Diffuse Midline Glioma, H3 K27-Altered

MONDO:1060171 Pathograph 10 Show in embeddings browser diffuse glioma

Diffuse midline glioma, H3 K27-altered, is a highly aggressive CNS tumor predominantly affecting children and young adults, arising in midline structures including the pons (diffuse intrinsic pontine glioma/DIPG), thalamus, and spinal cord. WHO 2021 classification defines this entity by the presence of H3 K27M mutation (in H3F3A or HIST1H3B/C) or H3 K27 trimethylation loss through other mechanisms (e.g., EZHIP overexpression). The H3 K27M mutation acts as a dominant negative, inhibiting PRC2-mediated H3K27 trimethylation and causing global epigenetic dysregulation. The tumor is universally WHO grade 4, and the infiltrative location typically precludes surgical resection. Prognosis is extremely poor with median survival of 9-11 months for DIPG.

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9
Pathophys.
1
Histopath.
5
Phenotypes
10
Pathograph
7
Genes
4
Medical Actions
3
Subtypes
1
Trials
16
References
1
Deep Research
🏷

Classifications

ICD-O Morphology
Glioma
Harrison's Part
ONCOLOGY HEMATOLOGY
◆

Subtypes

3
Diffuse Intrinsic Pontine Glioma (DIPG)
The most common form, arising in the pons with characteristic diffuse infiltration of pontine structures. Presents with classic triad of cranial nerve deficits, ataxia, and long tract signs. Diagnosis often made on imaging without biopsy. Median survival is less than 12 months.
Show evidence (1 reference)
PMID:19338403 SUPPORT Human Clinical
"Diffuse intrinsic pontine gliomas constitute ~ 60-75% of tumors found within the pediatric brainstem. These malignant lesions present with rapidly progressive symptoms such as cranial nerve, long tract, or cerebellar dysfunctions."
This review identifies DIPG as the dominant pediatric brainstem glioma subtype and describes the rapidly progressive cranial nerve, long tract, and cerebellar presentation summarized in this subtype.
Thalamic H3 K27M-Mutant Glioma
H3 K27-altered glioma arising in the thalamus, often in children, adolescents, and younger adults. May present with hemiparesis, hydrocephalus, or cognitive changes. Bilateral thalamic involvement can occur.
Show evidence (1 reference)
PMID:24285547 SUPPORT Human Clinical
"We found that high-grade thalamic gliomas from young adults, like those from children and adolescents, frequently had H3F3A K27M."
This thalamic glioma cohort directly establishes H3 K27M-altered thalamic tumors as a recognized midline subgroup enriched in younger patients.
Spinal Cord H3 K27M-Mutant Glioma
H3 K27-altered glioma arising in the spinal cord. Presents with progressive sensory or motor deficits from intramedullary cord involvement. This subtype is rare and clinically aggressive.
Show evidence (1 reference)
PMID:35079510 SUPPORT Human Clinical
"Spinal cord DMG, H3K27M-mutant is relatively rare, with poor prognosis, and there are no effective treatment protocols."
This case report identifies spinal cord H3 K27M-mutant diffuse midline glioma as a rare aggressive spinal subtype.
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Pathophysiology

9
H3 K27M Oncohistone Mutation
Lysine-to-methionine substitution at position 27 of histone H3 (K27M) occurs in H3F3A (encoding H3.3) or HIST1H3B/HIST1H3C (encoding H3.1). Despite being present in only 5-15% of total H3 molecules, the mutant histone acts as a dominant negative, sequestering and inhibiting the PRC2 complex.
astrocyte CL:0000127 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves astrocyte (CL:0000127). CL:0000127 is a cell type from the Cell Ontology.
histone H3K27 methyltransferase activity GO:0046976 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased histone H3K27 methyltransferase activity (GO:0046976). GO:0046976 is a molecular function from the Gene Ontology. ↓ DECREASED
pons UBERON:0000988 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in pons (UBERON:0000988). UBERON:0000988 is an anatomical location from the Uberon multi-species anatomy ontology. dorsal plus ventral thalamus UBERON:0001897 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in dorsal plus ventral thalamus (UBERON:0001897). UBERON:0001897 is an anatomical location from the Uberon multi-species anatomy ontology. spinal cord UBERON:0002240 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in spinal cord (UBERON:0002240). UBERON:0002240 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
PRC2 Complex Inhibition and H3K27me3 Loss Mutant H3 K27M sequesters EZH2/PRC2 complex
Show evidence (1 reference)
PMID:41528563 SUPPORT Human Clinical
"H3 K27-altered diffuse midline glioma (DMG) is a molecularly defined, highly aggressive tumor entity since the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS)."
This abstract defines H3 K27-altered DMG as a molecularly defined aggressive entity, supporting the disease context for this mutation-driven tumor.
PRC2 Complex Inhibition and H3K27me3 Loss
The H3 K27M mutant histone binds to and inhibits EZH2, the catalytic subunit of PRC2, which normally trimethylates H3K27. This results in global loss of H3K27me3, a repressive epigenetic mark, leading to aberrant gene activation and loss of cell identity.
negative regulation of gene expression, epigenetic GO:0045814 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of gene expression, epigenetic (GO:0045814). GO:0045814 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Epigenetic Derepression and Aberrant Gene Activation Loss of H3K27me3 derepresses developmental and oncogenic genes
Epigenetic Derepression and Aberrant Gene Activation
Global loss of H3K27me3 causes derepression of genes normally silenced during development, including proliferative and stemness genes. Paradoxically, some loci show retained or increased H3K27me3, suggesting complex redistribution rather than simple loss.
gene expression GO:0010467 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased gene expression (GO:0010467). GO:0010467 is a biological process from the Gene Ontology. ↑ INCREASED cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Loss of Glial Differentiation Epigenetic changes block normal differentiation programs
GD2 Surface Antigen Expression H3 K27M-mutant paediatric high-grade gliomas show upregulation of ganglioside-synthesis pathway component genes relative to H3 wild-type paediatric high-grade gliomas, which the authors read as the oncohistone driving GD2 overexpression. GD2 is therefore a downstream product of the epigenetic derepression programme rather than of the differentiation block.
Loss of Glial Differentiation
Epigenetic dysregulation prevents normal glial differentiation, maintaining cells in a proliferative, undifferentiated state. This contributes to the aggressive behavior and treatment resistance of these tumors.
astrocyte CL:0000127 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves astrocyte (CL:0000127). CL:0000127 is a cell type from the Cell Ontology.
glial cell differentiation GO:0010001 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glial cell differentiation (GO:0010001). GO:0010001 is a biological process from the Gene Ontology. ↓ DECREASED
GD2 Surface Antigen Expression
Patient-derived H3 K27M-mutant glioma cells express the disialoganglioside GD2 uniformly and at high levels, at all three midline sites (pons, thalamus and spinal cord). The reported specificity contrast is against H3 wild-type, GD2-negative paediatric glioma cultures, which GD2-CAR T cells do not kill; GD2 expression in normal brain has been reported separately, and the argument for a therapeutic window rests instead on the absence of significant neurotoxicity in human trials using the same 14g2a-derived binding domain. GD2 is synthesised by GD2 synthase (B4GALNT1); CRISPR deletion of B4GALNT1 abolishes GD2-CAR T cell recognition, establishing the ganglioside as the operative surface target rather than a bystander marker. This node is the therapeutic vulnerability that GD2-directed CAR T cell therapy addresses; it is not by itself a driver of tumour growth.
H3 K27M-mutant glioma cell CL:0001064 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves H3 K27M-mutant glioma cell, annotated with malignant cell (CL:0001064). CL:0001064 is a cell type from the Cell Ontology.
ganglioside biosynthetic process GO:0001574 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased ganglioside biosynthetic process (GO:0001574). GO:0001574 is a biological process from the Gene Ontology. ↑ INCREASED
pons UBERON:0000988 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in pons (UBERON:0000988). UBERON:0000988 is an anatomical location from the Uberon multi-species anatomy ontology. dorsal plus ventral thalamus UBERON:0001897 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in dorsal plus ventral thalamus (UBERON:0001897). UBERON:0001897 is an anatomical location from the Uberon multi-species anatomy ontology. spinal cord UBERON:0002240 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in spinal cord (UBERON:0002240). UBERON:0002240 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
GD2-CAR T Cell-Mediated Tumour Cytotoxicity High, homogeneous GD2 expression permits antigen-dependent recognition and killing of glioma cells by GD2-directed CAR T cells. This edge is intervention-conditioned — it is realised only when GD2-CAR T cells are administered.
Show evidence (3 references)
PMID:29662203 SUPPORT In Vitro
"Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2."
Establishes uniform high GD2 surface expression on patient-derived H3 K27M-mutant glioma cultures, the observation this node records.
PMID:29662203 SUPPORT In Vitro
"In patient-derived cultures of pediatric H3K27M thalamic (QCTB-R059, derived from resection)4, and spinal cord (SU-pSCG1, derived post-mortem) DMGs, GD2 is also highly and uniformly expressed"
Names thalamic and spinal cord patient-derived DMG cultures as also expressing GD2 uniformly and highly, so the antigen is not confined to the pons. This is why the node carries all three midline locations rather than pons alone.
PMID:35130560 SUPPORT Human Clinical
"We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells"
The first-in-human trial report restates high GD2 expression on H3K27M-mutated glioma as the rationale for targeting this antigen.
GD2-CAR T Cell-Mediated Tumour Cytotoxicity
Autologous T cells engineered with a GD2-directed chimeric antigen receptor (GD2 binding domain, 4-1BB co-stimulatory domain, CD3-zeta signalling domain) recognise GD2 on midline glioma cells and mediate antigen-dependent cytotoxicity. In orthotopic xenografts this clears engrafted tumour except for residual GD2-low cells; in the phase I trial it produced volumetric tumour reduction and neurological improvement in a subset of patients. Because the tumour sits in the brainstem or cord, the same inflammatory response produces tumour inflammation-associated neurotoxicity.
GD2-CAR-engineered cytotoxic T cell CL:0000910 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves GD2-CAR-engineered cytotoxic T cell, annotated with cytotoxic T cell (CL:0000910). CL:0000910 is a cell type from the Cell Ontology.
T cell mediated cytotoxicity GO:0001913 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased T cell mediated cytotoxicity (GO:0001913). GO:0001913 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Anti-CAR Adaptive Immune Response The infused CAR construct carries murine-derived and engineered junctional sequences that are foreign to the host, so the therapeutic cell product is itself presented as an antigen and provokes an adaptive response against it.
Show evidence (2 references)
PMID:29662203 SUPPORT Model Organism
"In five independent patient-derived H3-K27M+ DMG orthotopic xenograft models, systemic administration of GD2-targeted CAR T cells cleared engrafted tumors except for a small number of residual GD2lo glioma cells."
Preclinical xenograft evidence that GD2-CAR T cells clear H3 K27M-mutant tumour, and that GD2-low cells escape.
PMID:39537919 SUPPORT Human Clinical
"Four patients demonstrated major volumetric tumour reductions (52, 54, 91 and 100%), with a further three patients exhibiting smaller reductions."
Phase I human evidence that GD2-CAR T cell administration produces measurable antitumour activity in this disease.
Anti-CAR Adaptive Immune Response
Recipients mount a host adaptive immune response directed at the CAR construct rather than at the tumour. Peripheral CD4+ and CD8+ T cells react against epitopes concentrated in the murine-derived and engineered junctional regions of the receptor, and cerebrospinal-fluid B cells clonally expand and secrete human anti-CAR antibodies (HACAs) that bind GD2-CAR-expressing cells and impede their cytotoxic activity. This is an immunogenicity mechanism against the therapeutic product, distinct from tumour-intrinsic antigen loss.
cerebrospinal fluid B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cerebrospinal fluid B cell, annotated with B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology. anti-CAR-reactive T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves anti-CAR-reactive T cell, annotated with T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
adaptive immune response GO:0002250 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased adaptive immune response (GO:0002250). GO:0002250 is a biological process from the Gene Ontology. ↑ INCREASED immunoglobulin production GO:0002377 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased immunoglobulin production (GO:0002377). GO:0002377 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Loss of GD2-CAR T Cell Persistence HACA titres vary inversely with circulating CAR T cell persistence, and non-engineered lymphocytes outcompete CAR T cells in the CSF compartment.
Show evidence (1 reference)
PPR:PPR1276296 Preprint · not peer-reviewed SUPPORT Human Clinical
"This was associated with appearance of circulating Human Anti-CAR Antibodies (HACAs) that bound cells expressing the GD2-CAR, as well as clonal expansion of CSF B cells which produced HACA which impeded the cytotoxic activity of GD2-CAR T cells."
Directly reports the CSF B cell clonal expansion and HACA production that define this node. Non-peer-reviewed preprint - see the node notes.
Loss of GD2-CAR T Cell Persistence
GD2-CAR T cells in the cerebrospinal fluid show limited persistence and clonal expansion while non-engineered lymphocytes expand and come to dominate the CSF immune compartment. Circulating HACA levels correlate inversely with circulating CAR T cell persistence, consistent with immune-mediated clearance of the engineered product.
GD2-CAR-engineered T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves GD2-CAR-engineered T cell, annotated with T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
T cell proliferation GO:0042098 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell proliferation (GO:0042098). GO:0042098 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Acquired Resistance to GD2-CAR T Cell Therapy Without persisting effector cells the antitumour response is not sustained, and tumour growth resumes.
Show evidence (2 references)
PPR:PPR1276296 Preprint · not peer-reviewed SUPPORT Human Clinical
"CSF GD2-CAR T cells manifested limited persistence and clonal expansion, while non-engineered CSF lymphocytes underwent significant clonal expansion and repertoire stabilization, ultimately dominating the CSF immune compartment."
Reports the limited CSF persistence and clonal expansion of the engineered cells that this node records.
PPR:PPR1276296 Preprint · not peer-reviewed SUPPORT Human Clinical
"levels of circulating HACA inversely correlated with circulating CAR T cell persistence"
Links the anti-CAR antibody response upstream to the loss of persistence recorded here. Correlative, not interventional.
Acquired Resistance to GD2-CAR T Cell Therapy
Initial clinical and radiographic benefit from GD2-CAR T cells is followed in many patients by loss of durable response and tumour progression. Responses are not uniformly lost - one trial patient remained in complete response beyond 30 months - so this node records a frequent rather than a universal outcome. Appearance of circulating HACA has been temporally associated with disease progression, identifying anti-CAR immunity as a contributor to acquired resistance alongside the GD2-low residual populations seen preclinically.
Show evidence (3 references)
PPR:PPR1276296 Preprint · not peer-reviewed SUPPORT Human Clinical
"the durability of response has been limited in many patients"
The preprint's own statement of the outcome this node records, and the source of the "many patients" wording used in the description.
PPR:PPR1276296 Preprint · not peer-reviewed SUPPORT Human Clinical
"In several cases, appearance of circulating HACA temporally correlated with disease progression"
Ties the anti-CAR antibody response to clinical progression, the resistance outcome recorded by this node.
PMID:39537919 SUPPORT Human Clinical
"begin to identify potential contributors to, or correlates of, loss of durable response in patients"
The peer-reviewed phase I report states that loss of durable response occurs and that its contributors are only beginning to be identified; it does not itself attribute the loss to anti-CAR immunity. The same report describes a complete response ongoing beyond 30 months, which is why this is PARTIAL support for a "many patients" claim rather than a universal one.
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Histopathology

1
Infiltrative Midline Glioma VERY_FREQUENT
Diffuse midline glioma, H3 K27M-mutant is an infiltrative midline glioma.
Show evidence (1 reference)
PMID:35169084 SUPPORT Human Clinical
"Diffuse midline glioma(DMG), H3 K27M-mutant is an infiltrative midline"
Abstract describes H3 K27M-mutant diffuse midline glioma as infiltrative and midline.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Diffuse Midline Glioma, H3 K27-Altered Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

5
Eye 1
Diplopia FREQUENT HP:0000651 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diplopia (HP:0000651). HP:0000651 is a phenotype from the Human Phenotype Ontology.
Nervous System 4
Cranial Nerve Palsy VERY_FREQUENT Cranial nerve paralysis HP:0006824 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cranial nerve paralysis (HP:0006824). HP:0006824 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19338403 SUPPORT Human Clinical
"These malignant lesions present with rapidly progressive symptoms such as cranial nerve, long tract, or cerebellar dysfunctions."
This review lists cranial nerve dysfunction among hallmark rapidly progressive DIPG symptoms, supporting cranial nerve palsy as a common neurological manifestation.
Ataxia VERY_FREQUENT HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19338403 SUPPORT Human Clinical
"These malignant lesions present with rapidly progressive symptoms such as cranial nerve, long tract, or cerebellar dysfunctions."
Cerebellar dysfunction is a core presentation of DIPG and commonly manifests clinically as ataxia, supporting this phenotype.
Long Tract Signs VERY_FREQUENT Hemiparesis HP:0001269 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemiparesis (HP:0001269). HP:0001269 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19338403 SUPPORT Human Clinical
"These malignant lesions present with rapidly progressive symptoms such as cranial nerve, long tract, or cerebellar dysfunctions."
This review identifies long tract dysfunction as a hallmark of DIPG presentation; in this entry it is represented by pyramidal weakness and hemiparesis.
Headache FREQUENT HP:0002315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Headache (HP:0002315). HP:0002315 is a phenotype from the Human Phenotype Ontology.
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Genetic Associations

