From Code to Chaos: How IDH Mutation Shapes the Epigenome in Gliomas

As the name suggests, diffuse gliomas are glial-derived tumors that spread extensively throughout the brain. Although diffuse gliomas were once believed to be the same disease in all age groups, it is now clear that there are substantial differences between pediatric and adult-type diffuse gliomas. Genes that encode isocitrate dehydrogenases (IDH) are frequently mutated in gliomas in adults and are uncommon in children. While IDH mutation is mostly common in glioma, a range of other human cancers, such as acute myeloid leukemia (AML; ≈۳۰%), chondrosarcoma (≈۵۰%), and cholangiocarcinoma (≈۱۵–۲۰%) have shown altered IDH status. Traditionally, the glioma diagnosis was based solely on the tumor microscopic appearance, but according to the latest CNS WHO guidelines, molecular analyses are now the key component of diagnosis and it has become a regular practice to use an R۱۳۲H-specific antibody to assess gliomas. The IDH mutations draw attention to the crucial interaction between epigenetics and metabolism. The gain-of-function mutation of IDH۱ affects the Krebs cycle and disrupts the conversion of isocitrate to α-ketoglutarate (α-KG), favoring the production of the oncometabolite D-۲-hydroxyglutarate (D-۲HG). This compound, structurally similar to α-KG, inhibits a group of enzymes known as αKG-dependent dioxygenases (αKGDs), including TET, KDM, and EglN, which can convert α-KG to succinate through decarboxylation while simultaneously hydroxylating different substrates. Reduced activity of TET and KDM enzymes leads to hypermethylation of DNA and histones, respectively, whereas inhibiting EglN activity results in HIF stabilization. Together, these alterations affect gene expression, cell division, and differentiation processes. This substantial epigenetic reprogramming can affect glioma growth and therapeutic response. IDH mutations are strongly associated with hypermethylation of CpG islands in promoter regions of genes. Notably, the glioma-CpG island methylator phenotype (G-CIMP) high type tends to show a better prognosis owing to its distinct biology. However, this epigenetic state is not static, as IDH-mutant gliomas can lose much of their DNA methylation during tumor progression. Recent clinical trials with IDH inhibitors have shown promise in reversing some of the epigenetic and metabolic aberrations in this matter. Moving beyond current therapies, such as DNA methyltransferase inhibitors and histone deacetylase inhibitors, epigenetic therapy is rapidly evolving, with several promising approaches on the horizon. These include novel inhibitors targeting histone modifiers and chromatin remodelers, the use of CRISPR-based epigenetic editing for precision therapy, and the exploration of RNA modifications in epitranscriptomics. The integration of epigenetic therapy with immunotherapy and the development of multi-omics biomarkers are expected to enhance the precision and efficacy of treatment, moving the field closer to personalized medicine.

کلیدواژه ها:

Glioma ، IDH ، Isocitrate Dehydrogenase ، Epigenetics ، Brain