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Diffuse midline glioma, H3 K27M–mutant (view source)

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===Additional Description:===

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Mutually exclusive: IDH1 mutation, EGFR amplification

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Rare co-occurrence: BRAF V600E

==Gene Mutations (SNV/INDEL)==

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==Epigenomics (Methylation)==

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The lysine 27 to methionine substitution in histone variant H3.3 (H3.3-K27M) mutation leads to a global reduction of H3K27 trimethylation in a dominant manner by sequestering an enzymatic subunit of the polycomb repressive complex 2 (PRC2). As a consequence, the epigenetic setting of the cell including DNA methylation is altered and drives gene expression changes towards tumorigenesis (6).

==Genes and Main Pathways Involved==

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The lysine 27 to methionine substitution in histone variant H3.3 (H3.3-K27M) is the most common mutation in pediatric high grade gliomas (6).

==Diagnostic Testing Methods==

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Histopathology, immunohistochemistry, FISH, sequencing, SNP array

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==

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H3-K27M mutation associated with aggressive behavior and poor prognosis

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Two year survival rate of <10%.

==Familial Forms==

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MUTYH germline mutation reported in one case (5)

==Other Information==

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K27M mutation alters an important site of post-translational modification in the histone H3 variants and leads to altered DNA methylation and gene expression profiles thought to drive gliomagenesis. There are ongoing studies targeting histone modifying enzymes. A small molecule inhibitor of histone demethylase KDM6B (JMJD3) and a histone deacetylase inhibitor panobinostat are under investigation (2,5).

==Links==

Lindacooley

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