7
H3F3A (Somatic Mutation (K27M))
HIST1H3B/HIST1H3C (Somatic Mutation (K27M))
ACVR1 (Somatic Mutation)
Gene: ACVR1 hgnc:171 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ACVR1 (hgnc:171). hgnc:171 is a gene from the HUGO Gene Nomenclature Committee.
TP53 (Somatic Mutation)
Gene: TP53 hgnc:11998 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TP53 (hgnc:11998). hgnc:11998 is a gene from the HUGO Gene Nomenclature Committee.
PPM1D (Somatic Mutation)
Gene: PPM1D hgnc:9277 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PPM1D (hgnc:9277). hgnc:9277 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:35105861 SUPPORT Human Clinical
"truncating mutations in PPM1D that increase the stability of its phosphatase are clonal driver events in 11% of Diffuse Midline Gliomas (DMGs) and are enriched in primary pontine tumors."
Human whole-genome analysis identifies truncating PPM1D mutations as recurrent clonal driver events in diffuse midline glioma, particularly pontine tumors.
PDGFRA (Amplification/Mutation)
Gene: PDGFRA hgnc:8803 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PDGFRA (hgnc:8803). hgnc:8803 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:23970477 SUPPORT Human Clinical
"Genome-wide analyses of copy number imbalances previously showed that platelet-derived growth factor receptor α (PDGFRA) is the most frequent target of focal amplification in pediatric HGGs, including DIPGs."
This pediatric high-grade glioma study identifies PDGFRA as the most frequent focal amplification target in pediatric high-grade gliomas, including DIPG.
PMID:23970477 SUPPORT Human Clinical
"Somatic-activating mutations were identified in 14.4% (13 of 90) of nonbrainstem pediatric HGGs and 4.7% (2 of 43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described."
The same cohort study also documents activating PDGFRA mutations in DIPG, supporting the mutation component of this genetic association.
EZHIP (Overexpression)
Gene: EZHIP hgnc:33738 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EZHIP (hgnc:33738). hgnc:33738 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:36882456 SUPPORT Human Clinical
"We show that these tumours have recurrent and mutually exclusive mutations in either ACVR1 or EGFR and are characterised by high expression of EZHIP associated to its promoter hypomethylation."
This molecular profiling study shows that H3-wild-type H3K27me3-loss diffuse midline gliomas are marked by EZHIP overexpression, supporting EZHIP-driven H3 K27-altered disease in the absence of canonical H3 K27M mutations.
💊

Medical Actions

4
Radiation Therapy
Action: Radiation TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Radiation Therapy (NCIT:C15313). NCIT:C15313 is a clinical intervention from the NCI Thesaurus. NCIT:C15313
Focal radiation therapy (54-59.4 Gy) is the only treatment with established benefit, providing transient neurological improvement and progression-free survival benefit without improving overall survival.
Show evidence (1 reference)
PMID:19338403 SUPPORT Human Clinical
"Standard therapy involves radiotherapy, which produces transient neurological improvement with a progression-free survival benefit, but provides no improvement in overall survival."
This treatment review identifies radiotherapy as the standard modality for DIPG, providing temporary neurologic improvement and delaying progression without curing the disease.
Corticosteroids
Action: systemic corticosteroid therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is systemic corticosteroid therapy (NCIT:C122080). NCIT:C122080 is a clinical intervention from the NCI Thesaurus. Ontology label: Systemic Corticosteroid Therapy NCIT:C122080
Dexamethasone reduces peritumoral edema and provides symptomatic relief. Standard supportive measure during radiation and at progression.
ONC201 (DRD2 Antagonist)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Small molecule DRD2 antagonist and ClpP agonist showing promising activity in H3 K27M-mutant gliomas. Crosses blood-brain barrier. Currently in clinical trials and received FDA Breakthrough Therapy designation.
Show evidence (1 reference)
PMID:36382108 SUPPORT Human Clinical
"Five (22.7%) patients, all of whom initiated ONC201 following radiation and prior to recurrence, were alive at 2 years from diagnosis."
This phase I pediatric trial showed an encouraging early survival signal after ONC201 initiation following radiation, supporting it as a promising but still investigational treatment.
GD2-Directed CAR T Cell Therapy
Action: GD2-directed chimeric antigen receptor T-cell therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is GD2-directed chimeric antigen receptor T-cell therapy, annotated with Chimeric Antigen Receptor T-Cell Therapy (NCIT:C126102). NCIT:C126102 is a clinical intervention from the NCI Thesaurus. Ontology label: Chimeric Antigen Receptor T-Cell Therapy NCIT:C126102
Autologous T cells engineered to express a GD2-directed chimeric antigen receptor (4-1BB co-stimulatory and CD3-zeta signalling domains), given intravenously after lymphodepleting chemotherapy and, in patients with benefit, by subsequent intracerebroventricular infusion. Investigational (phase I, NCT04196413). All treated patients developed tumour inflammation-associated neurotoxicity, which is manageable but requires neurocritical care because of the brainstem or cord location. Durability of response has so far been limited in many patients, though one trial patient remains in complete response beyond 30 months.
Mechanism Target:
ACTIVATES GD2-CAR T Cell-Mediated Tumour Cytotoxicity — The therapy does not alter GD2 expression; it supplies the effector arm that turns pre-existing high tumour GD2 into antigen-dependent killing. The link therefore points at the cytotoxicity node the therapy brings into being, which is also why that node's incoming edge is intervention-conditioned.
Show evidence (1 reference)
PMID:39537919 SUPPORT Human Clinical
"Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models"
States that the engineered T cells act by targeting GD2 and eradicate tumour, i.e. that the therapy produces the antigen-dependent cytotoxicity this link points at.
Show evidence (2 references)
PMID:39537919 SUPPORT Human Clinical
"Sequential IV, followed by ICV GD2-CART, induced tumour regressions and neurological improvements in patients with DIPG and those with sDMG."
Phase I result supporting sequential intravenous then intracerebroventricular GD2-CAR T cells as an active investigational treatment in this disease.
PMID:35130560 SUPPORT Human Clinical
"Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care."
Documents the location-dependent, reversible toxicity profile that governs how this treatment must be delivered.
🔬

Clinical Trials

1
NCT04196413 PHASE_I RECRUITING
Phase 1 dose-escalation trial of autologous GD2-directed CAR T cells (GD2CART) in children and adults with H3K27M-mutant diffuse midline glioma of the pons, spinal cord, or other midline sites, given intravenously with optional subsequent intracerebroventricular infusions. Source of both the peer-reviewed efficacy reports and the correlative anti-CAR immunity analysis curated in this entry.
Show evidence (1 reference)
clinicaltrials:NCT04196413 SUPPORT Human Clinical
"The primary purpose of this study is to test whether CAR T cells targeting GD2 (GD2CART) can be successfully made and safely given to children and adults with H3K27M-mutant diffuse midline glioma (DMG)."
Trial record confirming the population and intervention underlying the GD2-CAR T cell treatment and resistance mechanisms curated here.
{ }

Source YAML

click to show 
name: Diffuse Midline Glioma, H3 K27-Altered
creation_date: '2026-01-26T02:55:13Z'
description: >-
  Diffuse midline glioma, H3 K27-altered, is a highly aggressive CNS tumor
  predominantly affecting children and young adults, arising in midline structures
  including the pons (diffuse intrinsic pontine glioma/DIPG), thalamus, and spinal
  cord. WHO 2021 classification defines this entity by the presence of H3 K27M
  mutation (in H3F3A or HIST1H3B/C) or H3 K27 trimethylation loss through other
  mechanisms (e.g., EZHIP overexpression). The H3 K27M mutation acts as a dominant
  negative, inhibiting PRC2-mediated H3K27 trimethylation and causing global
  epigenetic dysregulation. The tumor is universally WHO grade 4, and the infiltrative
  location typically precludes surgical resection. Prognosis is extremely poor with
  median survival of 9-11 months for DIPG.
categories:
- Central Nervous System Neoplasm
- Pediatric Brain Tumor
- Molecularly Defined Tumor
- High-Grade Glioma
parents:
- diffuse glioma
has_subtypes:
- name: Diffuse Intrinsic Pontine Glioma (DIPG)
  description: >-
    The most common form, arising in the pons with characteristic diffuse
    infiltration of pontine structures. Presents with classic triad of cranial
    nerve deficits, ataxia, and long tract signs. Diagnosis often made on imaging
    without biopsy. Median survival is less than 12 months.
  evidence:
  - reference: PMID:19338403
    reference_title: "Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diffuse intrinsic pontine gliomas constitute ~ 60-75% of tumors found within the pediatric brainstem. These malignant lesions present with rapidly progressive symptoms such as cranial nerve, long tract, or cerebellar dysfunctions."
    explanation: This review identifies DIPG as the dominant pediatric brainstem glioma subtype and describes the rapidly progressive cranial nerve, long tract, and cerebellar presentation summarized in this subtype.
- name: Thalamic H3 K27M-Mutant Glioma
  description: >-
    H3 K27-altered glioma arising in the thalamus, often in children,
    adolescents, and younger adults. May present with hemiparesis,
    hydrocephalus, or cognitive changes. Bilateral thalamic involvement can
    occur.
  evidence:
  - reference: PMID:24285547
    reference_title: "H3F3A K27M mutations in thalamic gliomas from young adult patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found that high-grade thalamic gliomas from young adults, like those from children and adolescents, frequently had H3F3A K27M."
    explanation: This thalamic glioma cohort directly establishes H3 K27M-altered thalamic tumors as a recognized midline subgroup enriched in younger patients.
- name: Spinal Cord H3 K27M-Mutant Glioma
  description: >-
    H3 K27-altered glioma arising in the spinal cord. Presents with progressive
    sensory or motor deficits from intramedullary cord involvement. This subtype
    is rare and clinically aggressive.
  evidence:
  - reference: PMID:35079510
    reference_title: "Spinal Cord Diffuse Midline Glioma, H3K27M- mutant Effectively Treated with Bevacizumab: A Report of Two Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spinal cord DMG, H3K27M-mutant is relatively rare, with poor prognosis, and there are no effective treatment protocols."
    explanation: This case report identifies spinal cord H3 K27M-mutant diffuse midline glioma as a rare aggressive spinal subtype.
pathophysiology:
- name: H3 K27M Oncohistone Mutation
  description: >-
    Lysine-to-methionine substitution at position 27 of histone H3 (K27M) occurs
    in H3F3A (encoding H3.3) or HIST1H3B/HIST1H3C (encoding H3.1). Despite being
    present in only 5-15% of total H3 molecules, the mutant histone acts as a
    dominant negative, sequestering and inhibiting the PRC2 complex.
  evidence:
  - reference: PMID:41528563
    reference_title: "Early distant progression in adult Histone-3 K27-altered diffuse midline gliomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: H3 K27-altered diffuse midline glioma (DMG) is a molecularly defined, highly aggressive tumor entity since the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS).
    explanation: This abstract defines H3 K27-altered DMG as a molecularly defined aggressive entity, supporting the disease context for this mutation-driven tumor.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  molecular_functions:
  - preferred_term: histone H3K27 methyltransferase activity
    modifier: DECREASED
    term:
      id: GO:0046976
      label: histone H3K27 methyltransferase activity
  locations:
  - preferred_term: pons
    term:
      id: UBERON:0000988
      label: pons
  - preferred_term: dorsal plus ventral thalamus
    term:
      id: UBERON:0001897
      label: dorsal plus ventral thalamus
  - preferred_term: spinal cord
    term:
      id: UBERON:0002240
      label: spinal cord
  downstream:
  - target: PRC2 Complex Inhibition and H3K27me3 Loss
    description: Mutant H3 K27M sequesters EZH2/PRC2 complex
- name: PRC2 Complex Inhibition and H3K27me3 Loss
  description: >-
    The H3 K27M mutant histone binds to and inhibits EZH2, the catalytic subunit
    of PRC2, which normally trimethylates H3K27. This results in global loss of
    H3K27me3, a repressive epigenetic mark, leading to aberrant gene activation
    and loss of cell identity.
  biological_processes:
  - preferred_term: negative regulation of gene expression, epigenetic
    modifier: DECREASED
    term:
      id: GO:0045814
      label: negative regulation of gene expression, epigenetic
  downstream:
  - target: Epigenetic Derepression and Aberrant Gene Activation
    description: Loss of H3K27me3 derepresses developmental and oncogenic genes
- name: Epigenetic Derepression and Aberrant Gene Activation
  description: >-
    Global loss of H3K27me3 causes derepression of genes normally silenced during
    development, including proliferative and stemness genes. Paradoxically, some
    loci show retained or increased H3K27me3, suggesting complex redistribution
    rather than simple loss.
  biological_processes:
  - preferred_term: gene expression
    modifier: INCREASED
    term:
      id: GO:0010467
      label: gene expression
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  downstream:
  - target: Loss of Glial Differentiation
    description: Epigenetic changes block normal differentiation programs
  - target: GD2 Surface Antigen Expression
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Upregulation of ganglioside synthesis pathway component genes, including
      B4GALNT1 (GD2 synthase)
    description: >-
      H3 K27M-mutant paediatric high-grade gliomas show upregulation of
      ganglioside-synthesis pathway component genes relative to H3 wild-type
      paediatric high-grade gliomas, which the authors read as the oncohistone
      driving GD2 overexpression. GD2 is therefore a downstream product of the
      epigenetic derepression programme rather than of the differentiation
      block.
    evidence:
    - reference: PMID:29662203
      reference_title: "Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M(+) diffuse midline gliomas."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Upregulation of ganglioside synthesis pathway component genes in H3K27M mutant pediatric high-grade gliomas relative to H3 WT pediatric high-grade gliomas suggests this mutation drives GD2 overexpression."
      explanation: Attributes GD2 overexpression to the H3 K27M mutation acting through derepressed ganglioside-synthesis genes, which is what this edge asserts. The authors' own hedge ("suggests") is why the edge is typed indirect rather than DIRECT.
- name: Loss of Glial Differentiation
  description: >-
    Epigenetic dysregulation prevents normal glial differentiation, maintaining
    cells in a proliferative, undifferentiated state. This contributes to the
    aggressive behavior and treatment resistance of these tumors.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: glial cell differentiation
    modifier: DECREASED
    term:
      id: GO:0010001
      label: glial cell differentiation
- name: GD2 Surface Antigen Expression
  description: >-
    Patient-derived H3 K27M-mutant glioma cells express the disialoganglioside GD2
    uniformly and at high levels, at all three midline sites (pons, thalamus and
    spinal cord). The reported specificity contrast is against H3 wild-type,
    GD2-negative paediatric glioma cultures, which GD2-CAR T cells do not kill;
    GD2 expression in normal brain has been reported separately, and the argument
    for a therapeutic window rests instead on the absence of significant
    neurotoxicity in human trials using the same 14g2a-derived binding domain.
    GD2 is synthesised by GD2 synthase (B4GALNT1); CRISPR deletion of B4GALNT1
    abolishes GD2-CAR T cell recognition, establishing the ganglioside as the
    operative surface target rather than a bystander marker. This node is the
    therapeutic vulnerability that GD2-directed CAR T cell therapy addresses; it
    is not by itself a driver of tumour growth.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: H3 K27M-mutant glioma cell
    term:
      id: CL:0001064
      label: malignant cell
  biological_processes:
  - preferred_term: ganglioside biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0001574
      label: ganglioside biosynthetic process
  locations:
  - preferred_term: pons
    term:
      id: UBERON:0000988
      label: pons
  - preferred_term: dorsal plus ventral thalamus
    term:
      id: UBERON:0001897
      label: dorsal plus ventral thalamus
  - preferred_term: spinal cord
    term:
      id: UBERON:0002240
      label: spinal cord
  evidence:
  - reference: PMID:29662203
    reference_title: "Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M(+) diffuse midline gliomas."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2."
    explanation: Establishes uniform high GD2 surface expression on patient-derived H3 K27M-mutant glioma cultures, the observation this node records.
  - reference: PMID:29662203
    reference_title: "Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M(+) diffuse midline gliomas."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In patient-derived cultures of pediatric H3K27M thalamic (QCTB-R059, derived from resection)4, and spinal cord (SU-pSCG1, derived post-mortem) DMGs, GD2 is also highly and uniformly expressed"
    explanation: Names thalamic and spinal cord patient-derived DMG cultures as also expressing GD2 uniformly and highly, so the antigen is not confined to the pons. This is why the node carries all three midline locations rather than pons alone.
  - reference: PMID:35130560
    reference_title: "GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells"
    explanation: The first-in-human trial report restates high GD2 expression on H3K27M-mutated glioma as the rationale for targeting this antigen.
  downstream:
  - target: GD2-CAR T Cell-Mediated Tumour Cytotoxicity
    description: >-
      High, homogeneous GD2 expression permits antigen-dependent recognition and
      killing of glioma cells by GD2-directed CAR T cells. This edge is
      intervention-conditioned — it is realised only when GD2-CAR T cells are
      administered.
- name: GD2-CAR T Cell-Mediated Tumour Cytotoxicity
  description: >-
    Autologous T cells engineered with a GD2-directed chimeric antigen receptor
    (GD2 binding domain, 4-1BB co-stimulatory domain, CD3-zeta signalling domain)
    recognise GD2 on midline glioma cells and mediate antigen-dependent
    cytotoxicity. In orthotopic xenografts this clears engrafted tumour except for
    residual GD2-low cells; in the phase I trial it produced volumetric tumour
    reduction and neurological improvement in a subset of patients. Because the
    tumour sits in the brainstem or cord, the same inflammatory response produces
    tumour inflammation-associated neurotoxicity.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: GD2-CAR-engineered cytotoxic T cell
    term:
      id: CL:0000910
      label: cytotoxic T cell
  biological_processes:
  - preferred_term: T cell mediated cytotoxicity
    modifier: INCREASED
    term:
      id: GO:0001913
      label: T cell mediated cytotoxicity
  evidence:
  - reference: PMID:29662203
    reference_title: "Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M(+) diffuse midline gliomas."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In five independent patient-derived H3-K27M+ DMG orthotopic xenograft models, systemic administration of GD2-targeted CAR T cells cleared engrafted tumors except for a small number of residual GD2lo glioma cells."
    explanation: Preclinical xenograft evidence that GD2-CAR T cells clear H3 K27M-mutant tumour, and that GD2-low cells escape.
  - reference: PMID:39537919
    reference_title: "Intravenous and intracranial GD2-CAR T cells for H3K27M(+) diffuse midline gliomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four patients demonstrated major volumetric tumour reductions (52, 54, 91 and 100%), with a further three patients exhibiting smaller reductions."
    explanation: Phase I human evidence that GD2-CAR T cell administration produces measurable antitumour activity in this disease.
  downstream:
  - target: Anti-CAR Adaptive Immune Response
    description: >-
      The infused CAR construct carries murine-derived and engineered junctional
      sequences that are foreign to the host, so the therapeutic cell product is
      itself presented as an antigen and provokes an adaptive response against it.
- name: Anti-CAR Adaptive Immune Response
  description: >-
    Recipients mount a host adaptive immune response directed at the CAR construct
    rather than at the tumour. Peripheral CD4+ and CD8+ T cells react against
    epitopes concentrated in the murine-derived and engineered junctional regions
    of the receptor, and cerebrospinal-fluid B cells clonally expand and secrete
    human anti-CAR antibodies (HACAs) that bind GD2-CAR-expressing cells and
    impede their cytotoxic activity. This is an immunogenicity mechanism against
    the therapeutic product, distinct from tumour-intrinsic antigen loss.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cerebrospinal fluid B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: anti-CAR-reactive T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: adaptive immune response
    modifier: INCREASED
    term:
      id: GO:0002250
      label: adaptive immune response
  - preferred_term: immunoglobulin production
    modifier: INCREASED
    term:
      id: GO:0002377
      label: immunoglobulin production
  evidence:
  - reference: PPR:PPR1276296
    reference_title: "Anti-CAR Immunity Drives Acquired Therapeutic Resistance to GD2-CAR T Cell Therapy in Diffuse Midline Glioma"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This was associated with appearance of circulating Human Anti-CAR Antibodies (HACAs) that bound cells expressing the GD2-CAR, as well as clonal expansion of CSF B cells which produced HACA which impeded the cytotoxic activity of GD2-CAR T cells."
    explanation: Directly reports the CSF B cell clonal expansion and HACA production that define this node. Non-peer-reviewed preprint - see the node notes.
  notes: >-
    The anti-CAR immunity evidence is currently a non-peer-reviewed preprint
    (PPR:PPR1276296) reporting correlative single-cell RNA/TCR sequencing from
    NCT04196413. Host anti-CAR immune rejection was already suspected during the
    same trial - the first-in-human report describes increased lymphodepletion
    before a re-infusion "given the concern for immune rejection of the CAR T
    cells" (PMID:35130560) - but the HACA mechanism itself awaits peer review and
    should not be treated as settled.
  downstream:
  - target: Loss of GD2-CAR T Cell Persistence
    description: >-
      HACA titres vary inversely with circulating CAR T cell persistence, and
      non-engineered lymphocytes outcompete CAR T cells in the CSF compartment.
- name: Loss of GD2-CAR T Cell Persistence
  description: >-
    GD2-CAR T cells in the cerebrospinal fluid show limited persistence and clonal
    expansion while non-engineered lymphocytes expand and come to dominate the CSF
    immune compartment. Circulating HACA levels correlate inversely with
    circulating CAR T cell persistence, consistent with immune-mediated clearance
    of the engineered product.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: GD2-CAR-engineered T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: T cell proliferation
    modifier: DECREASED
    term:
      id: GO:0042098
      label: T cell proliferation
  evidence:
  - reference: PPR:PPR1276296
    reference_title: "Anti-CAR Immunity Drives Acquired Therapeutic Resistance to GD2-CAR T Cell Therapy in Diffuse Midline Glioma"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CSF GD2-CAR T cells manifested limited persistence and clonal expansion, while non-engineered CSF lymphocytes underwent significant clonal expansion and repertoire stabilization, ultimately dominating the CSF immune compartment."
    explanation: Reports the limited CSF persistence and clonal expansion of the engineered cells that this node records.
  - reference: PPR:PPR1276296
    reference_title: "Anti-CAR Immunity Drives Acquired Therapeutic Resistance to GD2-CAR T Cell Therapy in Diffuse Midline Glioma"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "levels of circulating HACA inversely correlated with circulating CAR T cell persistence"
    explanation: Links the anti-CAR antibody response upstream to the loss of persistence recorded here. Correlative, not interventional.
  downstream:
  - target: Acquired Resistance to GD2-CAR T Cell Therapy
    description: >-
      Without persisting effector cells the antitumour response is not sustained,
      and tumour growth resumes.
- name: Acquired Resistance to GD2-CAR T Cell Therapy
  description: >-
    Initial clinical and radiographic benefit from GD2-CAR T cells is followed in
    many patients by loss of durable response and tumour progression. Responses
    are not uniformly lost - one trial patient remained in complete response
    beyond 30 months - so this node records a frequent rather than a universal
    outcome. Appearance of circulating HACA has been temporally associated with
    disease progression, identifying anti-CAR immunity as a contributor to
    acquired resistance alongside the GD2-low residual populations seen
    preclinically.
  biological_scale: ORGANISM
  evidence:
  - reference: PPR:PPR1276296
    reference_title: "Anti-CAR Immunity Drives Acquired Therapeutic Resistance to GD2-CAR T Cell Therapy in Diffuse Midline Glioma"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the durability of response has been limited in many patients"
    explanation: The preprint's own statement of the outcome this node records, and the source of the "many patients" wording used in the description.
  - reference: PPR:PPR1276296
    reference_title: "Anti-CAR Immunity Drives Acquired Therapeutic Resistance to GD2-CAR T Cell Therapy in Diffuse Midline Glioma"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In several cases, appearance of circulating HACA temporally correlated with disease progression"
    explanation: Ties the anti-CAR antibody response to clinical progression, the resistance outcome recorded by this node.
  - reference: PMID:39537919
    reference_title: "Intravenous and intracranial GD2-CAR T cells for H3K27M(+) diffuse midline gliomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "begin to identify potential contributors to, or correlates of, loss of durable response in patients"
    explanation: The peer-reviewed phase I report states that loss of durable response occurs and that its contributors are only beginning to be identified; it does not itself attribute the loss to anti-CAR immunity. The same report describes a complete response ongoing beyond 30 months, which is why this is PARTIAL support for a "many patients" claim rather than a universal one.
histopathology:
- name: Infiltrative Midline Glioma
  finding_term:
    preferred_term: Diffuse Midline Glioma, H3 K27-Altered
    term:
      id: NCIT:C185368
      label: Diffuse Midline Glioma, H3 K27-Altered
  frequency: VERY_FREQUENT
  description: Diffuse midline glioma, H3 K27M-mutant is an infiltrative midline glioma.
  evidence:
  - reference: PMID:35169084
    reference_title: "[Diffuse midline glioma]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diffuse midline glioma(DMG), H3 K27M-mutant is an infiltrative midline"
    explanation: Abstract describes H3 K27M-mutant diffuse midline glioma as infiltrative and midline.

