Subtitle: Tumours defined by histone H3 alterations: diffuse midline glioma H3 K27-altered, diffuse hemispheric glioma H3 G34-mutant, giant cell tumour of bone (G34W), chondroblastoma (K36M), and tumours with H3K27me3 loss without mutation (MPNST, PFA ependymoma). Immunohistochemistry, a virtual slide and 8 MCQs.
Author: PathologyMCQ Editorial Board
Category: Molecular Pathology
Last Updated: October 2026
Read Time: 6 minutes
At-a-Glance
- K27M (H3-3A, H3C2): diffuse midline glioma, H3 K27-altered, grade 4.
- G34R/V (H3-3A): diffuse hemispheric glioma, grade 4.
- G34W (H3-3A): giant cell tumour of bone.
- K36M (H3-3B): chondroblastoma.
- H3K27me3 loss without mutation: MPNST (PRC2 loss) and posterior fossa ependymoma group A (EZHIP).
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What Histone Mutations Do
Histone H3 is encoded by several genes; the oncohistone mutations occur in H3-3A (H3F3A), H3-3B (H3F3B) and the canonical H3C2 (HIST1H3B). Each is a single amino-acid substitution near the N-terminal tail, and each blocks a specific chromatin mark: K27M inhibits PRC2 and causes global loss of H3K27 trimethylation; G34R/V/W alters SETD2-mediated K36 methylation; K36M blocks K36 methyltransferases. The mutation, the tumour type and the site are tightly linked, which is why mutation-specific antibodies work so well.
CNS Tumours
| Tumour | Alteration | Site and age | Key features |
|---|---|---|---|
| Diffuse midline glioma, H3 K27-altered | H3 K27M (H3-3A or H3C2); also EZHIP-overexpressing and EGFR-mutant subtypes | Pons, thalamus, spinal cord; children and young adults | Grade 4 regardless of histology; H3 K27M IHC positive, H3K27me3 lost; very poor prognosis |
| Diffuse hemispheric glioma, H3 G34-mutant | H3-3A G34R or G34V | Cerebral hemispheres; adolescents and young adults | Grade 4; ATRX and TP53 mutations, OLIG2 often negative, H3K27me3 retained, MGMT often methylated |
| Posterior fossa ependymoma group A (PFA) | No mutation; EZHIP overexpression (rare H3 K27M) | Posterior fossa; infants | Global H3K27me3 loss on IHC; worse prognosis than PFB |
| Other | Rare H3 K27M in gangliogliomas, pilocytic astrocytomas and circumscribed tumours | Various | K27M in a circumscribed tumour does not automatically make it a diffuse midline glioma |
Bone Tumours
| Tumour | Alteration | Site and age | IHC |
|---|---|---|---|
| Giant cell tumour of bone | H3-3A G34W (95%); rarely G34L, G34V, G34R | Epiphysis/metaphysis of long bones; skeletally mature young adults | G34W antibody positive in mononuclear stromal cells; negative in giant cells and in mimics |
| Chondroblastoma | H3-3B K36M (>90%); rarely H3-3A | Epiphysis and apophysis; adolescents | K36M antibody positive; also positive in a subset of chondromyxoid fibromas |
H3K27me3 Loss Without a Histone Mutation
- Malignant peripheral nerve sheath tumour: loss of H3K27me3 in about 50–70% of conventional MPNSTs, caused by inactivation of PRC2 components EED or SUZ12, often with NF1 and CDKN2A loss. Complete loss is specific but not sensitive. Epithelioid MPNST usually retains H3K27me3 and instead shows SMARCB1 (INI1) loss.
- Posterior fossa ependymoma group A: H3K27me3 loss through EZHIP overexpression.
- Radiation-induced sarcomas and some melanomas: H3K27me3 may be reduced, so interpret with the morphology.
Immunohistochemistry
| Antibody | Positive result means | Use |
|---|---|---|
| H3 K27M | Mutant protein present | Midline gliomas; interpret with H3K27me3 loss |
| H3K27me3 | Retained (normal) nuclear staining; loss is the abnormal result | MPNST, PFA ependymoma, K27M gliomas |
| H3 G34R / G34V | Mutant protein present | Diffuse hemispheric glioma |
| H3 G34W | Mutant protein present | Giant cell tumour of bone vs other giant-cell-rich lesions |
| H3 K36M | Mutant protein present | Chondroblastoma vs clear cell chondrosarcoma and other chondroid tumours |
Virtual Slide
A giant cell tumour of bone: the mononuclear stromal cells carry the G34W mutation; the osteoclast-like giant cells do not.
What to look for
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Question
Which of the following tumours is associated with loss of H3K27me3? A. Malignant peripheral nerve sheath tumour · B. Glioblastoma, IDH-wildtype · C. Hepatocellular carcinoma · D. Gastrointestinal stromal tumour
Show answer
A. Malignant peripheral nerve sheath tumour. Loss of H3K27me3 reflects PRC2 inactivation in conventional MPNST. Among gliomas it is the H3 K27-altered diffuse midline glioma, not adult glioblastoma, that loses H3K27me3.
Test Yourself: 8 MCQs
Histone H3 tumours: 8 MCQs
K27M, G34, K36M and H3K27me3 loss across CNS, bone and soft tissue, with instant explanations.
More practice: the question banks →
Exam Pearls
- K27M = midline, grade 4, H3K27me3 lost.
- G34R/V = hemispheric, grade 4, OLIG2 often negative, H3K27me3 retained.
- G34W = giant cell tumour of bone. K36M = chondroblastoma.
- H3K27me3 loss without mutation: conventional MPNST (PRC2) and PFA ependymoma (EZHIP).
- Epithelioid MPNST: INI1 loss, H3K27me3 usually retained.
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References
- WHO Classification of Tumours Editorial Board. Central Nervous System Tumours. 5th ed. IARC; 2021.
- WHO Classification of Tumours Editorial Board. Soft Tissue and Bone Tumours. 5th ed. IARC; 2020.
- Behjati S, et al. Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat Genet. 2013;45:1479–82.
- Prieto-Granada CN, et al. Loss of H3K27me3 expression is a highly sensitive marker for sporadic and radiation-induced MPNST. Am J Surg Pathol. 2016;40:479–89.
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