Compendium of Cancer Genome Aberrations

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

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==Primary Author(s)==
 
==Primary Author(s)==
   −
Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
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Linda D Cooley, MD, MBA
    
__TOC__
 
__TOC__
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==Cancer Category/Type==
 
==Cancer Category/Type==
   −
Put your text here
+
Brain tumor
    
==Cancer Sub-Classification / Subtype==
 
==Cancer Sub-Classification / Subtype==
   −
Put your text here
+
H3 K27M-mutant glioma
    
==Definition / Description of Disease==
 
==Definition / Description of Disease==
   −
Put your text here
+
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==
 
==Synonyms / Terminology==
   −
Put your text here
+
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==
 
==Epidemiology / Prevalence==
   −
Put your text here
+
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==
 
==Clinical Features==
   −
Put your text here
+
The clinical presentation – brainstem dysfunction, CSF obstruction, increase intracranial pressure, ataxia, cranial nerve injury, progressive sensorimotor deficits.
    
==Sites of Involvement==
 
==Sites of Involvement==
   −
Put your text here
+
Midline locations: brainstem (midbrain, pons, floor 4th ventricle, medulla oblongata), spinal cord, thalamus; Other locations: hypothalamus, pineal region, cerebellum
    
==Morphologic Features==
 
==Morphologic Features==
−
 
+
Histopathology – astrocytic morphology – can range from diffuse low-grade glioma to high grade glioma.
−
Put your text here
+
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==
−
  −
Put your text here or fill in the table
      
{| class="wikitable sortable"
 
{| class="wikitable sortable"
Line 46: Line 52:  
! Finding  !! Marker
 
! Finding  !! Marker
 
|-
 
|-
−
|Positive (universal) || CD1
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|Positive (universal) || H3F3A K27M, NCAM1, S100, Oligo2
 
|-
 
|-
−
|Positive (subset) || CD2
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|Positive (subset) || GFAP variable, MAP2 common, synaptophysin may be focal, TP53, MGMT
 
|-
 
|-
−
|Negative (universal) || CD3
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|Negative (universal) || Chromogranin-A, NeuN, IDH, EGFR
 
|-
 
|-
−
|Negative (subset) || CD4
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|Negative (subset) || ATRX
 
|}
 
|}
−
  −
===Additional Description:===
  −
  −
Put your text here
  −
  −
==Chromosomal Rearrangements (Gene Fusions)==
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  −
Put your text here or fill in the table
  −
  −
{| class="wikitable sortable"
  −
|-
  −
! 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:===
  −
  −
Put your text here
      
==Characteristic Chromosomal Aberrations / Patterns==
 
==Characteristic Chromosomal Aberrations / Patterns==
   −
Put your text here
+
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==
 
==Genomic Gain/Loss/LOH==
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! Chromosome Number !! Gain/Loss/Amp/LOH !! Region
 
! Chromosome Number !! Gain/Loss/Amp/LOH !! Region
 
|-
 
|-
−
| 8 || Gain || chr8:0-1000000
+
| 10 || Loss || Monosomy 10 or 10q loss
 
|-
 
|-
−
|7 || Loss || chr7:0-1000000
+
| 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:===
 
===Additional Description:===
   −
Put your text here
+
'''Mutually exclusive''': IDH1 mutation, EGFR amplification
 +
Rare co-occurrence: BRAF V600E
    
==Gene Mutations (SNV/INDEL)==
 
==Gene Mutations (SNV/INDEL)==
−
  −
Put your text here or fill in the table
      
{| 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)
 
|}
 
|}
−
  −
===Additional Description:===
     −
*Other Mutations
+
{| class="wikitable sortable"
−
Put your text here
+
|-
−
*Concomitant Mutations
+
! Other Mutations !! Concomitant Mutations  
−
Put your text here
+
|-
−
*Secondary Mutations
+
| || C228T TERT promoter mut
−
Put your text here
+
|-
−
*Mutually Exclusive
+
| || activating mutation or fusions targeting FGFR1 (1)
−
Put your text here
+
|-
 +
| || NTRK fusion ~4% pontine gliomas
 +
|}
    
==Epigenomics (Methylation)==
 
==Epigenomics (Methylation)==
   −
Put your text here
+
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==
 
==Genes and Main Pathways Involved==
   −
Put your text here
+
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==
 
==Diagnostic Testing Methods==
   −
Put your text here
+
Histopathology, immunohistochemistry, FISH, sequencing, SNP array
    
==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==
 
==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==
   −
Put your text here
+
H3-K27M mutation associated with aggressive behavior and poor prognosis
 +
Two year survival rate of <10%.
    
==Familial Forms==
 
==Familial Forms==
   −
Put your text here
+
MUTYH germline mutation reported in one case (5)
    
==Other Information==
 
==Other Information==
   −
Put your text here
+
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==
 
==Links==
−
  −
Put your links here
      
==References==
 
==References==
    
=== Reference Example, BOOK ===
 
=== Reference Example, BOOK ===
−
#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.
+
 
 +
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 ===
 
=== Reference Example, Journal Article ===
−
#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.
+
2. Meyronet D, et al. Characteristics of H3 K27M-mutant gliomas in adults. Neuro-Oncology 2017. https://doi.org/10.1093/neuonc/now274
−
 
  −
 
  −
Contributors
  −
Linda D Cooley, MD, MBA
  −
 
  −
Cancer Category/Type
  −
Brain Tumor
     −
Cancer Sub-Classification / Subtype
+
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
−
H3 K27M-mutant glioma
     −
Definition / Description of Disease
+
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
−
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.
+
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
−
 
  −
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
+
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
−
MUTYH germline mutation5 reported in one case
     −
Other Information
+
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.
−
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
+
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.
   −
References
+
[[Category:Brain, Cancer Genes H, Diseases G]]
−
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.
 
Lindacooley
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