phenotypes:
- category: Neurological
  name: Cranial Nerve Palsy
  frequency: VERY_FREQUENT
  description: >-
    Cranial nerve deficits are common in DIPG, particularly affecting CN VI
    (lateral gaze palsy) and CN VII (facial weakness). Part of the classic DIPG
    triad.
  phenotype_term:
    preferred_term: Cranial nerve paralysis
    term:
      id: HP:0006824
      label: Cranial nerve paralysis
  evidence:
  - reference: PMID:19338403
    reference_title: "Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These malignant lesions present with rapidly progressive symptoms such as cranial nerve, long tract, or cerebellar dysfunctions."
    explanation: This review lists cranial nerve dysfunction among hallmark rapidly progressive DIPG symptoms, supporting cranial nerve palsy as a common neurological manifestation.
- category: Neurological
  name: Ataxia
  frequency: VERY_FREQUENT
  description: >-
    Cerebellar ataxia from involvement of cerebellar pathways traversing the
    pons. Part of the classic DIPG triad.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:19338403
    reference_title: "Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These malignant lesions present with rapidly progressive symptoms such as cranial nerve, long tract, or cerebellar dysfunctions."
    explanation: Cerebellar dysfunction is a core presentation of DIPG and commonly manifests clinically as ataxia, supporting this phenotype.
- category: Neurological
  name: Long Tract Signs
  frequency: VERY_FREQUENT
  description: >-
    Pyramidal signs including spasticity, hyperreflexia, and weakness from
    corticospinal tract involvement. Part of the classic DIPG triad.
  phenotype_term:
    preferred_term: Hemiparesis
    term:
      id: HP:0001269
      label: Hemiparesis
  evidence:
  - reference: PMID:19338403
    reference_title: "Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These malignant lesions present with rapidly progressive symptoms such as cranial nerve, long tract, or cerebellar dysfunctions."
    explanation: This review identifies long tract dysfunction as a hallmark of DIPG presentation; in this entry it is represented by pyramidal weakness and hemiparesis.
- category: Neurological
  name: Headache
  frequency: FREQUENT
  description: >-
    Headache from increased intracranial pressure or direct tumor effects.
    May be accompanied by vomiting.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
- category: Neurological
  name: Diplopia
  frequency: FREQUENT
  description: >-
    Double vision from cranial nerve involvement, particularly CN VI causing
    lateral rectus weakness and inability to abduct the eye.
  phenotype_term:
    preferred_term: Diplopia
    term:
      id: HP:0000651
      label: Diplopia
genetic:
- name: H3F3A
  association: Somatic Mutation (K27M)
  notes: >-
    H3F3A encodes the replication-independent histone variant H3.3. K27M mutation
    is most common in DIPG (approximately 80%) and thalamic tumors. H3.3 K27M
    is associated with slightly older age at diagnosis (median 6-7 years).
- name: HIST1H3B/HIST1H3C
  association: Somatic Mutation (K27M)
  notes: >-
    HIST1H3B and HIST1H3C encode replication-dependent histone H3.1 variants.
    H3.1 K27M mutations occur in approximately 15% of DIPG, associated with
    younger age, ACVR1 mutations, and slightly better prognosis.
- name: ACVR1
  gene_term:
    preferred_term: ACVR1
    term:
      id: hgnc:171
      label: ACVR1
  association: Somatic Mutation
  notes: >-
    ACVR1 (activin A receptor type I, also known as ALK2) mutations occur in
    approximately 20-30% of DIPG, almost exclusively co-occurring with H3.1 K27M.
    These activating mutations drive BMP signaling and are also found in
    fibrodysplasia ossificans progressiva.
- name: TP53
  gene_term:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  association: Somatic Mutation
  notes: >-
    TP53 mutations occur in approximately 40-50% of DIPG, often co-occurring
    with H3.3 K27M. Associated with worse prognosis.
- name: PPM1D
  gene_term:
    preferred_term: PPM1D
    term:
      id: hgnc:9277
      label: PPM1D
  association: Somatic Mutation
  evidence:
  - reference: PMID:35105861
    reference_title: "PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "truncating mutations in PPM1D that increase the stability of its phosphatase are clonal driver events in 11% of Diffuse Midline Gliomas (DMGs) and are enriched in primary pontine tumors."
    explanation: Human whole-genome analysis identifies truncating PPM1D mutations as recurrent clonal driver events in diffuse midline glioma, particularly pontine tumors.
  notes: >-
    PPM1D (protein phosphatase Mg2+/Mn2+ dependent 1D) truncating mutations occur
    in approximately 10-15% of DIPG, functionally similar to TP53 loss.
- name: PDGFRA
  gene_term:
    preferred_term: PDGFRA
    term:
      id: hgnc:8803
      label: PDGFRA
  association: Amplification/Mutation
  evidence:
  - reference: PMID:23970477
    reference_title: "Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genome-wide analyses of copy number imbalances previously showed that platelet-derived growth factor receptor α (PDGFRA) is the most frequent target of focal amplification in pediatric HGGs, including DIPGs."
    explanation: This pediatric high-grade glioma study identifies PDGFRA as the most frequent focal amplification target in pediatric high-grade gliomas, including DIPG.
  - reference: PMID:23970477
    reference_title: "Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Somatic-activating mutations were identified in 14.4% (13 of 90) of nonbrainstem pediatric HGGs and 4.7% (2 of 43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described."
    explanation: The same cohort study also documents activating PDGFRA mutations in DIPG, supporting the mutation component of this genetic association.
  notes: >-
    PDGFRA amplification or activating mutations occur in approximately 30% of
    DIPG. Drives proliferation through RTK signaling.
- name: EZHIP
  gene_term:
    preferred_term: EZHIP
    term:
      id: hgnc:33738
      label: EZHIP
  association: Overexpression
  evidence:
  - reference: PMID:36882456
    reference_title: "Histone H3-wild type diffuse midline gliomas with H3K27me3 loss are a distinct entity with exclusive EGFR or ACVR1 mutation and differential methylation of homeobox genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show that these tumours have recurrent and mutually exclusive mutations in either ACVR1 or EGFR and are characterised by high expression of EZHIP associated to its promoter hypomethylation."
    explanation: This molecular profiling study shows that H3-wild-type H3K27me3-loss diffuse midline gliomas are marked by EZHIP overexpression, supporting EZHIP-driven H3 K27-altered disease in the absence of canonical H3 K27M mutations.
  notes: >-
    EZHIP (EZH inhibitory protein) overexpression can cause H3K27me3 loss in the
    absence of H3 K27M mutation. Defines a subset of H3 K27-altered tumors that
    lack histone mutations but have similar epigenetic phenotype.
treatments:
- name: Radiation Therapy
  description: >-
    Focal radiation therapy (54-59.4 Gy) is the only treatment with established
    benefit, providing transient neurological improvement and progression-free
    survival benefit without improving overall survival.
  therapeutic_modality: RADIOTHERAPY
  treatment_term:
    preferred_term: Radiation Therapy
    term:
      id: NCIT:C15313
      label: Radiation Therapy
  evidence:
  - reference: PMID:19338403
    reference_title: "Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Standard therapy involves radiotherapy, which produces transient neurological improvement with a progression-free survival benefit, but provides no improvement in overall survival."
    explanation: This treatment review identifies radiotherapy as the standard modality for DIPG, providing temporary neurologic improvement and delaying progression without curing the disease.
- name: Corticosteroids
  description: >-
    Dexamethasone reduces peritumoral edema and provides symptomatic relief.
    Standard supportive measure during radiation and at progression.
  treatment_term:
    preferred_term: systemic corticosteroid therapy
    term:
      id: NCIT:C122080
      label: Systemic Corticosteroid Therapy
- name: ONC201 (DRD2 Antagonist)
  description: >-
    Small molecule DRD2 antagonist and ClpP agonist showing promising activity
    in H3 K27M-mutant gliomas. Crosses blood-brain barrier. Currently in clinical
    trials and received FDA Breakthrough Therapy designation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:36382108
    reference_title: "Phase I dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five (22.7%) patients, all of whom initiated ONC201 following radiation and prior to recurrence, were alive at 2 years from diagnosis."
    explanation: This phase I pediatric trial showed an encouraging early survival signal after ONC201 initiation following radiation, supporting it as a promising but still investigational treatment.
- name: GD2-Directed CAR T Cell Therapy
  description: >-
    Autologous T cells engineered to express a GD2-directed chimeric antigen
    receptor (4-1BB co-stimulatory and CD3-zeta signalling domains), given
    intravenously after lymphodepleting chemotherapy and, in patients with
    benefit, by subsequent intracerebroventricular infusion. Investigational
    (phase I, NCT04196413). All treated patients developed tumour
    inflammation-associated neurotoxicity, which is manageable but requires
    neurocritical care because of the brainstem or cord location. Durability of
    response has so far been limited in many patients, though one trial patient
    remains in complete response beyond 30 months.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: GD2-directed chimeric antigen receptor T-cell therapy
    term:
      id: NCIT:C126102
      label: Chimeric Antigen Receptor T-Cell Therapy
  target_mechanisms:
  - target: GD2-CAR T Cell-Mediated Tumour Cytotoxicity
    treatment_effect: ACTIVATES
    description: >-
      The therapy does not alter GD2 expression; it supplies the effector arm
      that turns pre-existing high tumour GD2 into antigen-dependent killing.
      The link therefore points at the cytotoxicity node the therapy brings into
      being, which is also why that node's incoming edge is
      intervention-conditioned.
    evidence:
    - reference: PMID:39537919
      reference_title: "Intravenous and intracranial GD2-CAR T cells for H3K27M(+) diffuse midline gliomas."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models"
      explanation: States that the engineered T cells act by targeting GD2 and eradicate tumour, i.e. that the therapy produces the antigen-dependent cytotoxicity this link points at.
  evidence:
  - reference: PMID:39537919
    reference_title: "Intravenous and intracranial GD2-CAR T cells for H3K27M(+) diffuse midline gliomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequential IV, followed by ICV GD2-CART, induced tumour regressions and neurological improvements in patients with DIPG and those with sDMG."
    explanation: Phase I result supporting sequential intravenous then intracerebroventricular GD2-CAR T cells as an active investigational treatment in this disease.
  - reference: PMID:35130560
    reference_title: "GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care."
    explanation: Documents the location-dependent, reversible toxicity profile that governs how this treatment must be delivered.
clinical_trials:
- name: NCT04196413
  phase: PHASE_I
  status: RECRUITING
  description: >-
    Phase 1 dose-escalation trial of autologous GD2-directed CAR T cells
    (GD2CART) in children and adults with H3K27M-mutant diffuse midline glioma of
    the pons, spinal cord, or other midline sites, given intravenously with
    optional subsequent intracerebroventricular infusions. Source of both the
    peer-reviewed efficacy reports and the correlative anti-CAR immunity analysis
    curated in this entry.
  evidence:
  - reference: clinicaltrials:NCT04196413
    reference_title: "Phase 1 Clinical Trial of Autologous GD2 Chimeric Antigen Receptor (CAR) T Cells (GD2CART) for H3K27M-mutant Diffuse Midline Glioma (DMG)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The primary purpose of this study is to test whether CAR T cells targeting GD2 (GD2CART) can be successfully made and safely given to children and adults with H3K27M-mutant diffuse midline glioma (DMG)."
    explanation: Trial record confirming the population and intervention underlying the GD2-CAR T cell treatment and resistance mechanisms curated here.
notes: >-
  The WHO 2021 classification expanded this entity from H3 K27M-mutant to H3 K27-altered
  to include tumors with H3K27me3 loss through other mechanisms (e.g., EZHIP
  overexpression) that share similar biology and prognosis. Diagnosis requires
  demonstration of H3 K27M mutation by immunohistochemistry or sequencing, or
  loss of H3K27me3 with EZHIP overexpression.
disease_term:
  preferred_term: diffuse midline glioma, H3 K27-altered
  term:
    id: MONDO:1060171
    label: diffuse midline glioma, H3 K27-altered

