Atypical Teratoid/Rhabdoid Tumor

MONDO:0020560 Pathograph 15 Show in embeddings browser rhabdoid tumor

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly aggressive embryonal central nervous system tumor that predominantly affects infants and young children. AT/RT is defined by SMARCB1 loss and, rarely, SMARCA4 loss within the SWI/SNF chromatin-remodeling complex. Consistent with dismech cancer curation guidance, this entry treats AT/RT as the disease-level mechanism graph and models TYR, SHH, MYC, and the rare molecularly distinct SMARCA4-deficient group as subtype facets rather than separate disorder pages.

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5
Pathophys.
1
Histopath.
6
Phenotypes
2
Gaps
15
Pathograph
2
Genes
4
Medical Actions
4
Subtypes
2
Differentials
3
Datasets
5
Trials
1
Models
10
References
1
Deep Research
◆

Subtypes

4
AT/RT-TYR
Consensus methylation-defined molecular subgroup of AT/RT. It is retained as a flat subtype facet within the AT/RT disease graph rather than as a separate dismech disease page.
Show evidence (1 reference)
PMID:41374972 SUPPORT Other
"The integration of immunohistochemical markers with advanced molecular diagnostics-including next-generation sequencing, DNA methylation profiling, and gene enrichment analyses-has facilitated robust tumor classification and the identification of three molecular subgroups: TYR, SHH, and MYC."
This review explicitly names TYR as one of the three consensus molecular subgroups used to facet AT/RT without implying a separate disease page.
AT/RT-SHH
Consensus methylation-defined molecular subgroup of AT/RT. It is modeled as a molecular subgroup axis inside the AT/RT page. Integrated profiling has further resolved SHH-1A, SHH-1B, and SHH-2 patterns with distinct age, location, and germline-SMARCB1 distributions; these are retained here as within-SHH heterogeneity rather than promoted to independent disorders.
Show evidence (2 references)
PMID:41374972 SUPPORT Other
"The integration of immunohistochemical markers with advanced molecular diagnostics-including next-generation sequencing, DNA methylation profiling, and gene enrichment analyses-has facilitated robust tumor classification and the identification of three molecular subgroups: TYR, SHH, and MYC."
This review explicitly names SHH as one of the three consensus molecular subgroups used to facet AT/RT.
PMID:35501487 SUPPORT Human Clinical
"Consensus clustering of DNA methylation profiles and confirmatory t-SNE analysis of 65 ATRT-SHH yielded three robust molecular subgroups, i.e., SHH-1A, SHH-1B and SHH-2."
Integrated molecular analysis directly supports reproducible within-SHH subdivision without treating those patterns as separate diseases.
AT/RT-MYC
Consensus methylation-defined molecular subgroup of AT/RT. It is modeled as a molecular subgroup facet within the single AT/RT disease entry.
Show evidence (1 reference)
PMID:41374972 SUPPORT Other
"The integration of immunohistochemical markers with advanced molecular diagnostics-including next-generation sequencing, DNA methylation profiling, and gene enrichment analyses-has facilitated robust tumor classification and the identification of three molecular subgroups: TYR, SHH, and MYC."
This review explicitly names MYC as one of the three consensus molecular subgroups used to facet AT/RT.
AT/RT-SMARCA4
Rare SMARCA4-deficient AT/RT forms a molecular group distinct from the three SMARCB1-deficient consensus subgroups. It is associated with younger age, more germline variants, and inferior prognosis, although case numbers are small.
Show evidence (1 reference)
DOI:10.1007/s00401-020-02250-7 SUPPORT Human Clinical
"We show that they form a separate group segregating from SMARCB1 mutated ATRTs and from other SMARCA4-deficient tumors like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) or SMARCA4 mutated extra-cranial malignant rhabdoid tumors."
DNA methylation profiling of 14 AT/RT-SMARCA4 tumors directly establishes a separate molecular group.
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Discussions and Knowledge Gaps

