Background:The dysregulation of Isocitrate dehydrogenase(IDH)and the subsequent production of 2-Hydroxyglutrate(2HG)may alter the expression of epigenetic proteins in Grade 4 astrocytoma.The interplay mechanism betwee...Background:The dysregulation of Isocitrate dehydrogenase(IDH)and the subsequent production of 2-Hydroxyglutrate(2HG)may alter the expression of epigenetic proteins in Grade 4 astrocytoma.The interplay mechanism between IDH,O-6-methylguanine-DNA methyltransferase(MGMT)-promoter methylation,and protein methyltransferase proteins-5(PRMT5)activity,with tumor progression has never been described.Methods:A retrospective cohort of 34 patients with G4 astrocytoma is classified into IDH-mutant and IDH-wildtype tumors.Both groups were tested for MGMT-promoter methylation and PRMT5 through methylation-specific and gene expression PCR analysis.Inter-cohort statistical significance was evaluated.Results:Both IDH-mutant WHO grade 4 astrocytomas(n=22,64.7%)and IDH-wildtype glioblastomas(n=12,35.3%)had upregulated PRMT5 gene expression except in one case.Out of the 22 IDH-mutant tumors,10(45.5%)tumors showed MGMT-promoter methylation and 12(54.5%)tumors had unmethylated MGMT.All IDH-wildtype tumors had unmethylated MGMT.There was a statistically significant relationship between MGMT-promoter methylation and IDH in G4 astrocytoma(p-value=0.006).Statistically significant differences in progression-free survival(PFS)were also observed among all G4 astrocytomas that expressed PRMT5 and received either temozolomide(TMZ)or TMZ plus other chemotherapies,regardless of their IDH or MGMT-methylation status(p-value=0.0014).Specifically,IDH-mutant tumors that had upregulated PRMT5 activity and MGMT-promoter methylation,who received only TMZ,have exhibited longer PFS.Conclusions:The relationship between PRMT5,MGMT-promoter,and IDH is not tridirectional.However,accumulation of D2-hydroxyglutarate(2-HG),which partially activates 2-OG-dependent deoxygenase,may not affect their activities.In IDH-wildtype glioblastomas,the 2HG-2OG pathway is typically inactive,leading to PRMT5 upregulation.TMZ alone,compared to TMZ-plus,can increase PFS in upregulated PRMT5 tumors.Thus,using a PRMT5 inhibitor in G4 astrocytomas may help in tumor regression.展开更多
目的通过磁共振扩散峰度成像(diffusion kurtosis imaging,DKI)预测WHOⅡ级脑胶质瘤异柠檬酸脱氢酶(isocitrate dehydrogenase,IDH)基因状态。材料与方法收集经病理证实的25例WHOⅡ级脑胶质瘤患者的临床、影像资料,患者术前均行常规MRI...目的通过磁共振扩散峰度成像(diffusion kurtosis imaging,DKI)预测WHOⅡ级脑胶质瘤异柠檬酸脱氢酶(isocitrate dehydrogenase,IDH)基因状态。材料与方法收集经病理证实的25例WHOⅡ级脑胶质瘤患者的临床、影像资料,患者术前均行常规MRI及DKI扫描,测量肿瘤实质区、水肿区、同层面对侧正常脑白质(normal appearing white matter,NAWM)的DKI参数扩散各项异性分数(fractional anisotropy,FA)、平均扩散系数(mean diffusivity,MD)、平均扩散峰度(mean kurtosis,MK)、轴向扩散峰度(axial kurtosis,Ka)、径向扩散峰度(radial kurtosis,Kr),并对DKI参数校正处理,得到相对扩散各项异性分数(ratio of FA,rFA)、相对平均扩散系数(ratio of MD,rMD)、相对平均扩散峰度(ratio of MK,rMK)、相对轴向扩散峰度(ratio of Ka,rKa)、相对径向扩散峰度(ratio of Kr,rKr)值(肿瘤区、水肿区参数值除以对侧NAWM)。术后标本制作蜡块行Sanger基因测序分析。25例分为IDH突变型16例,IDH野生型9例,应用两独立样本t检验分析校正后两组DKI参数差异,受试者工作特征(receiver operating characteristic,ROC)曲线分析各参数值的诊断价值。结果 IDH野生型肿瘤实质区rFA值、rMK值均高于IDH突变型,而rMD值低于IDH突变型,两者之间差异有统计学意义(P<0.05);两组病例瘤周水肿各参数值差异无统计学意义。瘤体rMK值ROC曲线下面积为75.7%,当截点取0.515时,敏感性为77.8%。特异性为68.7%;rFA值ROC曲线下面积为72.9%,当截点取0.527时,敏感性为66.7%。特异性为93.7%;rMD值ROC曲线下面积为75.7%,当截点取1.261时,敏感性为87.5%。特异性为66.7%。结论 WHOⅡ级脑胶质瘤瘤体rMK、rFA、rMD值有助于判断IDH基因状态,并且rMK与rMD的敏感性及特异性均较高。展开更多
