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==Primary Author(s)==

==Primary Author(s)==

Linda D Cooley

Linda D Cooley, MD, MBA

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Histopathology – astrocytic morphology – can range from diffuse low-grade glioma to high grade glioma.

Histopathology – astrocytic morphology – can range from diffuse low-grade glioma to high grade glioma.

H3 K27M-mutant gliomas can display a broad spectrum of histological features, including giant, epithelioid, and rhabdoid cells; primitive neuroectodermal tumor–like foci; ependymal-like areas; sarcomatous transformation, as well as features that may wrongly suggest circumscribed gliomas such as neuropil-like islands, pilomyxoid features, ganglionic differentiation, and pleomorphic xanthoastrocytoma-like areas.

H3 K27M-mutant gliomas can display a broad spectrum of histological features, including giant, epithelioid, and rhabdoid cells; primitive neuroectodermal tumor–like foci; ependymal-like areas; sarcomatous transformation, as well as features that may wrongly suggest circumscribed gliomas such as neuropil-like islands, pilomyxoid features, ganglionic differentiation, and pleomorphic xanthoastrocytoma-like areas.

==Immunophenotype==

==Immunophenotype==

|Negative (subset) || ATRX

|Negative (subset) || ATRX

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==Characteristic Chromosomal Aberrations / Patterns==

==Characteristic Chromosomal Aberrations / Patterns==

H3-K27M mutation defines the entity.  K27M mutation occurs in either of 2 genes, H3F3A or HIST1H3B, which encode the histone H3 variants, H3.3 and H3.1, respectively (3).

H3-K27M mutation defines the entity.  K27M mutation occurs in either of 2 genes, H3F3A or HIST1H3B, which encode the histone H3 variants, H3.3 and H3.1, respectively (3).

Cooperating genetic alterations include: TP53 and ATRX mutations. A subset of K27M+ DIPGs have ACVR1 missense mutations (encodes the activin A receptor type-1 transmembrane protein, that lead to activation of the BMP-TGF signaling pathway). Other alterations found in K27M+ DIPGs include PIK3CA mutation, PDGFRA mutation or amplification, PPM1D mutation, and amplification of cell cycle genes including CCND1, CDK4 and CDK6 (3).

Cooperating genetic alterations include: TP53 and ATRX mutations. A subset of K27M+ DIPGs have ACVR1 missense mutations (encodes the activin A receptor type-1 transmembrane protein, that lead to activation of the BMP-TGF signaling pathway). Other alterations found in K27M+ DIPGs include PIK3CA mutation, PDGFRA mutation or amplification, PPM1D mutation, and amplification of cell cycle genes including CCND1, CDK4 and CDK6 (3).

 

==Genomic Gain/Loss/LOH==

==Genomic Gain/Loss/LOH==

===Additional Description:===

===Additional Description:===

Mutually exclusive: IDH1 mutation, EGFR amplification

'''Mutually exclusive''': IDH1 mutation, EGFR amplification

Rare co-occurrence: BRAF V600E

Rare co-occurrence: BRAF V600E

==Gene Mutations (SNV/INDEL)==

==Gene Mutations (SNV/INDEL)==

{| class="wikitable sortable"

{| class="wikitable sortable"

|-

|-

! Gene !! Mutation !! Oncogene/Tumor Suppressor/Other !! Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) !! Prevalence (COSMIC/TCGA/Other)

! Mutation % !! Mutation

| 100% || H3F3A or HIST1H3B/C K27M mutation – by definition

|-

|-

| TP53 || R273H || Tumor Suppressor || LOF || 20%

| ~70% || TP53, PPM1D, CHEK2, ATM

|-

| ~50% || PDGFRA, PIK3CA, PIK3R1, PTEN

|-

| ~20% || ACVR1 (DIPG)

|}

|}

*Other Mutations

! Other Mutations !! Concomitant Mutations  

==Epigenomics (Methylation)==

==Epigenomics (Methylation)==

==Links==

==Links==

==References==

==References==

8. Khuong-Quang D-A, et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathologica 2012;124:439-447.

8. Khuong-Quang D-A, et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathologica 2012;124:439-447.