classifications:
  icdo_morphology:
    classification_value: Glioma
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
references:
- reference: DOI:10.1002/jmri.28740
  title: 'The 2021 <scp>WHO</scp> Classification for Gliomas and Implications on Imaging Diagnosis: Part 2—Summary of Imaging Findings on Pediatric‐Type Diffuse High‐Grade Gliomas, Pediatric‐Type Diffuse Low‐Grade Gliomas, and Circumscribed Astrocytic Gliomas'
  found_in:
  - H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
  findings:
  - statement: 'The 2021 <scp>WHO</scp> Classification for Gliomas and Implications on Imaging Diagnosis: Part 2—Summary of Imaging Findings on Pediatric‐Type Diffuse High‐Grade Gliomas, Pediatric‐Type Diffuse Low‐Grade Gliomas, and Circumscribed Astrocytic Gliomas'
    supporting_text: The fifth edition of the World Health Organization (WHO) classification of central nervous system tumors published in 2021 advances the role of molecular diagnostics in the classification of gliomas by emphasizing integrated diagnoses based on histopathology and molecular information and grouping tumors based on genetic alterations.
    evidence:
    - reference: DOI:10.1002/jmri.28740
      reference_title: 'The 2021 <scp>WHO</scp> Classification for Gliomas and Implications on Imaging Diagnosis: Part 2—Summary of Imaging Findings on Pediatric‐Type Diffuse High‐Grade Gliomas, Pediatric‐Type Diffuse Low‐Grade Gliomas, and Circumscribed Astrocytic Gliomas'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The fifth edition of the World Health Organization (WHO) classification of central nervous system tumors published in 2021 advances the role of molecular diagnostics in the classification of gliomas by emphasizing integrated diagnoses based on histopathology and molecular information and grouping tumors based on genetic alterations.
      explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.1016/j.heliyon.2024.e24877
  title: New progress in the treatment of diffuse midline glioma with H3K27M alteration
  found_in:
  - H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
  findings:
  - statement: New progress in the treatment of diffuse midline glioma with H3K27M alteration
    supporting_text: New progress in the treatment of diffuse midline glioma with H3K27M alteration
- reference: DOI:10.1055/s-0043-1771192
  title: 'H3 K27M-Altered Diffuse Midline Gliomas: A Review'
  found_in:
  - H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
  findings:
  - statement: 'H3 K27M-Altered Diffuse Midline Gliomas: A Review'
    supporting_text: Diffuse midline glioma H3 K27M-altered is a recently renamed high-grade glioma in the 2021 World Health Organization (WHO) Classification of Central Nervous System Tumors, previously being labelled diffuse midline glioma H3 K27M-mutant in the 2016 update and diffuse intrinsic pontine glioma prior to 2016.
    evidence:
    - reference: DOI:10.1055/s-0043-1771192
      reference_title: 'H3 K27M-Altered Diffuse Midline Gliomas: A Review'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Diffuse midline glioma H3 K27M-altered is a recently renamed high-grade glioma in the 2021 World Health Organization (WHO) Classification of Central Nervous System Tumors, previously being labelled diffuse midline glioma H3 K27M-mutant in the 2016 update and diffuse intrinsic pontine glioma prior to 2016.
      explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.1080/14728222.2023.2277232
  title: 'Bench-to-bedside investigations of H3 K27-altered diffuse midline glioma: drug targets and potential pharmacotherapies'
  found_in:
  - H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
  findings:
  - statement: 'Bench-to-bedside investigations of H3 K27-altered diffuse midline glioma: drug targets and potential pharmacotherapies'
    supporting_text: 'Bench-to-bedside investigations of H3 K27-altered diffuse midline glioma: drug targets and potential pharmacotherapies'
- reference: DOI:10.1093/noajnl/vdaa142
  title: Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults
  found_in:
  - H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
  findings:
  - statement: Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults
    supporting_text: “Diffuse midline glioma (DMG), H3 K27M-mutant” is a new tumor entity established in the 2016 WHO classification of Tumors of the Central Nervous System that comprises a set of diffuse gliomas arising in midline structures and is molecularly defined by a K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1.
    evidence:
    - reference: DOI:10.1093/noajnl/vdaa142
      reference_title: Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: “Diffuse midline glioma (DMG), H3 K27M-mutant” is a new tumor entity established in the 2016 WHO classification of Tumors of the Central Nervous System that comprises a set of diffuse gliomas arising in midline structures and is molecularly defined by a K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1.
      explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.1111/bpa.12768
  title: Identification of prognostic markers in diffuse midline gliomas H3K27M‐mutant
  found_in:
  - H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
  findings:
  - statement: Pediatric diffuse midline gliomas are devastating diseases.
    supporting_text: Pediatric diffuse midline gliomas are devastating diseases.
    evidence:
    - reference: DOI:10.1111/bpa.12768
      reference_title: Identification of prognostic markers in diffuse midline gliomas H3K27M‐mutant
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Pediatric diffuse midline gliomas are devastating diseases.
      explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.1111/cns.14307
  title: Differences in survival prognosticators between children and adults with <scp>H3K27M</scp>‐mutant diffuse midline glioma
  found_in:
  - H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
  findings:
  - statement: H3K27M‐mutant diffuse midline glioma (DMG) is a rare and aggressive central nervous system tumor.
    supporting_text: H3K27M‐mutant diffuse midline glioma (DMG) is a rare and aggressive central nervous system tumor.
    evidence:
    - reference: DOI:10.1111/cns.14307
      reference_title: Differences in survival prognosticators between children and adults with <scp>H3K27M</scp>‐mutant diffuse midline glioma
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: H3K27M‐mutant diffuse midline glioma (DMG) is a rare and aggressive central nervous system tumor.
      explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.1186/s40478-024-01808-w
  title: 'Neuroradiological, genetic and clinical characteristics of histone H3 K27-mutant diffuse midline gliomas in the Kansai Molecular Diagnosis Network for CNS Tumors (Kansai Network): multicenter retrospective cohort'
  found_in:
  - H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
  findings:
  - statement: This study aims to elucidate the clinical and molecular characteristics, treatment outcomes and prognostic factors of patients with histone H3 K27-mutant diffuse midline glioma.
    supporting_text: This study aims to elucidate the clinical and molecular characteristics, treatment outcomes and prognostic factors of patients with histone H3 K27-mutant diffuse midline glioma.
    evidence:
    - reference: DOI:10.1186/s40478-024-01808-w
      reference_title: 'Neuroradiological, genetic and clinical characteristics of histone H3 K27-mutant diffuse midline gliomas in the Kansai Molecular Diagnosis Network for CNS Tumors (Kansai Network): multicenter retrospective cohort'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: This study aims to elucidate the clinical and molecular characteristics, treatment outcomes and prognostic factors of patients with histone H3 K27-mutant diffuse midline glioma.
      explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.32074/1591-951x-830
  title: Paediatric-type diffuse high-grade gliomas in the 5th CNS WHO Classification
  found_in:
  - H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
  findings:
  - statement: Paediatric-type diffuse high-grade gliomas in the 5th CNS WHO Classification
    supporting_text: Paediatric-type diffuse high-grade gliomas in the 5th CNS WHO Classification
- reference: DOI:10.3389/fonc.2020.602553
  title: 'Clinical Features and Molecular Markers on Diffuse Midline Gliomas With H3K27M Mutations: A 43 Cases Retrospective Cohort Study'
  found_in:
  - H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
  findings:
  - statement: Diffuse midline gliomas (DMG) with H3K27M mutations have been identified as a rare distinctive entity with unique genetic features, varied molecular alterations, and poor prognosis.
    supporting_text: Diffuse midline gliomas (DMG) with H3K27M mutations have been identified as a rare distinctive entity with unique genetic features, varied molecular alterations, and poor prognosis.
    evidence:
    - reference: DOI:10.3389/fonc.2020.602553
      reference_title: 'Clinical Features and Molecular Markers on Diffuse Midline Gliomas With H3K27M Mutations: A 43 Cases Retrospective Cohort Study'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Diffuse midline gliomas (DMG) with H3K27M mutations have been identified as a rare distinctive entity with unique genetic features, varied molecular alterations, and poor prognosis.
      explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.3389/fonc.2022.1082062
  title: 'Pediatric diffuse midline glioma H3K27- altered: A complex clinical and biological landscape behind a neatly defined tumor type'
  found_in:
  - H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
  findings:
  - statement: The 2021 World Health Organization Classification of Tumors of the Central Nervous System, Fifth Edition (WHO-CNS5), has strengthened the concept of tumor grade as a combination of histologic features and molecular alterations.
    supporting_text: The 2021 World Health Organization Classification of Tumors of the Central Nervous System, Fifth Edition (WHO-CNS5), has strengthened the concept of tumor grade as a combination of histologic features and molecular alterations.
    evidence:
    - reference: DOI:10.3389/fonc.2022.1082062
      reference_title: 'Pediatric diffuse midline glioma H3K27- altered: A complex clinical and biological landscape behind a neatly defined tumor type'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The 2021 World Health Organization Classification of Tumors of the Central Nervous System, Fifth Edition (WHO-CNS5), has strengthened the concept of tumor grade as a combination of histologic features and molecular alterations.
      explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.3390/biomedicines12061349
  title: 'The 2021 World Health Organization Central Nervous System Tumor Classification: The Spectrum of Diffuse Gliomas'
  found_in:
  - H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
  findings:
  - statement: The 2021 edition of the World Health Organization (WHO) classification of central nervous system tumors introduces significant revisions across various tumor types.
    supporting_text: The 2021 edition of the World Health Organization (WHO) classification of central nervous system tumors introduces significant revisions across various tumor types.
    evidence:
    - reference: DOI:10.3390/biomedicines12061349
      reference_title: 'The 2021 World Health Organization Central Nervous System Tumor Classification: The Spectrum of Diffuse Gliomas'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The 2021 edition of the World Health Organization (WHO) classification of central nervous system tumors introduces significant revisions across various tumor types.
      explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.3390/cancers15133478
  title: 'Molecular Characterization and Treatment Approaches for Pediatric H3 K27-Altered Diffuse Midline Glioma: Integrated Systematic Review of Individual Clinical Trial Participant Data'
  found_in:
  - H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
  findings:
  - statement: Diffuse midline glioma (DMG), H3 K27-altered are highly aggressive, incurable central nervous system (CNS) tumors.
    supporting_text: Diffuse midline glioma (DMG), H3 K27-altered are highly aggressive, incurable central nervous system (CNS) tumors.
    evidence:
    - reference: DOI:10.3390/cancers15133478
      reference_title: 'Molecular Characterization and Treatment Approaches for Pediatric H3 K27-Altered Diffuse Midline Glioma: Integrated Systematic Review of Individual Clinical Trial Participant Data'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Diffuse midline glioma (DMG), H3 K27-altered are highly aggressive, incurable central nervous system (CNS) tumors.
      explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.3390/cancers16101814
  title: 'Pediatric Diffuse Midline Glioma H3K27-Altered: From Developmental Origins to Therapeutic Challenges'
  found_in:
  - H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
  findings:
  - statement: Diffuse intrinsic pontine glioma (DIPG), now referred to as diffuse midline glioma (DMG), is a highly aggressive pediatric cancer primarily affecting children aged 4 to 9 years old.
    supporting_text: Diffuse intrinsic pontine glioma (DIPG), now referred to as diffuse midline glioma (DMG), is a highly aggressive pediatric cancer primarily affecting children aged 4 to 9 years old.
    evidence:
    - reference: DOI:10.3390/cancers16101814
      reference_title: 'Pediatric Diffuse Midline Glioma H3K27-Altered: From Developmental Origins to Therapeutic Challenges'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Diffuse intrinsic pontine glioma (DIPG), now referred to as diffuse midline glioma (DMG), is a highly aggressive pediatric cancer primarily affecting children aged 4 to 9 years old.
      explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.3390/cells13131122
  title: 'H3K27-Altered Diffuse Midline Glioma of the Brainstem: From Molecular Mechanisms to Targeted Interventions'
  found_in:
  - H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
  findings:
  - statement: Pediatric high-grade gliomas are a devastating subset of brain tumors, characterized by their aggressive pathophysiology and limited treatment options.
    supporting_text: Pediatric high-grade gliomas are a devastating subset of brain tumors, characterized by their aggressive pathophysiology and limited treatment options.
    evidence:
    - reference: DOI:10.3390/cells13131122
      reference_title: 'H3K27-Altered Diffuse Midline Glioma of the Brainstem: From Molecular Mechanisms to Targeted Interventions'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Pediatric high-grade gliomas are a devastating subset of brain tumors, characterized by their aggressive pathophysiology and limited treatment options.
      explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
- reference: DOI:10.3390/diagnostics14232617
  title: 'Clinico–Pathological Features of Diffuse Midline Glioma, H3 K27-Altered in Adults: A Comprehensive Review of the Literature with an Additional Single-Institution Case Series'
  found_in:
  - H3_K27_Altered_Diffuse_Midline_Glioma-deep-research-falcon.md
  findings:
  - statement: Diffuse midline glioma (DMG), H3 K27-altered, is a WHO grade 4 malignant glioma located at midline structures, including the thalamus, brainstem and spinal cord.
    supporting_text: Diffuse midline glioma (DMG), H3 K27-altered, is a WHO grade 4 malignant glioma located at midline structures, including the thalamus, brainstem and spinal cord.
    evidence:
    - reference: DOI:10.3390/diagnostics14232617
      reference_title: 'Clinico–Pathological Features of Diffuse Midline Glioma, H3 K27-Altered in Adults: A Comprehensive Review of the Literature with an Additional Single-Institution Case Series'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Diffuse midline glioma (DMG), H3 K27-altered, is a WHO grade 4 malignant glioma located at midline structures, including the thalamus, brainstem and spinal cord.
      explanation: Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
📚

