Diffuse midline glioma, H3 K27M–mutant

Primary Author(s)

Linda D Cooley, MD, MBA

Cancer Category/Type

Brain tumor

Cancer Sub-Classification / Subtype

H3 K27M-mutant glioma

Definition / Description of Disease

An infiltrative midline high-grade glioma with predominantly astrocytic differentiation and a K27M mutation in either H3F3A or HIST1H3B/C (1).

H3 K27M-mutant diffuse midline glioma predominates in children, but can be seen in adults. It is a grade IV tumor even when mitotic figures, microvascular proliferation and necrosis are absent.

In adults, this is a distinct subgroup of IDH wild-type gliomas characterized by a constant midline location, low rate of MGMT promoter methylation, and poor prognosis (2).

Synonyms / Terminology

Histone H3.3 is a protein that in humans is encoded by the H3F3A gene. Mutations of H3F3A are linked to certain cancers. p.Lys27Met were discovered in Diffuse Intrinsic Pontine Glioma (DIPG), where they are present 65-75% of tumors and confer a worse prognosis. p.Lys27Met alterations in HIST1H3B and HIST1H3C, which code for histone H3.1 have been reported in ~10% of DIPG (7,8).

Epidemiology / Prevalence

Adults (2): Predominately younger adults (<40 yrs); but can occur at any age 2-7.5% of adult IDH wild-type astrocytomas 37.5-66% of adult midline gliomas Pediatric & young adult3: Majority of diffuse intrinsic pontine gliomas (DIPG), thalamic glioblastomas (GBM) Median age 5-11 years with pontine tumors arising at ~7 years and thalamic tumors at ~11 years

Clinical Features

The clinical presentation – brainstem dysfunction, CSF obstruction, increase intracranial pressure, ataxia, cranial nerve injury, progressive sensorimotor deficits.

Sites of Involvement

Midline locations: brainstem (midbrain, pons, floor 4th ventricle, medulla oblongata), spinal cord, thalamus; Other locations: hypothalamus, pineal region, cerebellum

Morphologic Features

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.

Immunophenotype

Finding	Marker
Positive (universal)	H3F3A K27M, NCAM1, S100, Oligo2
Positive (subset)	GFAP variable, MAP2 common, synaptophysin may be focal, TP53, MGMT
Negative (universal)	Chromogranin-A, NeuN, IDH, EGFR
Negative (subset)	ATRX

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). 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

Put your text here or fill in the table

Chromosome Number	Gain/Loss/Amp/LOH	Region
10	Loss	Monosomy 10 or 10q loss
Xq21.1	Loss	ATRX loss
17p13.1	overexpression	TP53
4q12	gain/amplification	PDGFRA (1,8) - ~50% of DIPG
8q24.2	gain/amplification	MYC/PVT1 (1,8) ~35%
12q14.1/7q21.2/11q13.3	gain/amplification	CDK4/6, CCND1-3 (1) ~20%
2p25.1	gain/amplification	ID2 (1) ~10%
7q31.2	gain/amplification	MET (1) ~7%
	losses	5q, 6q, 17p, 21q common (8)
	gains	1q, 2 (1)

Additional Description:

Mutually exclusive: IDH1 mutation, EGFR amplification Rare co-occurrence: BRAF V600E

Gene Mutations (SNV/INDEL)

Mutation %	Mutation
100%	H3F3A or HIST1H3B/C K27M mutation – by definition
~70%	TP53, PPM1D, CHEK2, ATM
~50%	PDGFRA, PIK3CA, PIK3R1, PTEN
~20%	ACVR1 (DIPG)

Other Mutations	Concomitant Mutations
	C228T TERT promoter mut
	activating mutation or fusions targeting FGFR1 (1)
	NTRK fusion ~4% pontine gliomas

Epigenomics (Methylation)

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

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

Histopathology, immunohistochemistry, FISH, sequencing, SNP array

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

H3-K27M mutation associated with aggressive behavior and poor prognosis Two year survival rate of <10%.

Familial Forms

MUTYH germline mutation reported in one case (5)

Other Information

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).

References

Reference Example, BOOK

1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (Eds). WHO classification of tumours of the central nervous system (Revised 4th edition). IARC: Lyon 2016.

Reference Example, Journal Article

2. Meyronet D, et al. Characteristics of H3 K27M-mutant gliomas in adults. Neuro-Oncology 2017. https://doi.org/10.1093/neuonc/now274

3. Solomon DA, et al. Diffuse Midline Gliomas with Histone H3-K27M Mutation: A Series of 47 Cases Assessing the Spectrum of Morphologic Variation and Associated Genetic Alterations. Brain Pathology 2016;26:569-580. https://doi:10.1111/bpa.12336

4. Aboian MS, et al. Imaging Characteristics of Pediatric Diffuse Midline Gliomas with Histone H3 K27M Mutation. Am J Neuroradiol 2017. http://dx.doi.org/10.3174/ajnr.A5076

5. Kline CN, et al. Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy. Neuro-Oncology 2016. https://doi.org/10.1093/neuonc/now254

6. Wernig Marius. Functional Analysis of the H3.3‐K27M mutation in pediatric glioma. http://www.childhoodbraintumor.org/grant-summaries-and-abstracts/item/286-functional-analysis-of-the-h3-3-k27m-mutation-in-pediatric-glioma

7. Wu G, et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nature Genetics 2012;44:251-253.

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.