The interplay mechanism between IDH mutation, MGMT-promoter methylation, and PRMT5 activity in the progression of grade 4 astrocytoma: unraveling the complex triad theory  

作　　者：MAHER KURDI ALAA ALKHOTANI ABDULRAHMAN SABBAGH EYAD FAIZO AHMED I.LARY AHMED K.BAMAGA MAJID ALMANSOURI BADR HAFIZ THAMER ALSHARIF SALEH BAEESA 

机构地区：[1]Department of Pathology,Faculty of Medicine,King Abdulaziz University,Rabigh,Saudi Arabia [2]Department of Pathology,College of Medicine,Umm Al-Qura University,Makkah,Saudi Arabia [3]Department of Surgery,Faculty of Medicine,King Abdulaziz University,Jeddah,Saudi Arabia [4]Department of Surgery,Faculty of Medicine,University of Tabuk,Tabuk,Saudi Arabia [5]Section of Neurosurgery,Department of Surgery,King Abdulaziz Medical City,Jeddah,Saudi Arabia [6]Department of Pediatrics,Faculty of Medicine,King Abdulaziz University,Jeddah,Saudi Arabia [7]Department of Clinical Biochemistry,Faculty of Medicine,King Abdulaziz University,Jeddah,Saudi Arabia [8]Department of Neurosciences,King Faisal Specialist Hospital and Research Center,Jeddah,Saudi Arabia [9]Department of Surgery,King Abdulaziz Specialist Hospital,Taif,Saudi Arabia

出　　处：《Oncology Research》2024年第6期1037-1045,共9页肿瘤学研究（英文）

摘　　要：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.

关 键 词：Grade 4 astrocytoma GLIOBLASTOMA Isocitrate dehydrogenase(IDH) O-6-methylguanine-DNA methyltransferase(MGMT) Protein methyltransferase proteins-5(PRMT5) Progression-free survival(PFS) 

分 类 号：R739.4[医药卫生—肿瘤]