2
Which molecular and clinical strata can safely receive less toxic therapy, and which need novel intensification?
KNOWLEDGE GAP OPEN gap_atrt_risk_adapted_therapy
Attached to
treatments#Intensive Multiagent Chemotherapy treatments#Adjuvant Radiation Therapy
Subgroup and germline associations are based on small strata, while intensive multimodal therapy has substantial acute and long-term toxicity. Existing studies do not establish validated subgroup-specific de-escalation rules.
Show evidence (1 reference)
PMID:32105509 SUPPORT Human Clinical
"Subsets of patients who can be cured with less therapy may exist. The goal must be to continue to improve survival and reduce toxicity with refinements in therapy based on integration of biologic and clinical risk factors."
The prospective trial report explicitly identifies risk-adapted de-escalation and toxicity reduction as unresolved priorities.
Will differentiation therapy, CLDN6-directed immunotherapy, or other subgroup-informed targets produce durable clinical benefit?
EMERGING HYPOTHESIS OPEN gap_atrt_emerging_targets
Attached to
pathophysiology#Cycling Progenitor-Like Tumor State biochemical#Claudin-6 Membrane Expression
Differentiation-state manipulation and CLDN6 targeting are supported by patient-derived models and small tissue cohorts, but clinical efficacy and subgroup generalizability remain unproven.
Show evidence (1 reference)
PMID:40726147 SUPPORT In Vitro
"By directing tumor cells along their respective subtype-specific trajectories, we were able to induce a shift toward more differentiated, non-proliferative states."
Tumoroid perturbation supports the hypothesis but does not establish patient benefit.
⚙

