Glioblastoma Epigenomic Landscape [Neurosurgery Wiki]

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====== Glioblastoma Epigenomic Landscape ======

[[Glioblastoma]] (GBM) is a highly aggressive brain tumor characterized not only by genetic mutations but also by profound epigenetic dysregulation. The epigenomic landscape of GBM plays a key role in tumor heterogeneity, therapy resistance, and stemness.

=== 1. DNA Methylation Patterns ===
  * **MGMT promoter methylation**:
    - Predictive biomarker for response to temozolomide
    - Methylation silences DNA repair gene → increased chemotherapy sensitivity
  * **Global hypomethylation**:
    - Associated with genomic instability
  * **CpG island hypermethylation**:
    - Silences tumor suppressor genes (e.g., CDKN2A)

=== 2. Histone Modifications ===
  * Altered **H3K27me3** and **H3K9me3** in tumor suppressor regions
  * Abnormal **histone acetylation** affecting transcriptional regulation
  * H3K27me3 is particularly dysregulated in IDH-wildtype GBM

=== 3. Chromatin Accessibility ===
  * GBM cells, especially glioma stem-like cells (GSCs), show:
    - Increased chromatin accessibility in oncogenic loci
    - Reprogramming of enhancer regions
  * Identified using ATAC-seq and DNase-seq

=== 4. Epigenetic Subtypes ===
  * **IDH-mutant GBM**:
    - Associated with G-CIMP (CpG island methylator phenotype)
    - Epigenetically distinct, better prognosis
  * **IDH-wildtype GBM**:
    - Highly heterogeneous
    - Non-G-CIMP methylation patterns
    - Worse outcome

=== 5. Non-Coding RNAs ===
  * Dysregulation of **lncRNAs** and **miRNAs**
    - Examples: HOTAIR, miR-21
    - Influence gene silencing, proliferation, apoptosis
  * Contribute to GBM stemness and invasiveness

=== 6. Epigenetic Therapeutic Targets ===
  * **EZH2 inhibitors**: Target histone methylation (H3K27me3)
  * **HDAC inhibitors**: Reverse histone deacetylation
  * **DNMT inhibitors**: Alter DNA methylation patterns
  * **BET inhibitors**: Target transcriptional enhancers

=== 7. Epigenetic Plasticity and Resistance ===
  * Epigenetic shifts contribute to:
    - Treatment resistance
    - Cellular plasticity
    - Mesenchymal transformation of GSCs

=== 8. Technologies Used ===
  * Bisulfite sequencing (methylation)
  * ChIP-seq (histone marks)
  * ATAC-seq / DNase-seq (accessibility)
  * RNA-seq (non-coding RNAs)

----
The most aggressive and extremely malignant type of central nervous system cancer is Glioblastoma (GBM), which is characterized by an extremely short average survival time of less than 16 months. The primary cause of this phenomenon can be attributed to the extensively altered genome of GBM, which is characterized by the dysregulation of numerous critical signaling pathways and epigenetic regulations associated with proliferation, cellular growth, survival, and apoptosis. In light of this, different genetic alterations in critical signaling pathways and various epigenetic regulation mechanisms are associated with GBM and identified as distinguishing markers. Such GBM prognostic alterations are identified in PI3K/AKT, p53, RTK, RAS, RB, STAT3, and [[ZIP4 signaling pathway]]s, metabolic pathway (IDH1/2), as well as alterations in epigenetic regulation genes (MGMT, CDKN2A-p16INK4aCDKN2B-p15INK4b). The exploration of innovative diagnostic and therapeutic approaches that specifically target these pathways is of utmost importance to enhance future medication for GBM. This study provides a comprehensive overview of dysregulated epigenetic mechanisms and signaling pathways due to mutations, methylation, and copy number alterations of critical genes in GBM, with prevalence and emphasizing their significance
((Dakal TC, Kakde GS, Maurya PK. Genomic, epigenomic and transcriptomic landscape of glioblastoma. Metab Brain Dis. 2024 Dec;39(8):1591-1611. doi: 10.1007/s11011-024-01414-8. Epub 2024 Aug 24. PMID: 39180605.))