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DLC-1基因甲基化在骨髓增生异常综合征中的临床意义及地西他滨对DLC-1基因表达的影响

Clinical significance of hypermethylation of DLC-1 gene in myelodysplastic syndrome patients and effects of decitabine on DLC-1 gene expression

摘要:

目的 检测肝癌缺失基因(DLC-1)在骨髓增生异常综合征(MDS)患者中的异常甲基化情况及异常甲基化对MDS患者DLC-1基因的表达影响;探讨DLC-1基因甲基化对MDS的临床意义及MDS的表观遗传学药物地西他滨对DLC-1基因的表达影响.方法 选取福建医科大学附属协和医院血液内科2013至2015年收治的43例MDS患者,采用甲基特异性PCR法(MSP)定性检测MDS患者DIC基因甲基化状态,荧光实时定量PCR(RTFQ-PCR)检测MDS患者DLC-1基因的表达情况;根据MDS的世界卫生组织(WHO)预后积分系统(WPSS积分)标准及危险度分组将MDS患者分为极低危、低危、中危、高危、极高危5组(n=0、8、7、18、10),探讨DLC-1基因甲基化对MDS患者的临床意义.采用重亚硫酸盐测序PCR(BSP)法定量检测地西他滨作用前、后MDS患者DLC-1基因的甲基化状态,RTFQ-PCR检测MDS患者用药前、后DLC-1基因基因mRNA的表达变化.结果 MDS患者DLC-1基因的甲基化比例为55.16% (22/43),DLC-1基因甲基化阳性患者骨髓DLC-1基因mRNA的表达(0.32 ±0.06)显著低于DLC-1基因甲基化阴性患者(0.91 ±0.11) (P=0.008).对于MDS患者,危险度分层中、高危患者的DLC-1基因甲基化率为21/35,明显高于低危患者的1/8(P =0.006).8例采用含地西他滨治疗方案(地西他滨20 mg/m2,共5d,28 d为1疗程,4疗程以上)的患者治疗前、后的DLC基因甲基化率分别为57.50%±5.11%和14.13%±2.07%(P=0.010),DLC-1基因mRNA表达分别为0.28±0.06和0.67 ±0.08(P =0.015),差异均有统计学意义.结论 DLC-1基因甲基化在MDS患者中较为常见,且可能与不良预后相关;表观遗传学治疗药物地西他滨可逆转MDS患者DLC-1基因异常甲基化状态,使DLC-1基因表达上调,恢复其活性,可能是地西他滨治疗MDS患者的机制之一.

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abstracts:

Objective To detect the methylation status of DLC-1 gene in the patients with myelodysplastic syndrome(MDS),the effect of abnormal methylation of DLC-1 gene on the expression of DLC-1 gene,the clinical significance of methylation of DLC-1 gene in MDS patients,and the effect of decitabine on DLC-1 gene expression.Methods A total of 43 MDS patients were treated in Fujian Medical University Union Hospital from 2013 to 2015.Methylation status of DLC-1 gene in MDS patients were detected by the methylation specific PCR(MSP).The expression of DLC-1 gene mRNA was determined with real-time fluorescence quantitative PCR(RTFQ-PCR).MDS patients were divided into 5 groups (very lowrisk,low-risk,intermediate-risk,high-risk and very high-risk,n =0,8,7,18,10) according to WPSS classification.And the clinical significance of methylation of DLC-1 gene in patients with MDS were investigated.In order to investigate the change in gene methylation and expression of DLC-1 gene after treatment with decitabine,methylation statuses of DLC-1 gene in MDS patients before and after be treated with decitabine were detected by the bisulfite sequencing PCR (BSP).The expressions of DLC-1 gene mRNA of these patients were determined with RTFQ-PCR.Results Hypermethylation of CpG island of DLC-1 gene was observed in 55.16% (22/43) MDS patients.The expressions of DLC-1 gene mRNA in methylation positive patients were significantly lower than that in methylation negative patients (0.32 ± 0.06 vs 0.91 ±0.11) (P =0.008).For MDS patients,the DLC-1 methylation rate of intermediate-and high-risk patient was 21/35,which was significantly higher than that of low-risk patient (1/8,P =0.006).The methylation status of DLC-1 gene were monitored in 8 patients before and after treatment with the decitabine (decitabine 20 mg/m2,dl-d5/d28,more than 4 courses),the methylation rate of DLC-1 gene dropped from 57.50% ± 5.11% to 14.13% ± 2.07% after treatment (P =0.010).The expression of DLC-1 gene increased after treatment with decitabine (0.67 ± 0.08 vs 0.28 ± 0.06,P =0.015).Conclusions Methylation of DLC-1 gene is common in MDS patients and may be associated with poor prognosis.Decitabine may activate the expression of DLC-1 gene by demethylation,which may be one of the mechanisms for the treatment of patients with MDS.

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作者: 付海英 [1] 周华蓉 [1] 晏建国 [1] 陈聪杰 [1] 沈建箴 [1]
期刊: 《中华医学杂志》2017年97卷6期 412-417页 MEDLINEISTICPKUCSCD
栏目名称: 临床研究
DOI: 10.3760/cma.j.issn.0376-2491.2017.06.003
发布时间: 2017-03-15
基金项目:
National Natural Science Foundation of China Youth Science Fund Surface Project of National Natural Science Foundation of China Chinese Ministry of Education PHD Foundation Fujian Provincial Key Laboratory on Hematology Program National Key Clinical Specialty Discipline Construction Program of China Key Clinical Specialty Discipline Construction Program of Fujian Province of China(2012-149)国家自然科学基金青年科学基金 国家自然科学基金面上项目 教育部高等学校博士学科点专项科研基金 福建省血液病重点实验室基金 国家临床重点专科建设项目 福建省临床重点专科建设项目
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