文摘Background:The dysregulation of Isocitrate dehydrogenase(IDH)and the subsequent production of 2-Hydroxyglutrate(2HG)may alter the expression of epigenetic proteins in Grade 4 astrocytoma.The interplay mechanism between IDH,O-6-methylguanine-DNA methyltransferase(MGMT)-promoter methylation,and protein methyltransferase proteins-5(PRMT5)activity,with tumor progression has never been described.Methods:A retrospective cohort of 34 patients with G4 astrocytoma is classified into IDH-mutant and IDH-wildtype tumors.Both groups were tested for MGMT-promoter methylation and PRMT5 through methylation-specific and gene expression PCR analysis.Inter-cohort statistical significance was evaluated.Results:Both IDH-mutant WHO grade 4 astrocytomas(n=22,64.7%)and IDH-wildtype glioblastomas(n=12,35.3%)had upregulated PRMT5 gene expression except in one case.Out of the 22 IDH-mutant tumors,10(45.5%)tumors showed MGMT-promoter methylation and 12(54.5%)tumors had unmethylated MGMT.All IDH-wildtype tumors had unmethylated MGMT.There was a statistically significant relationship between MGMT-promoter methylation and IDH in G4 astrocytoma(p-value=0.006).Statistically significant differences in progression-free survival(PFS)were also observed among all G4 astrocytomas that expressed PRMT5 and received either temozolomide(TMZ)or TMZ plus other chemotherapies,regardless of their IDH or MGMT-methylation status(p-value=0.0014).Specifically,IDH-mutant tumors that had upregulated PRMT5 activity and MGMT-promoter methylation,who received only TMZ,have exhibited longer PFS.Conclusions:The relationship between PRMT5,MGMT-promoter,and IDH is not tridirectional.However,accumulation of D2-hydroxyglutarate(2-HG),which partially activates 2-OG-dependent deoxygenase,may not affect their activities.In IDH-wildtype glioblastomas,the 2HG-2OG pathway is typically inactive,leading to PRMT5 upregulation.TMZ alone,compared to TMZ-plus,can increase PFS in upregulated PRMT5 tumors.Thus,using a PRMT5 inhibitor in G4 astrocytomas may help in tumor regression.
文摘目的通过磁共振扩散峰度成像(diffusion kurtosis imaging,DKI)预测WHOⅡ级脑胶质瘤异柠檬酸脱氢酶(isocitrate dehydrogenase,IDH)基因状态。材料与方法收集经病理证实的25例WHOⅡ级脑胶质瘤患者的临床、影像资料,患者术前均行常规MRI及DKI扫描,测量肿瘤实质区、水肿区、同层面对侧正常脑白质(normal appearing white matter,NAWM)的DKI参数扩散各项异性分数(fractional anisotropy,FA)、平均扩散系数(mean diffusivity,MD)、平均扩散峰度(mean kurtosis,MK)、轴向扩散峰度(axial kurtosis,Ka)、径向扩散峰度(radial kurtosis,Kr),并对DKI参数校正处理,得到相对扩散各项异性分数(ratio of FA,rFA)、相对平均扩散系数(ratio of MD,rMD)、相对平均扩散峰度(ratio of MK,rMK)、相对轴向扩散峰度(ratio of Ka,rKa)、相对径向扩散峰度(ratio of Kr,rKr)值(肿瘤区、水肿区参数值除以对侧NAWM)。术后标本制作蜡块行Sanger基因测序分析。25例分为IDH突变型16例,IDH野生型9例,应用两独立样本t检验分析校正后两组DKI参数差异,受试者工作特征(receiver operating characteristic,ROC)曲线分析各参数值的诊断价值。结果 IDH野生型肿瘤实质区rFA值、rMK值均高于IDH突变型,而rMD值低于IDH突变型,两者之间差异有统计学意义(P<0.05);两组病例瘤周水肿各参数值差异无统计学意义。瘤体rMK值ROC曲线下面积为75.7%,当截点取0.515时,敏感性为77.8%。特异性为68.7%;rFA值ROC曲线下面积为72.9%,当截点取0.527时,敏感性为66.7%。特异性为93.7%;rMD值ROC曲线下面积为75.7%,当截点取1.261时,敏感性为87.5%。特异性为66.7%。结论 WHOⅡ级脑胶质瘤瘤体rMK、rFA、rMD值有助于判断IDH基因状态,并且rMK与rMD的敏感性及特异性均较高。
