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ARTICLE
The interplay mechanism between IDH mutation, MGMT-promoter methylation, and PRMT5 activity in the progression of grade 4 astrocytoma: unraveling the complex triad theory
MAHER KURDI1,*, ALAA ALKHOTANI2, ABDULRAHMAN SABBAGH3, EYAD FAIZO4, AHMED I. LARY5, AHMED K. BAMAGA6, MAJID ALMANSOURI7, BADR HAFIZ8, THAMER ALSHARIF9, SALEH BAEESA8
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
* Corresponding Author: MAHER KURDI. Email:
Oncology Research 2024, 32(6), 1037-1045. https://doi.org/10.32604/or.2024.051112
Received 28 February 2024; Accepted 22 March 2024; Issue published 23 May 2024
Abstract
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.
Graphical Abstract
Keywords
Cite This Article
APA Style
KURDI, M., ALKHOTANI, A., SABBAGH, A., FAIZO, E., LARY, A.I. et al. (2024). The interplay mechanism between IDH mutation, mgmt-promoter methylation, and PRMT5 activity in the progression of grade 4 astrocytoma: unraveling the complex triad theory. Oncology Research, 32(6), 1037-1045. https://doi.org/10.32604/or.2024.051112
Vancouver Style
KURDI M, ALKHOTANI A, SABBAGH A, FAIZO E, LARY AI, BAMAGA AK, et al. The interplay mechanism between IDH mutation, mgmt-promoter methylation, and PRMT5 activity in the progression of grade 4 astrocytoma: unraveling the complex triad theory. Oncol Res. 2024;32(6):1037-1045 https://doi.org/10.32604/or.2024.051112
IEEE Style
M. KURDI et al., "The interplay mechanism between IDH mutation, MGMT-promoter methylation, and PRMT5 activity in the progression of grade 4 astrocytoma: unraveling the complex triad theory," Oncol. Res., vol. 32, no. 6, pp. 1037-1045. 2024. https://doi.org/10.32604/or.2024.051112