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

Autor:	Kurdi M; Department of Pathology, Faculty of Medicine, King Abdulaziz University, Rabigh, Saudi Arabia., Alkhotani A; Department of Pathology, College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia., Sabbagh A; Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia., Faizo E; Department of Surgery, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia., Lary AI; Section of Neurosurgery, Department of Surgery, King Abdulaziz Medical City, Jeddah, Saudi Arabia., Bamaga AK; Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia., Almansouri M; Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia., Hafiz B; Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia., Alsharif T; Department of Surgery, King Abdulaziz Specialist Hospital, Taif, Saudi Arabia., Baeesa S; Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia.
Jazyk:	angličtina
Zdroj:	Oncology research [Oncol Res] 2024 May 23; Vol. 32 (6), pp. 1037-1045. Date of Electronic Publication: 2024 May 23 (Print Publication: 2024).
DOI:	10.32604/or.2024.051112
Abstrakt:	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 tri-directional. 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. Competing Interests: The authors have no relevant conflict of interest to disclose. (© 2024 Kurdi et al.)
Databáze:	MEDLINE
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