References & Deep Research

References

16
DOI:10.1002/jmri.28740
The 2021 <scp>WHO</scp> Classification for Gliomas and Implications on Imaging Diagnosis: Part 2—Summary of Imaging Findings on Pediatric‐Type Diffuse High‐Grade Gliomas, Pediatric‐Type Diffuse Low‐Grade Gliomas, and Circumscribed Astrocytic Gliomas
1 finding
The 2021 <scp>WHO</scp> Classification for Gliomas and Implications on Imaging Diagnosis: Part 2—Summary of Imaging Findings on Pediatric‐Type Diffuse High‐Grade Gliomas, Pediatric‐Type Diffuse Low‐Grade Gliomas, and Circumscribed Astrocytic Gliomas
"The fifth edition of the World Health Organization (WHO) classification of central nervous system tumors published in 2021 advances the role of molecular diagnostics in the classification of gliomas by emphasizing integrated diagnoses based on histopathology and molecular information and..."
Show evidence (1 reference)
DOI:10.1002/jmri.28740 SUPPORT Other
"The fifth edition of the World Health Organization (WHO) classification of central nervous system tumors published in 2021 advances the role of molecular diagnostics in the classification of gliomas by emphasizing integrated diagnoses based on histopathology and molecular information and..."
Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
DOI:10.1016/j.heliyon.2024.e24877
New progress in the treatment of diffuse midline glioma with H3K27M alteration
1 finding
New progress in the treatment of diffuse midline glioma with H3K27M alteration
"New progress in the treatment of diffuse midline glioma with H3K27M alteration"
DOI:10.1055/s-0043-1771192
H3 K27M-Altered Diffuse Midline Gliomas: A Review
1 finding
H3 K27M-Altered Diffuse Midline Gliomas: A Review
"Diffuse midline glioma H3 K27M-altered is a recently renamed high-grade glioma in the 2021 World Health Organization (WHO) Classification of Central Nervous System Tumors, previously being labelled diffuse midline glioma H3 K27M-mutant in the 2016 update and diffuse intrinsic pontine glioma..."
Show evidence (1 reference)
DOI:10.1055/s-0043-1771192 SUPPORT Human Clinical
"Diffuse midline glioma H3 K27M-altered is a recently renamed high-grade glioma in the 2021 World Health Organization (WHO) Classification of Central Nervous System Tumors, previously being labelled diffuse midline glioma H3 K27M-mutant in the 2016 update and diffuse intrinsic pontine glioma..."
Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
DOI:10.1080/14728222.2023.2277232
Bench-to-bedside investigations of H3 K27-altered diffuse midline glioma: drug targets and potential pharmacotherapies
1 finding
Bench-to-bedside investigations of H3 K27-altered diffuse midline glioma: drug targets and potential pharmacotherapies
"Bench-to-bedside investigations of H3 K27-altered diffuse midline glioma: drug targets and potential pharmacotherapies"
DOI:10.1093/noajnl/vdaa142
Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults
1 finding
Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults
"“Diffuse midline glioma (DMG), H3 K27M-mutant” is a new tumor entity established in the 2016 WHO classification of Tumors of the Central Nervous System that comprises a set of diffuse gliomas arising in midline structures and is molecularly defined by a K27M mutation in genes encoding the..."
Show evidence (1 reference)
DOI:10.1093/noajnl/vdaa142 SUPPORT Human Clinical
"“Diffuse midline glioma (DMG), H3 K27M-mutant” is a new tumor entity established in the 2016 WHO classification of Tumors of the Central Nervous System that comprises a set of diffuse gliomas arising in midline structures and is molecularly defined by a K27M mutation in genes encoding the..."
Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.
DOI:10.1111/bpa.12768
Identification of prognostic markers in diffuse midline gliomas H3K27M‐mutant
1 finding
Pediatric diffuse midline gliomas are devastating diseases.
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This study aims to elucidate the clinical and molecular characteristics, treatment outcomes and prognostic factors of patients with histone H3 K27-mutant diffuse midline glioma.
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Diffuse midline gliomas (DMG) with H3K27M mutations have been identified as a rare distinctive entity with unique genetic features, varied molecular alterations, and poor prognosis.
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The 2021 World Health Organization Classification of Tumors of the Central Nervous System, Fifth Edition (WHO-CNS5), has strengthened the concept of tumor grade as a combination of histologic features and molecular alterations.
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Diffuse midline glioma (DMG), H3 K27-altered are highly aggressive, incurable central nervous system (CNS) tumors.
"Diffuse midline glioma (DMG), H3 K27-altered are highly aggressive, incurable central nervous system (CNS) tumors."
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"Diffuse intrinsic pontine glioma (DIPG), now referred to as diffuse midline glioma (DMG), is a highly aggressive pediatric cancer primarily affecting children aged 4 to 9 years old."
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Clinico–Pathological Features of Diffuse Midline Glioma, H3 K27-Altered in Adults: A Comprehensive Review of the Literature with an Additional Single-Institution Case Series
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Diffuse midline glioma (DMG), H3 K27-altered, is a WHO grade 4 malignant glioma located at midline structures, including the thalamus, brainstem and spinal cord.
"Diffuse midline glioma (DMG), H3 K27-altered, is a WHO grade 4 malignant glioma located at midline structures, including the thalamus, brainstem and spinal cord."
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DOI:10.3390/diagnostics14232617 SUPPORT Human Clinical
"Diffuse midline glioma (DMG), H3 K27-altered, is a WHO grade 4 malignant glioma located at midline structures, including the thalamus, brainstem and spinal cord."
Deep research cited this publication as relevant literature for H3 K27 Altered Diffuse Midline Glioma.

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1. Disease Information
Edison Scientific Literature 70 citations 2026-04-05T15:49:04.719582

1. Disease Information

1.1 Concise overview

Diffuse midline glioma, H3 K27-altered is an infiltrative midline glioma defined by H3K27-pathway disruption (loss of H3K27 trimethylation) and is assigned CNS WHO grade 4 regardless of histologic features. It most commonly arises in midline CNS structures such as the pons/brainstem (historically “DIPG”), thalamus, and spinal cord and carries a poor prognosis, especially in children. (park2023the2021who pages 2-2, park2023the2021who pages 6-7, vallero2023pediatricdiffusemidline pages 2-3)

1.2 Key identifiers and ontology mapping

  • MONDO: MONDO:1060171 (vallero2023pediatricdiffusemidline pages 2-3)
  • WHO CNS classification: WHO CNS5 (2021), pediatric-type diffuse high-grade glioma family; DMG, H3 K27-altered is a tumor type within this family (gianno2022paediatrictypediffusehighgrade pages 1-2)
  • Diagnostic molecular criteria (WHO CNS5-aligned): midline location plus H3 K27M mutation OR EZHIP overexpression OR EGFR alteration → “diffuse midline glioma, H3 K27-altered” (park2023the2021who pages 2-2)

Not retrieved in this tool session: ICD-10/ICD-11 codes, MeSH IDs, Orphanet IDs, OMIM disease entry IDs. These may exist but were not present in the provided full-text evidence chunks.

1.3 Common synonyms / alternative names

  • “Diffuse midline glioma, H3 K27M-mutant” (WHO 2016 name)
  • “Diffuse intrinsic pontine glioma (DIPG)” (clinical/radiologic term for pontine cases)
  • “H3K27-altered diffuse midline glioma” (wisniewski2023h3k27maltereddiffuse pages 1-3, vallero2023pediatricdiffusemidline pages 2-3)

1.4 Evidence source types

The synthesis below is derived from aggregated resources: multicenter and single-center retrospective cohorts, systematic reviews, and contemporary narrative reviews, plus trial registry entries (ClinicalTrials.gov). (hayashi2024neuroradiologicalgeneticand pages 1-2, damodharan2023molecularcharacterizationand pages 1-2, NCT04808245 chunk 1, NCT04196413 chunk 2)

Preferred name MONDO ID WHO CNS grade / WHO 2021 (CNS5) definition criteria Major synonyms / alternative names Typical midline anatomical sites Key references (year; DOI URL; PMID if available)
Diffuse midline glioma, H3 K27-altered MONDO:1060171 CNS WHO grade 4. WHO CNS5 defines this as an infiltrative/diffuse midline glioma with loss of H3K27me3 and one of the following molecular features: H3 p.K28M (K27M) alteration in histone H3 isoforms, EZHIP overexpression, or EGFR alteration; diagnosis should be restricted to diffuse, midline, astrocytic tumors. (park2023the2021who pages 2-2, gue2024the2021world pages 15-16, broggi2024clinico–pathologicalfeaturesof pages 1-2, wisniewski2023h3k27maltereddiffuse pages 1-3, park2023the2021who pages 6-7) Diffuse midline glioma, H3 K27M-mutant; DMG, H3 K27-altered; H3K27-altered diffuse midline glioma; diffuse intrinsic pontine glioma (DIPG; historical/clinical term, especially for pontine tumors); pediatric-type diffuse high-grade glioma, H3 K27-altered subset. (vallero2023pediatricdiffusemidline pages 2-3, nonnenbroich2024h3k27altereddiffusemidline pages 1-2, wisniewski2023h3k27maltereddiffuse pages 1-3, park2023the2021who pages 7-7) Pons/brainstem (classic DIPG location), thalamus, spinal cord; other reported midline sites include cerebellum, third ventricle, mesencephalon, and multifocal midline locations. (vallero2023pediatricdiffusemidline pages 2-3, broggi2024clinico–pathologicalfeaturesof pages 1-2, schulte2020clinicalradiologicand pages 1-2, hayashi2024neuroradiologicalgeneticand pages 1-2) Vallero et al. 2023; https://doi.org/10.3389/fonc.2022.1082062; PMID not provided. (vallero2023pediatricdiffusemidline pages 2-3)
Diffuse midline glioma, H3 K27-altered MONDO:1060171 WHO CNS5 renamed the 2016 entity “diffuse midline glioma, H3 K27M-mutant” to “diffuse midline glioma, H3 K27-altered” to encompass additional mechanisms causing H3 K27 hypomethylation beyond canonical H3K27M mutation. (gue2024the2021world pages 15-16, wisniewski2023h3k27maltereddiffuse pages 1-3, park2023the2021who pages 6-7) Former WHO 2016 name: diffuse midline glioma, H3 K27M-mutant; older umbrella clinical usage: DIPG for pontine cases. (wisniewski2023h3k27maltereddiffuse pages 1-3, park2023the2021who pages 7-7) Midline CNS structures, especially pons, thalamus, spinal cord. (vallero2023pediatricdiffusemidline pages 2-3, broggi2024clinico–pathologicalfeaturesof pages 1-2, hayashi2024neuroradiologicalgeneticand pages 1-2) Gianno et al. 2022; https://doi.org/10.32074/1591-951x-830; PMID not provided. (gianno2022paediatrictypediffusehighgrade pages 1-2)
Diffuse midline glioma, H3 K27-altered MONDO:1060171 WHO-recognized molecular subtypes/mechanisms include: H3.3 p.K28M (H3F3A), H3.1/H3.2 p.K28M (HIST1H3B/HIST1H3C), H3-wildtype with EZHIP overexpression, and EGFR-altered tumors; all are assigned grade 4 regardless of histology. (gue2024the2021world pages 15-16, gianno2022paediatrictypediffusehighgrade pages 1-2, park2023the2021who pages 6-7) H3.3 K27M DMG; H3.1/H3.2 K27M DMG; H3-wildtype/EZHIP-overexpressing DMG; EGFR-altered DMG. (gue2024the2021world pages 15-16, gianno2022paediatrictypediffusehighgrade pages 1-2, park2023the2021who pages 6-7) Brainstem/pons, thalamus, spinal cord; age/site patterns differ by subtype, with pontine predominance in many pediatric H3.1/H3.2 cases and broader midline distribution in H3.3 cases. (vallero2023pediatricdiffusemidline pages 2-3, gianno2022paediatrictypediffusehighgrade pages 1-2) Park et al. 2023; https://doi.org/10.1002/jmri.28740; PMID not provided. (park2023the2021who pages 2-2, park2023the2021who pages 6-7)
Diffuse midline glioma, H3 K27-altered MONDO:1060171 Diagnostic pathology commonly uses immunohistochemistry for H3 K27M, H3 K27me3 loss, and EZHIP; diffuse strong H3 K27M staining with H3K27me3 loss supports diagnosis when integrated with diffuse midline astrocytic morphology. (broggi2024clinico–pathologicalfeaturesof pages 1-2) H3 K27M-positive diffuse midline glioma; H3K27me3-loss diffuse midline glioma (descriptor, not a formal synonym on its own). (broggi2024clinico–pathologicalfeaturesof pages 1-2, wisniewski2023h3k27maltereddiffuse pages 1-3) Same midline locations; pathology emphasis does not alter anatomic distribution. (broggi2024clinico–pathologicalfeaturesof pages 1-2) Broggi et al. 2024; https://doi.org/10.3390/diagnostics14232617; PMID not provided. (broggi2024clinico–pathologicalfeaturesof pages 1-2)
Diffuse midline glioma, H3 K27-altered MONDO:1060171 Review sources emphasize that although DMG is classified as a pediatric-type diffuse high-grade glioma, it also occurs in adults; adult series show thalamic predominance more often than pediatric series, which are often pontine. (broggi2024clinico–pathologicalfeaturesof pages 1-2, schulte2020clinicalradiologicand pages 1-2, park2023the2021who pages 6-7) Adult diffuse midline glioma, H3 K27-altered; pediatric diffuse midline glioma, H3 K27-altered. (broggi2024clinico–pathologicalfeaturesof pages 1-2, schulte2020clinicalradiologicand pages 1-2) Adults: commonly thalamus; children: often pons/brainstem; spinal cord occurs in both. (broggi2024clinico–pathologicalfeaturesof pages 1-2, schulte2020clinicalradiologicand pages 1-2, hayashi2024neuroradiologicalgeneticand pages 1-2) Schulte et al. 2020; https://doi.org/10.1093/noajnl/vdaa142; PMID not provided. (schulte2020clinicalradiologicand pages 1-2)
Diffuse midline glioma, H3 K27-altered MONDO:1060171 Concise WHO-style definition quoted in review literature: “An infiltrative midline glioma with loss of H3 p.K28me3 (K27me3) and either an H3 c.83A>T p.K28M substitution in one of the histone H3 isoforms, aberrant overexpression of EZHIP, or an EGFR mutation.” (wisniewski2023h3k27maltereddiffuse pages 1-3) DMG H3 K27-altered; previously DMG H3 K27M-mutant. (wisniewski2023h3k27maltereddiffuse pages 1-3) Midline CNS, especially pons, thalamus, spinal cord. (wisniewski2023h3k27maltereddiffuse pages 1-3) Wiśniewski et al. 2023; https://doi.org/10.1055/s-0043-1771192; PMID not provided. (wisniewski2023h3k27maltereddiffuse pages 1-3)

Table: This table summarizes the core identifiers, nomenclature changes, WHO CNS5 diagnostic criteria, synonyms, and typical anatomical sites for diffuse midline glioma, H3 K27-altered. It is useful as a compact reference for disease ontology and naming normalization in a knowledge base.

2. Etiology

2.1 Primary causal factors

DMG, H3 K27-altered is primarily driven by somatic alterations affecting histone H3 lysine-27 regulation, most commonly a K27M missense substitution in histone H3 genes, leading to epigenetic dysregulation. (mandorino2024pediatricdiffusemidline pages 1-2, gue2024the2021world pages 15-16)

2.2 Risk factors

  • Genetic risk factors (germline): No consistent inherited causal variants were identified in the retrieved sources; the defining events are described as tumor somatic alterations. (mandorino2024pediatricdiffusemidline pages 1-2, gue2024the2021world pages 15-16)
  • Environmental risk factors: No specific environmental exposures were identified in the retrieved evidence.

2.3 Protective factors

No validated protective factors (genetic or environmental) were identified in the retrieved evidence.

2.4 Gene–environment interactions

No gene–environment interaction evidence was identified in the retrieved sources.

