrofolate reductase(MTHFR) C677T gene polymorphism on C-erbB-2 methylation status and its association with cancer.
Methods The methylation status of CpG island in the promoter of C-erbB-2 oncogene in 247 pathologically confirmed tumor tissues and the matched adjacent tissues were detected by the methylation specific polymerase chain reaction(MSP).The MTHFR C677T polymorphism in 247 patients with cancer and 100 healthy subjects were analyzed by the PCR-based restriction fragment length polymorphism(PCR-RFLP) method.The C-erbB-2 oncoproteins in 43 colorectal carcinoma tissues and the matched adjacent tissues were examinated by immunohistochemistry(IHC) method.
Results The methylation rate of CpG island in the promoter region of the C-erbB-2 gene in tumor tissues was significantly lower than that in matched adjacent tissues(44.2%vs.74.4%,P=0.004).No correlation was observed between the methylation patterns of C-erbB-2 in tumor tissues and the clinicopathological characteristics of the patients.The frequency of MTHFR gene 677 T allele was significantly higher in cancer patients than in healthy subjects,and the combined variant genotypes(677CT+TT) significantly increased the risk of developing cancer(OR=1.619,95%CI: 1.012-2.588,P =0.043).Among the cancer patients,the methylation rate of C-erbB-2 gene was lower in individuals with CT/TT genotype than in those with CC CT/TT genotype(39.4%vs.50.0%).This difference was not significant(P=0.103).The distribution difference of C allele and T allele was not significant between subjects with methylated and unmethylated C-erbB-2 promoter CpG island(P =0.078).However,in breast cancer,the frequency of CC genotype and C allele was significantly higher in patients with methylated C-erbB-2 promoter CpG island than that in patients with unmethylated C-erbB-2 promoter CpG island(P =0.008 and 0.007,respectively).
The percentage of C-erbB-2 oncoprotein overexpression was significantly higher in 43 colorectal carcinoma tissues than that in matched adjacent tissues (67.4%vs.27.9%,P=0.000).There was no correlation of the overexpression of C-erbB-2 oncoprotein with patient age(P=0.586),sex(P=0.739),tumor localization(P=0.05),histological grade(P=0.815),lymph node metastases (P=0.594),but the C-erbB-2 oncoprotein overexpression was significantly associated with clinical stage(P=0.010).The hypomethylation of CpG island in the promoter region of the C-erbB-2 gene in colorectal carcinoma tissues was correlated with C-erbB-2 oncoprotein overexpression(P=0.03,r=0.331).
Conclusion C-erbB-2 promoter CpG island was hypomethylated in tumor tissues and MTHFR 677 CT/TT genotype increased the risk of developing cancer.Moreover,in breast cancer patients,the MTHFR gene C677T polymorphism had an evident effect on the methylation status of the C-erbB-2 gene.
In addition,the hypomethylation of CpG island in the promoter region of C-erbB-2 gene may be one of the important factors of C-erbB-2 oncoprotein overexpression in colorectal carcinomas and it would be a valuable marker as cancer molecular diagnosis and a therapy target.
方法:用甲基化特异性聚合酶链式反应(MSP)分析经病理证实的247例肿瘤及其肿瘤旁组织中C-erbB-2基因启动子区域CpG岛的甲基化状态,用聚合酶链式反应-限制性片段长度多态性法(PCR-RFLP)检测247例肿瘤患者及100例正常对照中MTHFR基因C677T多态性,并用免疫组织化学法(IHC)检测43例结直肠癌及癌旁组织中C-erbB-2蛋白的表达。
结果:在研究的所有肿瘤中,癌组织中的C-erbB-2基因启动子区CpG岛甲基化率明显低于癌旁组织(43.3%vs.69.2%,P=0.000),但未发现癌组织中C-erbB-2基因启动子区CpG岛甲基化与临床病理参数间的关联。肿瘤患者中MTHFR基因677位点T等位基因频率显著高于正常对照组,677 CT/TT基因型显著增加了肿瘤的风险(OR=1.619,95%CI:1.012-2.588,P=0.043)。肿瘤患者中,CT/TT基因型个体肿瘤组织中C-erbB-2甲基化率低于CC基因型个体(39.4%vs.50.O%),但差异不具有统计学意义(P=0.103);在肿瘤组织发生C-erbB-2甲基化与未甲基化的个体间C、T等位基因的分布差异也不具有显著性意义(P=0.078)。在乳腺癌C-erbB-2启动子区CpG岛发生甲基化的个体中CC基因型和C等位基因的频率显著高于未发生甲基化的个体(P值分别为0.008和0.007)。