Pathophysiology

5
SMARCB1 or SMARCA4 Inactivation
AT/RT is defined by inactivation of the SWI/SNF core subunits SMARCB1 and, more rarely, SMARCA4. This is the shared disease-defining lesion across the AT/RT molecular subgroups.
SMARCB1 hgnc:11103 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SMARCB1 (hgnc:11103). hgnc:11103 is a gene from the HUGO Gene Nomenclature Committee. SMARCA4 hgnc:11100 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SMARCA4 (hgnc:11100). hgnc:11100 is a gene from the HUGO Gene Nomenclature Committee.
SWI/SNF complex GO:0016514 Gene Ontology (GO) Relation: this pathophysiological event involves this protein complex This pathophysiological event involves SWI/SNF complex (GO:0016514). GO:0016514 is a protein complex from the Gene Ontology.
Downstream
SWI/SNF Chromatin Remodeling Defect Core subunit loss disables normal SWI/SNF chromatin remodeling
EZH2 Enzymatic Dependency SMARCB1 loss creates a preclinical dependency on EZH2 activity in rhabdoid tumors, including the AT/RT disease context.
Show evidence (1 reference)
PMID:41374972 SUPPORT Other
"AT/RT now encompasses CNS tumors characterized by SMARCB1 (INI-1) or SMARCA4 (BRG-1) alterations within the SWI/SNF chromatin-remodeling complex."
This review directly defines AT/RT by SMARCB1 or SMARCA4 alterations in the SWI/SNF complex, supporting the disease-defining initiating lesion.
SWI/SNF Chromatin Remodeling Defect
Loss of SMARCB1 or SMARCA4 impairs the SWI/SNF chromatin-remodeling machinery, shifting AT/RT biology toward an epigenetically driven tumor state.
chromatin remodeling GO:0006338 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chromatin remodeling (GO:0006338). GO:0006338 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Subtype-Specific Enhancer Dysregulation Epigenetic dysregulation segregates into distinct subgroup programs
Show evidence (1 reference)
PMID:40121526 SUPPORT In Vitro
"We observe that an activating protein 1 (AP-1)-dependent transcriptional regulatory network is lost in ATRT, and AP-1 and lineage-specific TFs TEAD1 and ZIC2 require SMARCB1 for enhancer binding."
Functional molecular experiments, rather than disease definition alone, show how SMARCB1 loss disables lineage-transcription-factor enhancer binding.
Subtype-Specific Enhancer Dysregulation
Despite a simple recurrent genetic landscape, AT/RT segregates into distinct epigenetic subgroups with different enhancer states and regulatory networks.
regulation of gene expression GO:0010468 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of gene expression (GO:0010468). GO:0010468 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Experimental models
Patient-derived AT/RT tumoroids ORGANOID Preserves subgroup-specific epigenetic and gene-expression programs for perturbation studies.
Downstream
Cycling Progenitor-Like Tumor State Subtype trajectories share a proliferative intermediate-precursor-like state
Show evidence (3 references)
PMID:26923874 SUPPORT Human Clinical
"Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified."
This methylation and integrated molecular profiling study identifies the three consensus molecular subgroups within AT/RT.
PMID:26923874 SUPPORT Human Clinical
"Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets."
This provides direct human-tumor evidence that subgroup biology is driven by enhancer and regulatory-network differences rather than additional recurrent coding mutations.
PMID:37020038 SUPPORT In Vitro
"We demonstrate that ATRT tumoroids retain subgroup-specific epigenetic and gene expression profiles."
In vitro AT/RT tumoroids recapitulate subgroup-specific epigenetic and transcriptional programs, reinforcing the atomic subgroup-program node.
Cycling Progenitor-Like Tumor State
Patient tumors contain a shared cycling intermediate-precursor-like cell population at the base of subtype-specific differentiation trajectories. Patient-derived tumoroids can be shifted toward differentiated, non-proliferative states, supporting differentiation arrest as an assayable contributor to malignant growth rather than inferring proliferation from clinical tempo alone.
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
Headache Rapid intracranial tumor growth produces pressure symptoms including headache.
Vomiting Intracranial tumor burden and pressure effects produce nausea and vomiting at presentation.
Ataxia Posterior fossa or cerebellar involvement by rapidly growing AT/RT can present with ataxia.
Hydrocephalus Tumor growth can obstruct cerebrospinal-fluid pathways, producing hydrocephalus.
Seizure Intracranial tumor involvement can provoke seizures at presentation.
Lethargy Raised intracranial pressure and tumor burden can produce lethargy.
Show evidence (2 references)
PMID:40726147 SUPPORT Human Clinical
"Furthermore, a shared cycling, intermediate precursor cell (IPC)-like cell population, interspersed throughout tumors, was consistently present within all ATRT samples."
Single-cell patient-tumor data directly demonstrate the shared cycling progenitor-like state instead of using clinical progression as a proxy for proliferation.
PMID:40726147 SUPPORT In Vitro
"By directing tumor cells along their respective subtype-specific trajectories, we were able to induce a shift toward more differentiated, non-proliferative states."
Patient-derived tumoroid perturbation shows that the precursor-like state is experimentally linked to proliferation and differentiation arrest.
EZH2 Enzymatic Dependency
SMARCB1-deficient rhabdoid tumor models show dependence on EZH2 enzymatic activity. In AT/RT patient molecular data, tumor-specific DNA hypermethylation is associated with PRC2 and suppressed neural-development genes. This is a preclinical mechanistic vulnerability, not established clinical efficacy of EZH2 inhibition.
Downstream
Cycling Progenitor-Like Tumor State EZH2/PRC2-associated repression helps maintain a low-differentiation malignant state.
Show evidence (2 references)
PMID:23620515 SUPPORT In Vitro
"The compound induces apoptosis and differentiation specifically in SMARCB1-deleted MRT cells."
Selective EZH2 inhibition directly induced differentiation and apoptosis in SMARCB1-deleted rhabdoid tumor cells.
DOI:10.26508/lsa.202302088 SUPPORT Human Clinical
"AT/RT-unique DNA hypermethylation was associated with polycomb repressive complex 2 and linked to suppressed genes with a role in neural development and tumorigenesis."
Primary-tumor methylation and expression analysis directly links the AT/RT epigenetic state to PRC2-associated repression of neural-development programs.
✶

