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 May 23;32(6):1037-1045. doi: 10.32604/or.2024.051112. eCollection 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.

Keywords: Glioblastoma; Grade 4 astrocytoma; Isocitrate dehydrogenase (IDH); O-6-methylguanine-DNA methyltransferase (MGMT); Progression-free survival (PFS); Protein methyltransferase proteins-5 (PRMT5).

MeSH terms

  • Adult
  • Aged
  • Astrocytoma* / genetics
  • Astrocytoma* / pathology
  • Brain Neoplasms* / genetics
  • Brain Neoplasms* / metabolism
  • Brain Neoplasms* / pathology
  • DNA Methylation
  • DNA Modification Methylases / genetics
  • DNA Modification Methylases / metabolism
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / metabolism
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Isocitrate Dehydrogenase* / genetics
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Grading
  • Promoter Regions, Genetic*
  • Protein-Arginine N-Methyltransferases* / genetics
  • Protein-Arginine N-Methyltransferases* / metabolism
  • Retrospective Studies
  • Temozolomide / pharmacology
  • Temozolomide / therapeutic use
  • Tumor Suppressor Proteins* / genetics
  • Tumor Suppressor Proteins* / metabolism

Substances

  • DNA Modification Methylases
  • DNA Repair Enzymes
  • Isocitrate Dehydrogenase
  • MGMT protein, human
  • PRMT5 protein, human
  • Protein-Arginine N-Methyltransferases
  • Temozolomide
  • Tumor Suppressor Proteins