@Article{or.2024.051112,
AUTHOR = {MAHER KURDI, ALAA ALKHOTANI, ABDULRAHMAN SABBAGH, EYAD FAIZO, AHMED I. LARY, AHMED K. BAMAGA, MAJID ALMANSOURI, BADR HAFIZ, THAMER ALSHARIF, SALEH BAEESA},
TITLE = {The interplay mechanism between IDH mutation, MGMT-promoter methylation, and PRMT5 activity in the progression of grade 4 astrocytoma: unraveling the complex triad theory},
JOURNAL = {Oncology Research},
VOLUME = {32},
YEAR = {2024},
NUMBER = {6},
PAGES = {1037--1045},
URL = {http://www.techscience.com/or/v32n6/56603},
ISSN = {1555-3906},
ABSTRACT = { <b>Background:</b> 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 (<i>MGMT)</i>-promoter methylation, and protein methyltransferase proteins-5 (<i>PRMT5)</i> activity, with tumor progression has never been described. <b>Methods:</b> A retrospective cohort of 34 patients with G4 astrocytoma is classified into IDH-mutant and IDH-wildtype tumors. Both groups were tested for <i>MGMT</i>-promoter methylation and <i>PRMT5</i> through methylation-specific and gene expression PCR analysis. Inter-cohort statistical significance was evaluated. <b>Results:</b> Both IDH-mutant WHO grade 4 astrocytomas (n = 22, 64.7%) and IDH-wildtype glioblastomas (n = 12, 35.3%) had upregulated <i>PRMT5</i> gene expression except in one case. Out of the 22 IDH-mutant tumors, 10 (45.5%) tumors showed <i>MGMT</i>-promoter methylation and 12 (54.5%) tumors had unmethylated <i>MGMT</i>. All IDH-wildtype tumors had unmethylated <i>MGMT</i>. There was a statistically significant relationship between <i>MGMT</i>-promoter methylation and IDH in G4 astrocytoma (<i>p</i>-value = 0.006). Statistically significant differences in progression-free survival (PFS) were also observed among all G4 astrocytomas that expressed <i>PRMT5</i> and received either temozolomide (TMZ) or TMZ plus other chemotherapies, regardless of their IDH or <i>MGMT</i>-methylation status (<i>p</i>-value=0.0014). Specifically, IDH-mutant tumors that had upregulated <i>PRMT5</i> activity and <i>MGMT</i>-promoter methylation, who received only TMZ, have exhibited longer PFS. <b>Conclusions:</b> The relationship between <i>PRMT5</i>, <i>MGMT</i>-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 <i>PRMT5</i> upregulation. TMZ alone, compared to TMZ-plus, can increase PFS in upregulated <i>PRMT5</i> tumors. Thus, using a <i>PRMT5</i> inhibitor in G4 astrocytomas may help in tumor regression.},
DOI = {10.32604/or.2024.051112}
}