Histopathology

1
Composite Rhabdoid-Embryonal Histology
AT/RT is a polymorphous embryonal tumor with rhabdoid, primitive neuroectodermal, epithelial, and mesenchymal components rather than a uniform small-round-blue-cell morphology.
Show evidence (1 reference)
PMID:10437379 SUPPORT Human Clinical
"Histologically, atypical teratoid/rhabdoid tumor is defined as a polymorphous neoplasm often featuring rhabdoid, PNET, epithelial, and mesenchymal components."
This pathology series provides the disease-defining microscopic composite morphology used for histopathologic grounding.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Atypical Teratoid/Rhabdoid Tumor 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

6
Digestive 1
Vomiting FREQUENT HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vomiting (HP:0002013). HP:0002013 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16048294 SUPPORT Human Clinical
"Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
This cohort abstract directly reports nausea and vomiting among common presenting symptoms of AT/RT.
Context-specific annotations (1)
FREQUENT
46% in a 42-patient clinical cohort.
Show evidence (1 reference)
PMID:16048294 SUPPORT Human Clinical
"Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
The reported 46% maps to the HPO frequent range of 30-79%.
Nervous System 5
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.
Show evidence (1 reference)
PMID:16048294 SUPPORT Human Clinical
"Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
This cohort abstract directly reports headache as a common presenting symptom of AT/RT.
Context-specific annotations (1)
FREQUENT
36% in a 42-patient clinical cohort.
Show evidence (1 reference)
PMID:16048294 SUPPORT Human Clinical
"Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
The reported 36% maps to the HPO frequent range of 30-79%.
Ataxia OCCASIONAL 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:16048294 SUPPORT Human Clinical
"Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
This cohort abstract directly reports ataxia among the presenting neurologic manifestations of AT/RT.
Context-specific annotations (1)
OCCASIONAL
18% in a 42-patient clinical cohort.
Show evidence (1 reference)
PMID:16048294 SUPPORT Human Clinical
"Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
The reported 18% maps to the HPO occasional range of 5-29%.
Hydrocephalus FREQUENT HP:0000238 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrocephalus (HP:0000238). HP:0000238 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16048294 SUPPORT Human Clinical
"Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
This cohort abstract directly reports hydrocephalus as a common presenting feature of AT/RT.
Context-specific annotations (1)
FREQUENT
46% in a 42-patient clinical cohort.
Show evidence (1 reference)
PMID:16048294 SUPPORT Human Clinical
"Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
The reported 46% maps to the HPO frequent range of 30-79%.
Seizure OCCASIONAL HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16048294 SUPPORT Human Clinical
"Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
The cohort directly supports seizure as an AT/RT presenting phenotype.
Context-specific annotations (1)
OCCASIONAL
27% in a 42-patient clinical cohort.
Show evidence (1 reference)
PMID:16048294 SUPPORT Human Clinical
"Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
The reported 27% maps to the HPO occasional range of 5-29%.
Lethargy OCCASIONAL HP:0001254 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lethargy (HP:0001254). HP:0001254 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16048294 SUPPORT Human Clinical
"Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
The cohort directly supports lethargy as an AT/RT presenting phenotype.
Context-specific annotations (1)
OCCASIONAL
18% in a 42-patient clinical cohort.
Show evidence (1 reference)
PMID:16048294 SUPPORT Human Clinical
"Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
The reported 18% maps to the HPO occasional range of 5-29%.
🧬

Genetic Associations

2
SMARCB1 (Somatic/Germline Loss-of-Function)
Gene: SMARCB1 hgnc:11103 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SMARCB1 (hgnc:11103). hgnc:11103 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:41374972 SUPPORT Other
"AT/RT now encompasses CNS tumors characterized by SMARCB1 (INI-1) or SMARCA4 (BRG-1) alterations within the SWI/SNF chromatin-remodeling complex."
This review directly places SMARCB1 alteration at the center of AT/RT disease definition.
SMARCA4 (Rare Somatic/Germline Loss-of-Function)
Gene: SMARCA4 hgnc:11100 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SMARCA4 (hgnc:11100). hgnc:11100 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:41374972 SUPPORT Other
"AT/RT now encompasses CNS tumors characterized by SMARCB1 (INI-1) or SMARCA4 (BRG-1) alterations within the SWI/SNF chromatin-remodeling complex."
This review directly supports rare SMARCA4-altered AT/RT as part of the disease spectrum.
💊