3. Phenotypes

3.1 Core clinical phenotype (especially pontine/brainstem cases)

A common presentation—classically described for DIPG/brainstem DMG—includes cranial neuropathies, long-tract (pyramidal) signs, and ataxia. Vallero et al. additionally specify long-tract findings such as hyperreflexia, clonus, increased tone, and Babinski sign. (vallero2023pediatricdiffusemidline pages 2-3, broggi2024clinico–pathologicalfeaturesof pages 1-2)

Mandorino et al. (2024) highlight pediatric presentations including coordination problems, limb weakness, speech difficulties, and vision impairment. (mandorino2024pediatricdiffusemidline pages 1-2)

3.2 Age of onset and course

  • Predominantly a pediatric disease; pediatric DMG/DIPG often affects children in early childhood/school age (e.g., 4–9 years in one review). (mandorino2024pediatricdiffusemidline pages 1-2, vallero2023pediatricdiffusemidline pages 2-3)
  • Adults are also affected, with adult cohorts showing frequent thalamic involvement and longer median survival than historical pediatric cohorts. (schulte2020clinicalradiologicand pages 1-2, broggi2024clinico–pathologicalfeaturesof pages 1-2)

3.3 Suggested HPO mappings

Clinical feature Phenotype type (symptom/sign) Typical age/setting Frequency or qualitative note Suggested HPO term(s)
Cranial nerve palsy / multiple cranial neuropathies Sign Most typical in pediatric pontine/brainstem DMG (classic DIPG presentation); also described in adult brainstem cases Part of the classic DIPG triad; commonly reported at presentation in pontine disease (vallero2023pediatricdiffusemidline pages 2-3, broggi2024clinico–pathologicalfeaturesof pages 1-2) Cranial nerve palsy [HP:0006999]; Abducens nerve palsy [HP:0001260]; Facial palsy [HP:0010628]
Long-tract signs / pyramidal tract dysfunction Sign Common in pediatric and adult brainstem DMG/DIPG Part of the classic DIPG triad; often includes hyperreflexia, clonus, increased tone, and Babinski sign (vallero2023pediatricdiffusemidline pages 2-3, broggi2024clinico–pathologicalfeaturesof pages 1-2, nonnenbroich2024h3k27altereddiffusemidline pages 1-2) Hyperreflexia [HP:0001347]; Clonus [HP:0002169]; Spasticity [HP:0001257]; Extensor plantar response [HP:0003487]
Ataxia / cerebellar signs / coordination problems Symptom/sign Very common in pediatric pontine DMG; also seen in adults with brainstem involvement Part of the classic DIPG triad; often manifests as gait instability or incoordination (vallero2023pediatricdiffusemidline pages 2-3, broggi2024clinico–pathologicalfeaturesof pages 1-2, mandorino2024pediatricdiffusemidline pages 1-2, nonnenbroich2024h3k27altereddiffusemidline pages 1-2) Ataxia [HP:0001251]; Gait ataxia [HP:0002066]; Dysmetria [HP:0001310]
Limb weakness Symptom/sign Pediatric-onset disease, especially brainstem DMG; may occur in adults as well Common presenting complaint reflecting corticospinal tract involvement (mandorino2024pediatricdiffusemidline pages 1-2) Muscle weakness [HP:0001324]; Paresis [HP:0004305]
Speech difficulties / dysarthria Symptom/sign Common in children with brainstem DMG Frequently accompanies cranial nerve and long-tract involvement (mandorino2024pediatricdiffusemidline pages 1-2) Dysarthria [HP:0001260]; Speech disorder [HP:0002167]
Vision impairment / diplopia / oculomotor disturbance Symptom/sign Common in pediatric brainstem DMG; also expected in adult pontine disease with cranial nerve involvement Often related to cranial neuropathy in pontine tumors (mandorino2024pediatricdiffusemidline pages 1-2, nonnenbroich2024h3k27altereddiffusemidline pages 1-2) Abnormality of vision [HP:0000504]; Diplopia [HP:0000651]; Gaze palsy [HP:0000605]
Nausea Symptom Can occur with thalamic or third-ventricular/midline tumors; reported in adult cases Less specific than DIPG triad; may accompany raised intracranial pressure or hydrocephalus (broggi2024clinico–pathologicalfeaturesof pages 1-2, nonnenbroich2024h3k27altereddiffusemidline pages 1-2) Nausea [HP:0002018]
Fatigue Symptom Reported in adult thalamic/midline cases Nonspecific but documented in adult presentation (nonnenbroich2024h3k27altereddiffusemidline pages 1-2) Fatigue [HP:0012378]
Walking impairment / gait disturbance Symptom/sign Pediatric and adult disease, especially with ataxia or weakness Reflects cerebellar signs and/or corticospinal dysfunction; common functional consequence (mandorino2024pediatricdiffusemidline pages 1-2) Gait disturbance [HP:0001288]; Abnormality of gait [HP:0001288]
Childhood onset Clinical course feature Most commonly ages 5-10 years; DIPG often described in children 4-9 years old Predominantly pediatric tumor overall (vallero2023pediatricdiffusemidline pages 2-3, mandorino2024pediatricdiffusemidline pages 1-2) Childhood onset [HP:0011463]
Young adult/adult onset Clinical course feature Adults can be affected, often with thalamic predominance Less common than pediatric disease; adult cases may show somewhat less aggressive clinical behavior than pediatric disease (broggi2024clinico–pathologicalfeaturesof pages 1-2, schulte2020clinicalradiologicand pages 1-2) Adult onset [HP:0003581]
Rapidly progressive neurologic decline Clinical course feature Characteristic of both pediatric and adult DMG, especially untreated/progressive disease Qualitatively severe and progressive; prognosis remains poor and disease is highly aggressive (broggi2024clinico–pathologicalfeaturesof pages 1-2, mandorino2024pediatricdiffusemidline pages 1-2, nonnenbroich2024h3k27altereddiffusemidline pages 1-2) Progressive neurologic deterioration [HP:0002344]

Table: This table summarizes the characteristic clinical presentation of diffuse midline glioma, H3 K27-altered, including the classic DIPG triad and other common symptoms, with suggested HPO mappings. It is useful for phenotype curation and disease knowledge base annotation.

3.4 Quality-of-life impact

Neurologic deficits (ataxia, cranial nerve palsies, long-tract signs/weakness) directly impair gait, speech, vision, and daily function; radiotherapy is used palliatively to reduce symptoms but does not cure disease. (vallero2023pediatricdiffusemidline pages 2-3, mandorino2024pediatricdiffusemidline pages 1-2)

4. Genetic / Molecular Information

4.1 Causal genes and defining alterations

WHO CNS5 recognizes DMG, H3 K27-altered as defined by H3 K27M mutation, or alternative molecular mechanisms including EZHIP overexpression or EGFR alteration, all producing loss of H3K27 methylation. (park2023the2021who pages 2-2, gue2024the2021world pages 15-16, park2023the2021who pages 6-7)

A review definition consistent with WHO CNS5 is quoted as: “An infiltrative midline glioma with loss of H3 p.K28me3 (K27me3) and either … p.K28M (K27M) … aberrant overexpression of EZHIP, or an EGFR mutation (CNS WHO grade 4).” (wisniewski2023h3k27maltereddiffuse pages 1-3)

4.2 Frequencies of major alterations (selected cohorts)

  • Pediatric/combined cohorts: Dufour et al. report H3F3A K27M ~63.6% and HIST1H3B K27M ~15.9% among interpretable tumors; ~20.5% were histone wild-type in their cohort. (dufour2020identificationofprognostic pages 8-10)
  • Kansai multicenter cohort (n=93 DMG): MGMT promoter methylation 9%, FGFR1 mutation 14%, EGFR mutation 3%, TERT promoter mutation 3%, BRAF V600E 1%, HIST1H3B K27M 2%. (hayashi2024neuroradiologicalgeneticand pages 1-2)

4.3 Prognostic molecular markers

  • TP53 alteration/p53 overexpression is repeatedly associated with worse outcomes (damodharan2023molecularcharacterizationand pages 1-2, wang2021clinicalfeaturesand pages 3-4)
  • PDGFRA amplification, 17p loss, and complex chromosomal profiles were associated with worse survival in a pediatric cohort. (dufour2020identificationofprognostic pages 8-10)
  • MGMT promoter methylation is uncommon and was not associated with OS in an adult cohort analysis; this supports the concept that temozolomide benefit may be limited in many cases. (gong2023differencesinsurvival pages 7-9, hayashi2024neuroradiologicalgeneticand pages 1-2)
Alteration (gene/marker) Alteration type Typical context (pediatric/adult; location) Frequency/statistic with cohort details Prognostic association (direction, OS/PFS) Evidence type (cohort/systematic review/review) Key citation (DOI URL and year)
H3 K27M in histone H3 genes (overall) Somatic missense driver altering histone H3 lysine 27 biology Predominantly pediatric DMG/DIPG in midline structures; also occurs in adults ~85% of DIPG/DMG tumors harbor K27M mutations in H3.3/H3.1 genes in review synthesis (mandorino2024pediatricdiffusemidline pages 1-2) Defining oncogenic event; associated with universally poor prognosis overall, but not itself a within-DMG stratifier in this summary (mandorino2024pediatricdiffusemidline pages 1-2) Review https://doi.org/10.3390/cancers16101814 (2024) (mandorino2024pediatricdiffusemidline pages 1-2)
H3F3A p.K27M (H3.3) Somatic missense driver Pediatric and adult DMG; pediatric pontine/thalamic/spinal, adult predominantly thalamic in one cohort Dufour 2020: 28/44 interpretable cases (63.6%); Schulte 2020: adult cohort mutations exclusively in H3F3A among sequenced tumors; Damodharan 2023 identifies H3.3 as a prominent alteration across trial IPD (dufour2020identificationofprognostic pages 8-10, schulte2020clinicalradiologicand pages 1-2, damodharan2023molecularcharacterizationand pages 1-2) Worse OS versus H3.1/HIST1H3B in pediatric disease; Damodharan 2023 found H3.3 associated with worse OS (dufour2020identificationofprognostic pages 8-10, damodharan2023molecularcharacterizationand pages 1-2) Cohort + adult cohort + systematic review/IPD https://doi.org/10.1111/bpa.12768 (2020); https://doi.org/10.1093/noajnl/vdaa142 (2020); https://doi.org/10.3390/cancers15133478 (2023) (dufour2020identificationofprognostic pages 8-10, schulte2020clinicalradiologicand pages 1-2, damodharan2023molecularcharacterizationand pages 1-2)
HIST1H3B p.K27M (H3.1) Somatic missense driver More typical in younger pediatric pontine tumors; uncommon in adults Dufour 2020: 7 cases (15.9% of interpretable tumors); Hayashi 2024: 2% HIST1H3B p.K27M in multicenter cohort; absent in Schulte adult sequencing subset (dufour2020identificationofprognostic pages 8-10, hayashi2024neuroradiologicalgeneticand pages 1-2, schulte2020clinicalradiologicand pages 1-2) Pediatric Dufour cohort: longer median OS than H3F3A-mutant tumors (12.1 vs 7.9 months), suggesting relatively better prognosis than H3.3-mutant disease (dufour2020identificationofprognostic pages 8-10) Cohort + multicenter cohort + adult cohort https://doi.org/10.1111/bpa.12768 (2020); https://doi.org/10.1186/s40478-024-01808-w (2024); https://doi.org/10.1093/noajnl/vdaa142 (2020) (dufour2020identificationofprognostic pages 8-10, hayashi2024neuroradiologicalgeneticand pages 1-2, schulte2020clinicalradiologicand pages 1-2)
TP53 alteration / p53 overexpression Tumor suppressor mutation / IHC surrogate Common in pediatric and adult DMG; not location-specific Dufour 2020: TP53 mutations in 57.1% of H3K27-mutant tumors; Schulte 2020: TP53 frequently co-mutated in adults; Wang 2021 identified p53 overexpression as a negative factor (dufour2020identificationofprognostic pages 8-10, schulte2020clinicalradiologicand pages 1-2, wang2021clinicalfeaturesand pages 3-4) Worse OS: Damodharan 2023 IPD review found TP53 associated with worse OS; Wang 2021 found p53 overexpression independently adverse for OS (damodharan2023molecularcharacterizationand pages 1-2, wang2021clinicalfeaturesand pages 3-4) Cohort + adult cohort + systematic review/IPD https://doi.org/10.1111/bpa.12768 (2020); https://doi.org/10.3390/cancers15133478 (2023); https://doi.org/10.3389/fonc.2020.602553 (2021) (dufour2020identificationofprognostic pages 8-10, damodharan2023molecularcharacterizationand pages 1-2, wang2021clinicalfeaturesand pages 3-4)
ACVR1 alteration Activating kinase mutation Mainly pediatric pontine/brainstem DMG Dufour 2020: 11.8% in pediatric cohort; highlighted in reviews of pediatric disease (dufour2020identificationofprognostic pages 8-10, vallero2023pediatricdiffusemidline pages 2-3) Favorable direction in Damodharan 2023 trial IPD review (“protective effect”) for OS relative to other genotypes (damodharan2023molecularcharacterizationand pages 1-2) Cohort + systematic review/IPD https://doi.org/10.1111/bpa.12768 (2020); https://doi.org/10.3390/cancers15133478 (2023) (dufour2020identificationofprognostic pages 8-10, damodharan2023molecularcharacterizationand pages 1-2)
PDGFRA amplification Receptor tyrosine kinase amplification Pediatric H3K27-mutant DMG; often brainstem-predominant cohorts Dufour 2020: PDGFRA amplification in 20.6% (dufour2020identificationofprognostic pages 8-10) Worse survival: significantly associated with shorter OS in Dufour 2020 (dufour2020identificationofprognostic pages 8-10) Cohort https://doi.org/10.1111/bpa.12768 (2020) (dufour2020identificationofprognostic pages 8-10)
FGFR1 mutation Activating kinase mutation More often thalamic/spinal and adult-enriched subsets; also seen in long-term survivor subgroup Hayashi 2024: 14% FGFR1-mutant in 93-patient DMG cohort; Schulte 2020: FGFR1 frequently co-mutated in adults (hayashi2024neuroradiologicalgeneticand pages 1-2, schulte2020clinicalradiologicand pages 1-2) Not established as uniformly favorable in all cohorts, but FGFR1/BRAF co-altered DMG has longer median OS >3 years in separate 2024 subtype study; long-term survivor data suggest MAPK pathway enrichment (hayashi2024neuroradiologicalgeneticand pages 1-2) Multicenter cohort + adult cohort https://doi.org/10.1186/s40478-024-01808-w (2024); https://doi.org/10.1093/noajnl/vdaa142 (2020) (hayashi2024neuroradiologicalgeneticand pages 1-2, schulte2020clinicalradiologicand pages 1-2)
BRAF p.V600E / BRAF co-alteration Activating kinase mutation Rare in standard DMG cohorts; enriched in distinct thalamic H3 K27/BRAF-FGFR1 co-altered subtype Hayashi 2024: BRAF p.V600E in 1% of DMG cohort (hayashi2024neuroradiologicalgeneticand pages 1-2) Rare alone in standard DMG; prognostic value not clear in Hayashi cohort, but MAPK-pathway co-altered long survivors reported elsewhere (hayashi2024neuroradiologicalgeneticand pages 1-2) Multicenter cohort https://doi.org/10.1186/s40478-024-01808-w (2024) (hayashi2024neuroradiologicalgeneticand pages 1-2)
EGFR mutation/alteration Mutation/amplification defining subtype in some tumors Midline DMG subset; more emphasized in WHO/review classification than common pediatric cohorts Hayashi 2024: EGFR mutation 3%; WHO/review sources recognize EGFR-altered DMG subtype (hayashi2024neuroradiologicalgeneticand pages 1-2, gianno2022paediatrictypediffusehighgrade pages 1-2) Prognostic effect not clearly defined in cited cohort excerpt (hayashi2024neuroradiologicalgeneticand pages 1-2) Multicenter cohort + review/classification https://doi.org/10.1186/s40478-024-01808-w (2024); https://doi.org/10.32074/1591-951x-830 (2022) (hayashi2024neuroradiologicalgeneticand pages 1-2, gianno2022paediatrictypediffusehighgrade pages 1-2)
MGMT promoter methylation Epigenetic DNA methylation biomarker Pediatric/adult DMG, often infrequent Hayashi 2024: MGMT promoter methylation 9%; Gong 2023 noted MGMT methylation status was not associated with adult OS (hayashi2024neuroradiologicalgeneticand pages 1-2, gong2023differencesinsurvival pages 7-9) No clear OS benefit signal in adult cohort; helps explain limited benefit of temozolomide in many DMGs (gong2023differencesinsurvival pages 7-9) Multicenter cohort + cohort analysis https://doi.org/10.1186/s40478-024-01808-w (2024); https://doi.org/10.1111/cns.14307 (2023) (hayashi2024neuroradiologicalgeneticand pages 1-2, gong2023differencesinsurvival pages 7-9)
TERT promoter mutation Promoter hotspot mutation Adult-enriched/older diffuse glioma biology; uncommon in DMG Hayashi 2024: 3% TERT promoter mutation (hayashi2024neuroradiologicalgeneticand pages 1-2) Prognostic significance not established in the cited excerpt (hayashi2024neuroradiologicalgeneticand pages 1-2) Multicenter cohort https://doi.org/10.1186/s40478-024-01808-w (2024) (hayashi2024neuroradiologicalgeneticand pages 1-2)
ATRX loss/mutation Chromatin remodeling alteration Seen in adult DMG and subsets of pediatric DMG Schulte 2020: ATRX frequently co-mutated in adults; Broggi 2024 review notes ATRX loss in ~15% of adult cases (schulte2020clinicalradiologicand pages 1-2, broggi2024clinico–pathologicalfeaturesof pages 1-2) Gong 2023: intact ATRX expression associated with longer survival in adults, implying ATRX loss may be unfavorable (gong2023differencesinsurvival pages 7-9) Adult cohort + adult review + cohort analysis https://doi.org/10.1093/noajnl/vdaa142 (2020); https://doi.org/10.3390/diagnostics14232617 (2024); https://doi.org/10.1111/cns.14307 (2023) (schulte2020clinicalradiologicand pages 1-2, broggi2024clinico–pathologicalfeaturesof pages 1-2, gong2023differencesinsurvival pages 7-9)
Complex chromosomal profile / 17p loss Copy-number/chromosomal instability markers Pediatric H3K27-mutant DMG Dufour 2020: complex chromosomal profiles common (70.6%); 17p loss specifically identified among adverse markers (dufour2020identificationofprognostic pages 8-10) Both complex chromosomal profile and 17p loss significantly associated with worse survival (dufour2020identificationofprognostic pages 8-10) Cohort https://doi.org/10.1111/bpa.12768 (2020) (dufour2020identificationofprognostic pages 8-10)

Table: This table summarizes major molecular alterations reported in diffuse midline glioma, H3 K27-altered, with representative frequencies and prognostic associations across key pediatric, adult, and multicenter cohorts. It is useful for comparing defining drivers, recurrent co-alterations, and biomarkers linked to survival.

