Diffuse midline glioma, H3 K27M–mutant

Primary Author(s)

Linda D Cooley

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

Additional Description:

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Chromosomal Rearrangements (Gene Fusions)

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Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence
t(9;22)	BCR-ABL1	der(22)	5%
t(8;21)	RUNX1-RUNXT1	der(8)	5%

Additional Description:

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Characteristic Chromosomal Aberrations / Patterns

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Genomic Gain/Loss/LOH

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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%

Additional Description:

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Gene Mutations (SNV/INDEL)

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Gene	Mutation	Oncogene/Tumor Suppressor/Other	Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)	Prevalence (COSMIC/TCGA/Other)
TP53	R273H	Tumor Suppressor	LOF	20%

Additional Description:

• Other Mutations

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• Concomitant Mutations

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• Secondary Mutations

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• Mutually Exclusive

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Epigenomics (Methylation)

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Genes and Main Pathways Involved

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Diagnostic Testing Methods

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Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

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Familial Forms

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Other Information

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Links

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References

Reference Example, BOOK

1. Arber DA, Brunning RD, Le Beau MM, Falini B, Vardiman JW, Porwit A, Thiele J, Bloomfield CD (2008). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4thedition.Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p117-118.

Reference Example, Journal Article

1. Li Y, Mehta PK, Nizetic D, Kaneko Y, Chan GCF, Chan LC, Squire J, Scherer SW and Hitzler JK (2001). Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat Genet 28:220-221, PMID 11431691.

Contributors 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 prognosis2.

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 DIPG7,8.

Epidemiology / Prevalence Adults2: 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 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 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, respectively3. 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 CDK63.

Genomic Gain/Loss/LOH Chromosome location Gain/Loss/Amp/LOH Region 10 loss Monosomy 10 / 10q loss Xq21.1 loss ATRX loss 17p13.1 Overexpression TP53 4q12 Gain/Amplification PDGFRA1,8 - ~50% of DIPG 8q24.2 Gain/Amplification MYC/PVT11,8 ~35% 12q14.1/7q21.2/11q13.3 Gain/Amplification CDK4/6, CCND1-31 ~20% 2p25.1 Gain/Amplification ID21 ~10% 7q31.2 Gain/Amplification MET1 ~7% losses 5q, 6q, 17p, 21q common8 gains 1q, 21

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

Mutations (SNV/INDEL in COSMIC) 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 FGFR11 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 tumorigenesis6.

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 gliomas6.

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 mutation5 reported in one case

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 investigation2,5.

Links

References 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. Meyronet D, et al. Characteristics of H3 K27M-mutant gliomas in adults. Neuro-Oncology 2017. https://doi.org/10.1093/neuonc/now274 2. Solomon DA, et al. K27M Brain Pathology 2016;26:569-580. doi:10.1111/bpa.12336 3. 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 4. 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 5. 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 6. Wu G, et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nature Genetics 2012;44:251-253. 7. 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.