BRCA1基因甲基化及甲硫氨酸合成酶与乳腺癌发病的关系

摘要

Background and purpose: Promoter hypermethylation is an early event in tumorigenesis.Global under-methylation (hypomethylation) and site-specific over-methylation (hypermethylation) are common features of human tumors.Methionine synthase (MS) is the key enzyme involved in methyl donor-generated and provided methyl in DNA methylation.This study investigated the mRNA expression and promoter methylation status of the BRCA1 gene in breast cancer and the effects of mRNA expression in the MS gene in BRCA1 methylation as well as their association with breast cancer morbidity.Methods: RT-PCR was used to detect mRNA expressions in the BRCA1 gene and MS gene, and sensitive methylation-specific-PCR (MSP) was used to detect the promoter methylation status of the BRCA1 gene.Thirty-one samples of breast cancer and tumor adjacent tissues, as well as 9 cases of benign breast disease were detected.Results: Significant differences in the BRCA1 mRNA expression were observed among all three tissues.Methylation of the BRCA1 gene in breast cancer increased significantly in comparison with the tumor adjacent tissues and benign breast disease tissues (x2=7.631, P＜0.05).The BRCA1 methylated tumors closely correlated with histologic grades and negative expression of estrogen receptor (ER) (P＜0.05).The mRNA expression of MS in breast cancer tissues was significantly lower than in both benign breast disease tissues and tumor adjacent tissues (P＜0.05).There was a correlation between methylation of BRCA1 and expression of MS in breast cancer tissues (r=0.419, P＜0.05).Conclusion: Methylation of BRCA1 could be a contributor to the risk of breast cancer.The MS gene may be able to regulate the expression of tumor-related genes by affecting the methylation status.%背景与目的:启动子异常甲基化是肿瘤发生的早期事件,肿瘤组织中存在的DNA甲基化异常可以概括为广泛低甲基化伴局部高甲基化.甲硫氨酸合成酶(methionine synthase,MS)是参与甲基供体生成的关键酶,为DNA的甲基化提供甲基.本研究探讨抑癌基因BRCA1 mRNA在乳腺癌组织中的表达及启动子区甲基化状态,及MS基因mRNA表达与BRCA1基因甲基化的关系.方法:应用RT-PCR及甲基化特异性PCR(methylationspecific PCR,MSP)技术检测乳腺癌组织、相应癌旁组织(距癌>3 cm)和乳腺良性病变组织中BRCA1 mRNA的表达及其启动子甲基化状态,并检测MS mRNA的表达水平.结果:乳腺癌组织、癌旁组织及良性病变组织BRCA1mRNA表达差异有统计学意义(P<0.05);乳腺癌组织中BRCA1基因启动子区甲基化检出率明显高于癌旁组织和良性病变组织(χ2=7.631,P<0.05),BRCA1基因启动子区甲基化与散发性乳腺癌组织学分级、雌激素受体(estrogen receptor,ER)相关(P<0.05).乳腺癌组织MS基因表达量明显低于乳腺良性病变及乳腺癌旁组织(P<0.05).MS mRNA的表达与BRCA1基因甲基化的发生有相关性(r=0.419,P<0.05).结论:BRCA1甲基化能够增加乳腺癌的患病风险,MS基因可能通过影响部分肿瘤相关基因发生甲基化而调控其表达.