5. Environmental Information

No validated environmental, lifestyle, or infectious causal factors were identified in the retrieved evidence. The disease definition and therapeutic strategies in these sources center on tumor-intrinsic somatic alterations and local CNS anatomy. (mandorino2024pediatricdiffusemidline pages 1-2, gue2024the2021world pages 15-16)

6. Mechanism / Pathophysiology

6.1 Core epigenetic mechanism

H3 K27 alterations (e.g., K27M) and EZHIP overexpression converge on polycomb repressive complex 2 (PRC2) interference, producing global reduction of H3K27me2/H3K27me3 and widespread gene-expression dysregulation that supports aggressive glioma biology. (gue2024the2021world pages 15-16)

6.2 Causal chain (simplified)

  1. Somatic H3K27-pathway alteration (H3 K27M, EZHIP overexpression, or EGFR-altered subtype) (park2023the2021who pages 2-2, gue2024the2021world pages 15-16)
  2. Loss of H3K27me3 and altered chromatin states → abnormal transcriptional programs (gue2024the2021world pages 15-16)
  3. Infiltrative glioma growth in critical midline structures (pons/thalamus/spinal cord) (vallero2023pediatricdiffusemidline pages 2-3, schulte2020clinicalradiologicand pages 1-2)
  4. Neurologic deficits from local tract/nuclei involvement (cranial nerves, corticospinal tracts, cerebellar pathways) leading to the classic phenotype triad and progressive disability (vallero2023pediatricdiffusemidline pages 2-3, broggi2024clinico–pathologicalfeaturesof pages 1-2)

6.3 Pathways and processes (ontology suggestions)

  • GO Biological Process (suggested): chromatin organization; histone H3-K27 methylation; negative regulation of gene expression (epigenetic); gliogenesis; regulation of cell proliferation.
  • GO Cellular Component (suggested): Polycomb repressive complex 2 (PRC2); nucleosome; chromatin.
  • Cell types (CL, suggested): astrocyte (astrocytic lineage tumor); oligodendrocyte precursor cell / glial progenitor-like states are commonly discussed in DMG biology (not quantitatively detailed in retrieved excerpts).

6.4 Advanced profiling (single-cell/spatial/multi-omics)

The retrieved evidence set emphasizes molecular profiling via biopsy/NGS and methylation profiling, but does not provide detailed single-cell or spatial transcriptomics results in the accessible excerpts. (nonnenbroich2024h3k27altereddiffusemidline pages 1-2)

7. Anatomical Structures Affected

7.1 Organ/tissue localization

Primary involvement is the central nervous system, particularly midline structures: - Brainstem/pons (classic DIPG) - Thalamus - Spinal cord (vallero2023pediatricdiffusemidline pages 2-3, schulte2020clinicalradiologicand pages 1-2, hayashi2024neuroradiologicalgeneticand pages 1-2)

7.2 Suggested UBERON mappings

  • Pons (UBERON:0000988)
  • Thalamus (UBERON:0001897)
  • Spinal cord (UBERON:0002240)

8. Temporal Development

8.1 Onset and progression

Disease is typically subacute to progressive with rapid neurologic decline reflecting infiltrative growth in critical midline structures. Pediatric presentations are common; adult presentations occur and may have different site distribution and outcomes. (mandorino2024pediatricdiffusemidline pages 1-2, schulte2020clinicalradiologicand pages 1-2)

8.2 Staging

No formal staging system specific to DMG was identified in the retrieved evidence; clinically, course is commonly framed as diagnosis → post-radiotherapy period → progression/recurrence, with consideration of re-irradiation at recurrence. (vallero2023pediatricdiffusemidline pages 2-3, damodharan2023molecularcharacterizationand pages 1-2)

9. Inheritance and Population

9.1 Epidemiology

  • Vallero et al. summarize pediatric burden as ~20% of pediatric CNS tumors with ~200–300 new cases/year in the United States (as reported in their review context). (vallero2023pediatricdiffusemidline pages 2-3)
  • An adult-focused review cites incidence around 2.32 cases per 1 million persons/year in adults (>20 years). (broggi2024clinico–pathologicalfeaturesof pages 1-2)

9.2 Inheritance

This is not typically a Mendelian inherited disorder; it is defined by tumor somatic alterations. No penetrance/carrier frequency/founder-effect data were identified in the retrieved evidence.

10. Diagnostics

10.1 Imaging

MRI is widely described as the diagnostic gold standard for pontine/brainstem cases; Vallero et al. note typical DIPG imaging criteria such as a lesion involving >50% of the pons. (vallero2023pediatricdiffusemidline pages 2-3)

10.2 Tissue diagnosis and molecular confirmation

  • Biopsy in brainstem lesions has historically been debated, but multiple sources describe a trend toward stereotactic biopsy to enable immunohistochemistry and molecular profiling (NGS, methylation profiling). (vallero2023pediatricdiffusemidline pages 2-3, nonnenbroich2024h3k27altereddiffusemidline pages 1-2, damodharan2023molecularcharacterizationand pages 1-2)
  • WHO-aligned pathologic workup commonly includes IHC for H3 K27M and assessment of H3K27me3 loss, with EZHIP evaluation where relevant; strong diffuse H3 K27M immunoreactivity with H3K27me3 loss supports diagnosis. (broggi2024clinico–pathologicalfeaturesof pages 1-2)

10.3 Differential diagnosis (high level)

Midline gliomas without H3 K27 alteration and other pediatric high-grade gliomas (e.g., hemispheric H3 G34-mutant tumors) are key considerations in the modern WHO framework. (park2023the2021who pages 2-2)

11. Outcome / Prognosis

11.1 Survival statistics (selected recent/large cohorts)

  • Kansai multicenter cohort (n=93, 24 hospitals): median PFS 9.9 months and median OS 16.6 months (hayashi2024neuroradiologicalgeneticand pages 1-2). The Kaplan–Meier figure region containing these medians is shown in the extracted survival-curve images. (hayashi2024neuroradiologicalgeneticand media dec99d06, hayashi2024neuroradiologicalgeneticand media 8f7749a2, hayashi2024neuroradiologicalgeneticand media 14f6a8a7)
  • Adult cohort (n=60): OS reported as 27.6 months in Schulte et al. (schulte2020clinicalradiologicand pages 1-2, schulte2020clinicalradiologicand pages 7-8)
  • Mixed-age cohort (n=43): median OS 12.83 months with 12- and 24-month OS rates 53.8% and 40.2%, respectively. (wang2021clinicalfeaturesand pages 3-4)
  • Reviews emphasize poor pediatric prognosis with survival often around 12 months and very low long-term survival. (mandorino2024pediatricdiffusemidline pages 1-2)

11.2 Prognostic factors (clinical)

  • Performance status (KPS) is repeatedly prognostic; KPS ≥80 (Kansai cohort) and KPS ≥70 (Wang cohort) are associated with improved OS. (hayashi2024neuroradiologicalgeneticand pages 1-2, wang2021clinicalfeaturesand pages 3-4)
  • Adjuvant radiotherapy and chemoradiotherapy are associated with improved OS in retrospective analyses. (wang2021clinicalfeaturesand pages 3-4, gong2023differencesinsurvival pages 7-9)

12. Treatment

12.1 Standard of care / real-world implementation

Radiotherapy remains the principal standard palliative treatment, with typical fractionated dosing in the ~54–60 Gy range (Vallero) and 59 Gy cited in a pediatric review context. (vallero2023pediatricdiffusemidline pages 2-3, mandorino2024pediatricdiffusemidline pages 1-2)

Real-world practice patterns from the Kansai multicenter cohort (n=93) include: - Resection (when feasible) in 36% - Adjuvant radiation + chemotherapy in 83% - Temozolomide use in 76% - Bevacizumab use in 42% (hayashi2024neuroradiologicalgeneticand pages 1-2)

Damodharan et al. (2023) systematic review of individual participant trial data highlights that re-irradiation was the only statistically significant modality associated with survival benefit in their pooled analysis. (damodharan2023molecularcharacterizationand pages 1-2)

12.2 Emerging therapies (2023–2024 prioritized)

  • Imipridones / ONC201-class agents: Recent reviews summarize multiple clinical datasets with median OS values around ~16–22 months depending on cohort and timing, and emphasize earlier post-radiotherapy administration as potentially beneficial. (nonnenbroich2024h3k27altereddiffusemidline pages 4-6, yang2024newprogressin pages 3-5)
  • Epigenetic therapies (HDAC inhibition): panobinostat continues to be studied, including approaches to improve delivery such as convection-enhanced delivery (CED). (rechberger2023benchtobedsideinvestigationsof pages 13-15, nonnenbroich2024h3k27altereddiffusemidline pages 9-10)
  • Cellular immunotherapy and vaccines: Multiple active trials target H3K27M neoantigens (vaccine or engineered effector cells) and GD2 CAR-T approaches. (NCT04808245 chunk 1, NCT04196413 chunk 2, NCT07501156 chunk 1)

MAXO (suggested) intervention terms (high-level, for KB annotation): external beam radiotherapy; stereotactic biopsy; chemotherapy; immunotherapy; CAR T-cell therapy; peptide vaccination; re-irradiation; convection-enhanced delivery.

12.3 Key clinical trials (ClinicalTrials.gov)

Modality/therapy Target/mechanism NCT ID Phase Population (age; mutation requirement; setting) Delivery/route Primary outcomes Status and start date URL
GD2 CAR T cells GD2-directed CAR T-cell immunotherapy after lymphodepleting chemotherapy (fludarabine/cyclophosphamide) for DMG/DIPG; efficacy assessed with RANO 2.0, OS/PFS/PPS endpoints in protocol (yang2024newprogressin pages 3-5, NCT04196413 chunk 2) NCT04196413 Phase 1 Age 2–60 years; H3K27M or H3K27I mutation required; DIPG and spinal DMG; recurrent/progressive setting allowed per eligibility framework (NCT04196413 chunk 2) Cellular infusion after preparative regimen; CAR T-cell infusion (clinical route not fully specified in excerpt) (NCT04196413 chunk 2) Safety/toxicity including suspected AEs/SAEs and toxicity resolution; radiographic response rate by RANO 2.0; OS; PFS; post-progression survival (NCT04196413 chunk 2) Recruiting; start 2020-06 (yang2024newprogressin pages 3-5, NCT04196413 chunk 2) https://clinicaltrials.gov/study/NCT04196413
H3K27M peptide vaccine + atezolizumab Long mutant H3K27M peptide vaccine to induce H3K27M-specific T cells, combined with involved-field radiotherapy and anti–PD-L1 checkpoint blockade (atezolizumab); imiquimod used as local adjuvant (NCT04808245 chunk 1) NCT04808245 Phase 1 Adults with newly diagnosed H3.1K27M or H3.3K27M diffuse midline glioma; single-arm multicenter trial; planned n=15 (NCT04808245 chunk 1) Vaccine administered subcutaneously; atezolizumab IV every 3 weeks; concurrent/serial with radiotherapy (NCT04808245 chunk 1) Safety (regimen-limiting toxicity) and immunogenicity measured by H3K27M-specific T cells/IFN-γ ELISpot on PBMCs (NCT04808245 chunk 1) Active, not recruiting; start 2023-02-15 (NCT04808245 chunk 1) https://clinicaltrials.gov/study/NCT04808245
Split-course hypofractionated radiation with stereotactic biopsy (SPORT-DMG) Radiation-based management strategy integrating stereotactic biopsy and split-course/hypofractionated radiotherapy for DMG (yang2024newprogressin pages 3-5) NCT05077735 Phase 2 DMG population; trial table identifies diffuse midline glioma with radiation intervention; detailed mutation/age criteria not available in excerpt (yang2024newprogressin pages 3-5) Radiation: hypofractionated/split-course radiotherapy; stereotactic biopsy component (yang2024newprogressin pages 3-5) Patient-reported/clinical outcomes include quality-of-life assessment and questionnaire administration; full primary endpoint wording not available in excerpt (yang2024newprogressin pages 3-5) Recruiting; start 2021-10 (yang2024newprogressin pages 3-5) https://clinicaltrials.gov/study/NCT05077735
Panobinostat (PBTC-047) HDAC inhibition (panobinostat/LBH589) targeting epigenetic dysregulation in DIPG/DMG (yang2024newprogressin pages 3-5) NCT02717455 Phase 1 Children with diffuse intrinsic pontine glioma; mutation requirement not specified in excerpt; pediatric pontine DMG-relevant population (yang2024newprogressin pages 3-5) Drug administration route not specified in excerpt (known panobinostat trial listed as drug intervention) (yang2024newprogressin pages 3-5) Primary outcomes not specified in excerpt; trial identified as phase I panobinostat study (yang2024newprogressin pages 3-5) Active, not recruiting; start 2016-06 (yang2024newprogressin pages 3-5) https://clinicaltrials.gov/study/NCT02717455
H3K27M-specific engineered immune effector cells (EIEs) Autologous H3K27M-specific immune effectors generated from PBMCs stimulated with H3K27M antigen-primed autologous dendritic cells; product contains CD8+, CD4+, CD56+ populations (NCT07501156 chunk 1) NCT07501156 Phase 1/2 Age 2–70 years; recurrent or refractory DMG/DIPG; confirmed H3K27M-positive disease; KPS ≥60; planned n=30 (NCT07501156 chunk 1) 1–2 intravenous infusions once weekly at 1×10^5–1×10^7 EIEs/kg after leukapheresis-based manufacturing (NCT07501156 chunk 1) Safety by CTCAE v4.0 adverse effects; success rate of EIE generation; ELISPOT evidence of target-specific T cells; objective response by RECIST v1.1 (NCT07501156 chunk 1) Recruiting; start 2026-03-18 (NCT07501156 chunk 1) https://clinicaltrials.gov/study/NCT07501156

Table: This table summarizes key current and emerging ClinicalTrials.gov studies for diffuse midline glioma, H3 K27-altered, spanning CAR-T, peptide vaccination, radiation strategy, HDAC inhibition, and engineered immune effector cell approaches. It is useful for quickly comparing mechanism, eligibility, route, endpoints, and recruitment status across major active protocols.

13. Prevention

No established primary prevention strategies are supported by the retrieved evidence, consistent with a disease primarily driven by sporadic somatic alterations and presenting as a rare CNS tumor. Secondary prevention (screening) is not established; diagnosis is typically symptom- and imaging-driven. (mandorino2024pediatricdiffusemidline pages 1-2, vallero2023pediatricdiffusemidline pages 2-3)

14. Other Species / Natural Disease

No naturally occurring veterinary analogs were identified in the retrieved evidence.

15. Model Organisms

The retrieved evidence set references preclinical models (e.g., murine models used to test epigenetic combinations) but does not provide detailed, model-by-model phenotype recapitulation in the accessible excerpts. (nonnenbroich2024h3k27altereddiffusemidline pages 4-6)

Expert opinions / analysis (authoritative sources)

  • Contemporary expert reviews emphasize that despite extensive clinical trial activity, radiotherapy remains the only proven standard, and progress likely requires combination therapies, improved delivery across the BBB/BBTB, and molecularly guided strategies. (nonnenbroich2024h3k27altereddiffusemidline pages 1-2, nonnenbroich2024h3k27altereddiffusemidline pages 9-10)
  • Drug-delivery concepts such as maximizing “drug–tumor residence time” and focusing on combinational regimens are emphasized as necessary to overcome resistance and clearance limitations. (rechberger2023benchtobedsideinvestigationsof pages 13-15)

Notes on PMID availability

The provided full-text evidence chunks and trial registry records include DOI URLs and publication months/years but did not include PMIDs for most articles. Where PMID is required for downstream normalization, the DOI URLs provided here can be used to programmatically map to PubMed records.

References

  1. (vallero2023pediatricdiffusemidline pages 2-3): Stefano Gabriele Vallero, Luca Bertero, Giovanni Morana, Paola Sciortino, Daniele Bertin, Anna Mussano, Federica Silvia Ricci, Paola Peretta, and Franca Fagioli. Pediatric diffuse midline glioma h3k27- altered: a complex clinical and biological landscape behind a neatly defined tumor type. Frontiers in Oncology, Jan 2023. URL: https://doi.org/10.3389/fonc.2022.1082062, doi:10.3389/fonc.2022.1082062. This article has 62 citations.

  2. (gianno2022paediatrictypediffusehighgrade pages 1-2): Francesca Gianno, Isabella Giovannoni, Barbara Cafferata, Francesca Diomedi-Camassei, Simone Minasi, Sabina Barresi, Francesca Romana Buttarelli, Viola Alesi, Antonello Cardoni, Manila Antonelli, Chiara Puggioni, Giovanna Stefania Colafati, Andrea Carai, Maria Vinci, Angela Mastronuzzi, Evelina Miele, Rita Alaggio, Felice Giangaspero, and Sabrina Rossi. Paediatric-type diffuse high-grade gliomas in the 5th cns who classification. Pathologica, 114:422-435, Dec 2022. URL: https://doi.org/10.32074/1591-951x-830, doi:10.32074/1591-951x-830. This article has 66 citations.

  3. (schulte2020clinicalradiologicand pages 1-2): Jessica D Schulte, Robin A Buerki, Sarah Lapointe, Annette M Molinaro, Yalan Zhang, Javier E Villanueva-Meyer, Arie Perry, Joanna J Phillips, Tarik Tihan, Andrew W Bollen, Melike Pekmezci, Nicholas Butowski, Nancy Ann Oberheim Bush, Jennie W Taylor, Susan M Chang, Philip Theodosopoulos, Manish K Aghi, Shawn L Hervey-Jumper, Mitchel S Berger, David A Solomon, and Jennifer L Clarke. Clinical, radiologic, and genetic characteristics of histone h3 k27m-mutant diffuse midline gliomas in adults. Neuro-oncology Advances, Oct 2020. URL: https://doi.org/10.1093/noajnl/vdaa142, doi:10.1093/noajnl/vdaa142. This article has 124 citations and is from a peer-reviewed journal.