所检测的43例结直肠癌组织和癌旁组织中,癌蛋白C-erbB-2过度表达率分别为67.4%和27.9%,差异具有统计学意义(P=0.000)。C-erbB-2癌蛋白表达水平与肿瘤分期相关(P=0.010),与年龄(P=0.586)、性别(P=0.739)、肿瘤部位(P=0.05)、组织学分级(P=0.815)、淋巴结转移(P=0.594)等参数均无明显相关。结直肠癌组织中C-erbB-2基因启动子区CpG岛甲基化状态与癌蛋白表达水平相关(P=0.03,r=0.331)。
结论:在癌组织中C-erbB-2基因启动子区CpG岛呈低甲基化状态,MTHFR基因677 CT/TT基因型显著增加了肿瘤的风险;在乳腺癌中,MTHFR基因C677T多态性对C-erbB-2基因启动子区CpG岛的甲基化有明显影响。
C-erbB-2基因启动子区CpG岛的低甲基化可能是结直肠癌组织C-erbB-2癌蛋白过度表达的重要因素之一,有望成为有用的肿瘤分子诊断标记和治疗靶点。
Objective To explore the methylation status of CpG island in the promoter region of C-erbB-2 gene in tumor and matched adjacent tissues and the expression of C-erbB-2 oncoprotein and to realize the effect of methylation status in C-erbB-2 gene promoter region on the oncoprotein expression.To investigate the effect of methylenetetrahydrofolate reductase(MTHFR) C677T gene polymorphism on C-erbB-2 methylation status and its association with cancer.
Methods The methylation status of CpG island in the promoter of C-erbB-2 oncogene in 247 pathologically confirmed tumor tissues and the matched adjacent tissues were detected by the methylation specific polymerase chain reaction(MSP).The MTHFR C677T polymorphism in 247 patients with cancer and 100 healthy subjects were analyzed by the PCR-based restriction fragment length polymorphism(PCR-RFLP) method.The C-erbB-2 oncoproteins in 43 colorectal carcinoma tissues and the matched adjacent tissues were examinated by immunohistochemistry(IHC) method.
Results The methylation rate of CpG island in the promoter region of the C-erbB-2 gene in tumor tissues was significantly lower than that in matched adjacent tissues(44.2%vs.74.4%,P=0.004).No correlation was observed between the methylation patterns of C-erbB-2 in tumor tissues and the clinicopathological characteristics of the patients.The frequency of MTHFR gene 677 T allele was significantly higher in cancer patients than in healthy subjects,and the combined variant genotypes(677CT+TT) significantly increased the risk of developing cancer(OR=1.619,95%CI: 1.012-2.588,P =0.043).Among the cancer patients,the methylation rate of C-erbB-2 gene was lower in individuals with CT/TT genotype than in those with CC CT/TT genotype(39.4%vs.50.0%).This difference was not significant(P=0.103).The distribution difference of C allele and T allele was not significant between subjects with methylated and unmethylated C-erbB-2 promoter CpG island(P =0.078).However,in breast cancer,the frequency of CC genotype and C allele was significantly higher in patients with methylated C-erbB-2 promoter CpG island than that in patients with unmethylated C-erbB-2 promoter CpG island(P =0.008 and 0.007,respectively).
The percentage of C-erbB-2 oncoprotein overexpression was significantly higher in 43 colorectal carcinoma tissues than that in matched adjacent tissues (67.4%vs.27.9%,P=0.000).There was no correlation of the overexpression of C-erbB-2 oncoprotein with patient age(P=0.586),sex(P=0.739),tumor localization(P=0.05),histological grade(P=0.815),lymph node metastases (P=0.594),but the C-erbB-2 oncoprotein overexpression was significantly associated with clinical stage(P=0.010).The hypomethylation of CpG island in the promoter region of the C-erbB-2 gene in colorectal carcinoma tissues was correlated with C-erbB-2 oncoprotein overexpression(P=0.03,r=0.331).
Conclusion C-erbB-2 promoter CpG island was hypomethylated in tumor tissues and MTHFR 677 CT/TT genotype increased the risk of developing cancer.Moreover,in breast cancer patients,the MTHFR gene C677T polymorphism had an evident effect on the methylation status of the C-erbB-2 gene.
In addition,the hypomethylation of CpG island in the promoter region of C-erbB-2 gene may be one of the important factors of C-erbB-2 oncoprotein overexpression in colorectal carcinomas and it would be a valuable marker as cancer molecular diagnosis and a therapy target.
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