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

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 (-promoter methylation, and protein methyltransferase proteins-5 ( 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 -promoter methylation and 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 gene expression except in one case. Out of the 22 IDH-mutant tumors, 10 (45.5%) tumors showed -promoter methylation and 12 (54.5%) tumors had unmethylated . All IDH-wildtype tumors had unmethylated . There was a statistically significant relationship between -promoter methylation and IDH in G4 astrocytoma (-value = 0.006). Statistically significant differences in progression-free survival (PFS) were also observed among all G4 astrocytomas that expressed and received either temozolomide (TMZ) or TMZ plus other chemotherapies, regardless of their IDH or -methylation status (-value=0.0014). Specifically, IDH-mutant tumors that had upregulated activity and -promoter methylation, who received only TMZ, have exhibited longer PFS.

Conclusions: The relationship between , -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 upregulation. TMZ alone, compared to TMZ-plus, can increase PFS in upregulated tumors. Thus, using a inhibitor in G4 astrocytomas may help in tumor regression.