  4. (park2023the2021who pages 2-2): Yae Won Park, Philipp Vollmuth, Martha Foltyn‐Dumitru, Felix Sahm, Sung Soo Ahn, Jong Hee Chang, and Se Hoon Kim. The 2021 who classification for gliomas and implications on imaging diagnosis: part 2—summary of imaging findings on pediatric‐type diffuse high‐grade gliomas, pediatric‐type diffuse low‐grade gliomas, and circumscribed astrocytic gliomas. Journal of Magnetic Resonance Imaging, 58:690-708, Apr 2023. URL: https://doi.org/10.1002/jmri.28740, doi:10.1002/jmri.28740. This article has 48 citations and is from a domain leading peer-reviewed journal.

  5. (park2023the2021who pages 6-7): Yae Won Park, Philipp Vollmuth, Martha Foltyn‐Dumitru, Felix Sahm, Sung Soo Ahn, Jong Hee Chang, and Se Hoon Kim. The 2021 who classification for gliomas and implications on imaging diagnosis: part 2—summary of imaging findings on pediatric‐type diffuse high‐grade gliomas, pediatric‐type diffuse low‐grade gliomas, and circumscribed astrocytic gliomas. Journal of Magnetic Resonance Imaging, 58:690-708, Apr 2023. URL: https://doi.org/10.1002/jmri.28740, doi:10.1002/jmri.28740. This article has 48 citations and is from a domain leading peer-reviewed journal.

  6. (wisniewski2023h3k27maltereddiffuse pages 1-3): Karol Wiśniewski, Andrew Ghaly, Kate Drummond, and Andreas Fahlstrӧm. H3 k27m-altered diffuse midline gliomas: a review. Indian Journal of Neurosurgery, 12:104-115, Jul 2023. URL: https://doi.org/10.1055/s-0043-1771192, doi:10.1055/s-0043-1771192. This article has 9 citations.

  7. (hayashi2024neuroradiologicalgeneticand pages 1-2): Nobuhide Hayashi, Junya Fukai, Hirokazu Nakatogawa, Hiroshi Kawaji, Ema Yoshioka, Yoshinori Kodama, Kosuke Nakajo, Takehiro Uda, Kentaro Naito, Noriyuki Kijima, Yoshiko Okita, Naoki Kagawa, Yoshinobu Takahashi, Naoya Hashimoto, Hideyuki Arita, Koji Takano, Daisuke Sakamoto, Tomoko Iida, Yoshiki Arakawa, Takeshi Kawauchi, Yukihiko Sonoda, Yuta Mitobe, Kenichi Ishibashi, Masahide Matsuda, Takamune Achiha, Takahiro Tomita, Masahiro Nonaka, Keijiro Hara, Noriyoshi Takebe, Takashi Tsuzuki, Yoshikazu Nakajima, Shiro Ohue, Nobuyuki Nakajima, Akira Watanabe, Akihiro Inoue, Masao Umegaki, Daisuke Kanematsu, Asako Katsuma, Miho Sumida, Tomoko Shofuda, Masayuki Mano, Manabu Kinoshita, Kanji Mori, Naoyuki Nakao, and Yonehiro Kanemura. Neuroradiological, genetic and clinical characteristics of histone h3 k27-mutant diffuse midline gliomas in the kansai molecular diagnosis network for cns tumors (kansai network): multicenter retrospective cohort. Acta Neuropathologica Communications, Jul 2024. URL: https://doi.org/10.1186/s40478-024-01808-w, doi:10.1186/s40478-024-01808-w. This article has 4 citations and is from a peer-reviewed journal.

  8. (damodharan2023molecularcharacterizationand pages 1-2): Sudarshawn Damodharan, Alexandra Abbott, Kaitlyn Kellar, Qianqian Zhao, and Mahua Dey. Molecular characterization and treatment approaches for pediatric h3 k27-altered diffuse midline glioma: integrated systematic review of individual clinical trial participant data. Cancers, 15:3478, Jul 2023. URL: https://doi.org/10.3390/cancers15133478, doi:10.3390/cancers15133478. This article has 7 citations.

  9. (NCT04808245 chunk 1): A MultIceNTER Phase I Peptide VaCcine Trial for the Treatment of H3-Mutated Gliomas. German Cancer Research Center. 2023. ClinicalTrials.gov Identifier: NCT04808245

  10. (NCT04196413 chunk 2): GD2 CAR T Cells in Diffuse Intrinsic Pontine Gliomas (DIPG) & Spinal Diffuse Midline Glioma(DMG). Stanford University. 2020. ClinicalTrials.gov Identifier: NCT04196413

  11. (gue2024the2021world pages 15-16): Racine Gue and Dhairya A. Lakhani. The 2021 world health organization central nervous system tumor classification: the spectrum of diffuse gliomas. Biomedicines, 12:1349, Jun 2024. URL: https://doi.org/10.3390/biomedicines12061349, doi:10.3390/biomedicines12061349. This article has 13 citations.

  12. (broggi2024clinico–pathologicalfeaturesof pages 1-2): Giuseppe Broggi, Serena Salzano, Maria Failla, Giuseppe Maria Vincenzo Barbagallo, Francesco Certo, Magda Zanelli, Andrea Palicelli, Maurizio Zizzo, Nektarios Koufopoulos, Gaetano Magro, and Rosario Caltabiano. Clinico–pathological features of diffuse midline glioma, h3 k27-altered in adults: a comprehensive review of the literature with an additional single-institution case series. Diagnostics, 14:2617, Nov 2024. URL: https://doi.org/10.3390/diagnostics14232617, doi:10.3390/diagnostics14232617. This article has 7 citations.

  13. (nonnenbroich2024h3k27altereddiffusemidline pages 1-2): Leo F. Nonnenbroich, Samantha M. Bouchal, Elena Millesi, Julian S. Rechberger, Soumen Khatua, and David J. Daniels. H3k27-altered diffuse midline glioma of the brainstem: from molecular mechanisms to targeted interventions. Cells, 13:1122, Jun 2024. URL: https://doi.org/10.3390/cells13131122, doi:10.3390/cells13131122. This article has 14 citations.

  14. (park2023the2021who pages 7-7): Yae Won Park, Philipp Vollmuth, Martha Foltyn‐Dumitru, Felix Sahm, Sung Soo Ahn, Jong Hee Chang, and Se Hoon Kim. The 2021 who classification for gliomas and implications on imaging diagnosis: part 2—summary of imaging findings on pediatric‐type diffuse high‐grade gliomas, pediatric‐type diffuse low‐grade gliomas, and circumscribed astrocytic gliomas. Journal of Magnetic Resonance Imaging, 58:690-708, Apr 2023. URL: https://doi.org/10.1002/jmri.28740, doi:10.1002/jmri.28740. This article has 48 citations and is from a domain leading peer-reviewed journal.

  15. (mandorino2024pediatricdiffusemidline pages 1-2): Manuela Mandorino, Ahana Maitra, Domenico Armenise, Olga Maria Baldelli, Morena Miciaccia, Savina Ferorelli, Maria Grazia Perrone, and Antonio Scilimati. Pediatric diffuse midline glioma h3k27-altered: from developmental origins to therapeutic challenges. Cancers, 16:1814, May 2024. URL: https://doi.org/10.3390/cancers16101814, doi:10.3390/cancers16101814. This article has 21 citations.

  16. (dufour2020identificationofprognostic pages 8-10): Charlotte Dufour, Romain Perbet, Pierre Leblond, Romain Vasseur, Laurence Stechly, Adeline Pierache, Nicolas Reyns, Gustavo Touzet, Emilie Le Rhun, Matthieu Vinchon, Claude‐Alain Maurage, Fabienne Escande, and Florence Renaud. Identification of prognostic markers in diffuse midline gliomas h3k27m‐mutant. Brain Pathology, 30:179-190, Aug 2020. URL: https://doi.org/10.1111/bpa.12768, doi:10.1111/bpa.12768. This article has 40 citations and is from a domain leading peer-reviewed journal.

  17. (wang2021clinicalfeaturesand pages 3-4): Yuan Wang, Lan-lan Feng, Pei-gang Ji, Jing-hui Liu, Shao-chun Guo, Yu-long Zhai, Eric W. Sankey, Yue Wang, Yan-rong Xue, Na Wang, Miao Lou, Meng Xu, Min Chao, Guo-Dong Gao, Yan Qu, Li Gong, and Liang Wang. Clinical features and molecular markers on diffuse midline gliomas with h3k27m mutations: a 43 cases retrospective cohort study. Frontiers in Oncology, Feb 2021. URL: https://doi.org/10.3389/fonc.2020.602553, doi:10.3389/fonc.2020.602553. This article has 48 citations.

  18. (gong2023differencesinsurvival pages 7-9): Xuan Gong, S. Kuang, Dong-feng Deng, Jun Wu, Longbo Zhang, and Chaoyuan Liu. Differences in survival prognosticators between children and adults with h3k27m‐mutant diffuse midline glioma. CNS Neuroscience & Therapeutics, 29:3863-3875, Jun 2023. URL: https://doi.org/10.1111/cns.14307, doi:10.1111/cns.14307. This article has 17 citations and is from a peer-reviewed journal.

  19. (hayashi2024neuroradiologicalgeneticand media dec99d06): Nobuhide Hayashi, Junya Fukai, Hirokazu Nakatogawa, Hiroshi Kawaji, Ema Yoshioka, Yoshinori Kodama, Kosuke Nakajo, Takehiro Uda, Kentaro Naito, Noriyuki Kijima, Yoshiko Okita, Naoki Kagawa, Yoshinobu Takahashi, Naoya Hashimoto, Hideyuki Arita, Koji Takano, Daisuke Sakamoto, Tomoko Iida, Yoshiki Arakawa, Takeshi Kawauchi, Yukihiko Sonoda, Yuta Mitobe, Kenichi Ishibashi, Masahide Matsuda, Takamune Achiha, Takahiro Tomita, Masahiro Nonaka, Keijiro Hara, Noriyoshi Takebe, Takashi Tsuzuki, Yoshikazu Nakajima, Shiro Ohue, Nobuyuki Nakajima, Akira Watanabe, Akihiro Inoue, Masao Umegaki, Daisuke Kanematsu, Asako Katsuma, Miho Sumida, Tomoko Shofuda, Masayuki Mano, Manabu Kinoshita, Kanji Mori, Naoyuki Nakao, and Yonehiro Kanemura. Neuroradiological, genetic and clinical characteristics of histone h3 k27-mutant diffuse midline gliomas in the kansai molecular diagnosis network for cns tumors (kansai network): multicenter retrospective cohort. Acta Neuropathologica Communications, Jul 2024. URL: https://doi.org/10.1186/s40478-024-01808-w, doi:10.1186/s40478-024-01808-w. This article has 4 citations and is from a peer-reviewed journal.

  20. (hayashi2024neuroradiologicalgeneticand media 8f7749a2): Nobuhide Hayashi, Junya Fukai, Hirokazu Nakatogawa, Hiroshi Kawaji, Ema Yoshioka, Yoshinori Kodama, Kosuke Nakajo, Takehiro Uda, Kentaro Naito, Noriyuki Kijima, Yoshiko Okita, Naoki Kagawa, Yoshinobu Takahashi, Naoya Hashimoto, Hideyuki Arita, Koji Takano, Daisuke Sakamoto, Tomoko Iida, Yoshiki Arakawa, Takeshi Kawauchi, Yukihiko Sonoda, Yuta Mitobe, Kenichi Ishibashi, Masahide Matsuda, Takamune Achiha, Takahiro Tomita, Masahiro Nonaka, Keijiro Hara, Noriyoshi Takebe, Takashi Tsuzuki, Yoshikazu Nakajima, Shiro Ohue, Nobuyuki Nakajima, Akira Watanabe, Akihiro Inoue, Masao Umegaki, Daisuke Kanematsu, Asako Katsuma, Miho Sumida, Tomoko Shofuda, Masayuki Mano, Manabu Kinoshita, Kanji Mori, Naoyuki Nakao, and Yonehiro Kanemura. Neuroradiological, genetic and clinical characteristics of histone h3 k27-mutant diffuse midline gliomas in the kansai molecular diagnosis network for cns tumors (kansai network): multicenter retrospective cohort. Acta Neuropathologica Communications, Jul 2024. URL: https://doi.org/10.1186/s40478-024-01808-w, doi:10.1186/s40478-024-01808-w. This article has 4 citations and is from a peer-reviewed journal.

  21. (hayashi2024neuroradiologicalgeneticand media 14f6a8a7): Nobuhide Hayashi, Junya Fukai, Hirokazu Nakatogawa, Hiroshi Kawaji, Ema Yoshioka, Yoshinori Kodama, Kosuke Nakajo, Takehiro Uda, Kentaro Naito, Noriyuki Kijima, Yoshiko Okita, Naoki Kagawa, Yoshinobu Takahashi, Naoya Hashimoto, Hideyuki Arita, Koji Takano, Daisuke Sakamoto, Tomoko Iida, Yoshiki Arakawa, Takeshi Kawauchi, Yukihiko Sonoda, Yuta Mitobe, Kenichi Ishibashi, Masahide Matsuda, Takamune Achiha, Takahiro Tomita, Masahiro Nonaka, Keijiro Hara, Noriyoshi Takebe, Takashi Tsuzuki, Yoshikazu Nakajima, Shiro Ohue, Nobuyuki Nakajima, Akira Watanabe, Akihiro Inoue, Masao Umegaki, Daisuke Kanematsu, Asako Katsuma, Miho Sumida, Tomoko Shofuda, Masayuki Mano, Manabu Kinoshita, Kanji Mori, Naoyuki Nakao, and Yonehiro Kanemura. Neuroradiological, genetic and clinical characteristics of histone h3 k27-mutant diffuse midline gliomas in the kansai molecular diagnosis network for cns tumors (kansai network): multicenter retrospective cohort. Acta Neuropathologica Communications, Jul 2024. URL: https://doi.org/10.1186/s40478-024-01808-w, doi:10.1186/s40478-024-01808-w. This article has 4 citations and is from a peer-reviewed journal.

  22. (schulte2020clinicalradiologicand pages 7-8): Jessica D Schulte, Robin A Buerki, Sarah Lapointe, Annette M Molinaro, Yalan Zhang, Javier E Villanueva-Meyer, Arie Perry, Joanna J Phillips, Tarik Tihan, Andrew W Bollen, Melike Pekmezci, Nicholas Butowski, Nancy Ann Oberheim Bush, Jennie W Taylor, Susan M Chang, Philip Theodosopoulos, Manish K Aghi, Shawn L Hervey-Jumper, Mitchel S Berger, David A Solomon, and Jennifer L Clarke. Clinical, radiologic, and genetic characteristics of histone h3 k27m-mutant diffuse midline gliomas in adults. Neuro-oncology Advances, Oct 2020. URL: https://doi.org/10.1093/noajnl/vdaa142, doi:10.1093/noajnl/vdaa142. This article has 124 citations and is from a peer-reviewed journal.

  23. (nonnenbroich2024h3k27altereddiffusemidline pages 4-6): Leo F. Nonnenbroich, Samantha M. Bouchal, Elena Millesi, Julian S. Rechberger, Soumen Khatua, and David J. Daniels. H3k27-altered diffuse midline glioma of the brainstem: from molecular mechanisms to targeted interventions. Cells, 13:1122, Jun 2024. URL: https://doi.org/10.3390/cells13131122, doi:10.3390/cells13131122. This article has 14 citations.

  24. (yang2024newprogressin pages 3-5): Zhi Yang, Liang Sun, Haibin Chen, Caixing Sun, and Liang Xia. New progress in the treatment of diffuse midline glioma with h3k27m alteration. Heliyon, 10:e24877, Jan 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e24877, doi:10.1016/j.heliyon.2024.e24877. This article has 11 citations.

  25. (rechberger2023benchtobedsideinvestigationsof pages 13-15): Julian S. Rechberger, Samantha M. Bouchal, Erica A. Power, Leo F. Nonnenbroich, Cody L. Nesvick, and David J. Daniels. Bench-to-bedside investigations of h3 k27-altered diffuse midline glioma: drug targets and potential pharmacotherapies. Expert Opinion on Therapeutic Targets, 27:1071-1086, Nov 2023. URL: https://doi.org/10.1080/14728222.2023.2277232, doi:10.1080/14728222.2023.2277232. This article has 5 citations and is from a peer-reviewed journal.

  26. (nonnenbroich2024h3k27altereddiffusemidline pages 9-10): Leo F. Nonnenbroich, Samantha M. Bouchal, Elena Millesi, Julian S. Rechberger, Soumen Khatua, and David J. Daniels. H3k27-altered diffuse midline glioma of the brainstem: from molecular mechanisms to targeted interventions. Cells, 13:1122, Jun 2024. URL: https://doi.org/10.3390/cells13131122, doi:10.3390/cells13131122. This article has 14 citations.

  27. (NCT07501156 chunk 1): H3K27M-specific Immune Effector Cells Targeting DMG/DIPG. Shenzhen Geno-Immune Medical Institute. 2026. ClinicalTrials.gov Identifier: NCT07501156