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

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Oncology Research 2024年第6期32卷 1037-1045页

作者： MAHER KURDi ALAA ALKHOTANi ABDULRAHMAN SABBAGH EYAD FAiZO ahmed i.lary ahmed K.BAMAGA MAJiD ALMANSOURi BADR HAFiZ THAMER ALSHARiF SALEH BAEESA Department of Pathology Faculty of MedicineKing Abdulaziz UniversityRabighSaudi Arabia Department of Pathology College of MedicineUmm Al-Qura UniversityMakkahSaudi Arabia Department of Surgery Faculty of MedicineKing Abdulaziz UniversityJeddahSaudi Arabia Department of Surgery Faculty of MedicineUniversity of TabukTabukSaudi Arabia Section of Neurosurgery Department of SurgeryKing Abdulaziz Medical CityJeddahSaudi Arabia Department of Pediatrics Faculty of MedicineKing Abdulaziz UniversityJeddahSaudi Arabia Department of Clinical Biochemistry Faculty of MedicineKing Abdulaziz UniversityJeddahSaudi Arabia Department of Neurosciences King Faisal Specialist Hospital and Research CenterJeddahSaudi Arabia Department of Surgery King Abdulaziz Specialist HospitalTaifSaudi Arabia

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 *** 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 ***:A retrospective cohort of 34 patients with G4 astrocytoma is classified into iDH-mutant and iDH-wildtype *** groups were tested for MGMT-promoter methylation and PRMT5 through methylation-specific and gene expression PCR ***-cohort statistical significance was ***: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 *** of the 22 iDH-mutant tumors,10(45.5%)tumors showed MGMT-promoter methylation and 12(54.5%)tumors had unmethylated *** iDH-wildtype tumors had unmethylated *** 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 ***:The relationship between PRMT5,MGMT-promoter,and iDH is not ***,accumulation of D2-hydroxyglutarate(2-HG),which partially activates 2-OG-dependent deoxygenase,may not affect their *** iDH-wildtype glioblastomas,the 2HG-2OG pathway is typically inactive,leading to PRMT5 *** alone,compared to TMZ-plus,can increase PFS in upregulated PRMT5 ***,using a PRMT5 inhibitor in G4

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)

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