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pHGG - Coggle Diagram

- - - - High frequency of recurrent missense mutations in histone H3 @ amino acid 27.
        
        Lysine to methionine (H3 K27M)
        
        Location of mutations and antatomical positions of tumors
        
        25% mutations occur in 1 of 10 genes encoding the replication dependent H3.1 variant
        
        Most commonly HIST1H3B
        
        75% of K27M mutations occur in H3F3A ( 1 of 2 genes encoding H3.3)
        
        H3 K27M mutation is found in up to 80% of diffuse midline glioma (DMG)
        
        Arising in midline brain structures including, brainstem, pons (DIPG), thalamus and more rarely the cerebellum and spinal cord
        
        Median Ages of Diagnosis
        
        H3.1 K27M tumors almost exclusively occur in pons n youngest DMG patients, with median age of approx.. 5 years old and no difference in sex stratification
        
        H3.3 K27M tumors span a broader range of midline structures and ages with a median age of onset of approx. 8 y.o,
      - Tumors driven by K27 mutations are almost universally fatal with a life expectancy of 3 years
    - - Recurrent missense mutations in histone H3 @ amino acid 34
        
        Glycine to arginine or valine (H3 G34R/V)
        
        Location of mutations and anatomical positions of tumors
        
        H3 G34R/V are found in H3.3 encoded by the gene H3F3A
        
        It arises in the cerebral hemisphere primarily in the parietal or temporal lobes
        
        30% of hemispheric pHGG contain H3.3 G34R/V mutations
        
        Median age of diagnosis
        
        Young Adults with median age 15-19 years and a male predominance
      - Overall survival remains limited to 5 years after diagnosis
    - - molecular characteristics
        
        Amplification or mutations in PDGFRA, TP53, NF1, EGFR, or MYCN
    - - median age
        
        Median age of 2.8 months at time of presentation
      - molecular characteristics
        
        ~80% of these tumors harbor gene fusions in which one of the fusion partners is a receptor tyrosine kinase (RTK) such as: *NTRK, ALK, ROS1 or MET"
    - - H3.1 and H3.2 are the "canonical histones" with replication dependent peak expression during S phases.
        
        Generates a increase in nucleosomes to package newly replicated DNA
        
        H3.1 and H3.2 histone proteins are deposited during S-phase via CAF1 complex
      - H3.3 is the "non-canonical histone" or replication independent. It is expressed and incorporated into nucleosomes independent of the cell cycle.
        
        It is involved in regulation and maintenance of chromatin environment
        
        H3.2 histone protein is incorporated into open chromatin (transcriptionally active regions) via the HIRA complex
        
        H3.3 is incorporated into heterochromatin regions via DAXX-ATRX
      - 3 isoforms of H3 (H3.1, H3.2, H3.3) that are encoded by multigene family of 15 genes.
        
        Only 5 amino acid residues differentiate H3.1 and H3.2 from H3.3