Medical Actions

4
Maximal Safe Surgical Resection
Action: surgical resectionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical resection, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Surgery is used for diagnosis, decompression, and maximal cytoreduction before adjuvant therapy.
Show evidence (1 reference)
PMID:25646852 SUPPORT Human Clinical
"Maximal safe resection followed by craniospinal irradiation and systemic chemotherapy with ICE or VAC regimen is a reasonable treatment strategy in this uncommon malignancy."
This clinical series supports maximal safe resection as the surgical backbone of multimodality AT/RT treatment.
Intensive Multiagent Chemotherapy
Action: chemotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. Ontology label: Chemotherapy NCIT:C15632
Multiagent chemotherapy, often including high-dose chemotherapy with stem cell rescue, is a core component of contemporary AT/RT treatment protocols.
Show evidence (2 references)
PMID:32105509 SUPPORT Human Clinical
"After surgery, they received 2 courses of multiagent chemotherapy, followed by 3 courses of high-dose chemotherapy with peripheral blood stem cell rescue and involved-field radiation therapy."
ACNS0333 directly documents a modern intensive chemotherapy backbone that includes high-dose chemotherapy with stem cell rescue.
PMID:33138347 SUPPORT Human Clinical
"Aggressive therapy including early adjuvant radiotherapy and HDCT could be considered to improve outcomes of ATRT in children under the age of 3 years."
This multicenter infant cohort supports high-dose chemotherapy as part of aggressive therapy associated with improved outcomes in young children.
Adjuvant 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. Ontology label: Radiation Therapy NCIT:C15313
Focal or craniospinal radiation is used for local and neuraxis control and remains an important component of modern AT/RT therapy despite age-related toxicity concerns in infants.
Show evidence (2 references)
PMID:32105509 SUPPORT Human Clinical
"The ACNS0333 regimen dramatically improved survival compared with historical therapies for patients with AT/RT."
ACNS0333 used involved-field radiation as part of the regimen that improved survival relative to historical therapy.
PMID:33138347 SUPPORT Human Clinical
"Aggressive therapy including early adjuvant radiotherapy and HDCT could be considered to improve outcomes of ATRT in children under the age of 3 years."
This multicenter infant cohort directly supports early adjuvant radiotherapy as an outcome-improving component of aggressive therapy.
Tazemetostat (Investigational EZH2 Inhibition)
Category: Therapeutic 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
Agent: tazemetostat NCIT:C107506 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses tazemetostat (NCIT:C107506). NCIT:C107506 is a therapeutic agent from the NCI Thesaurus.
Tazemetostat is an investigational EZH2 inhibitor in AT/RT. Early-phase pediatric studies test it alone or in combination, but this entry does not assert established efficacy or standard-of-care status.
Mechanism Target:
INHIBITS EZH2 Enzymatic Dependency — Tazemetostat directly inhibits EZH2 enzymatic activity, the modeled preclinical dependency.
Show evidence (1 reference)
clinicaltrials:NCT02601937 SUPPORT Human Clinical
"This is a Phase I, open-label, dose escalation and dose expansion study with BID (suspension) and TID (tablet) oral dose of the enhancer of zeste homolog-2 (EZH2) inhibitor, tazemetostat."
The trial registry directly identifies tazemetostat as an EZH2 inhibitor in the relevant INI1-negative pediatric population.
Show evidence (1 reference)
clinicaltrials:NCT02601937 SUPPORT Human Clinical
"This is a Phase I, open-label, dose escalation and dose expansion study with BID (suspension) and TID (tablet) oral dose of the enhancer of zeste homolog-2 (EZH2) inhibitor, tazemetostat."
The registry establishes clinical investigation of the agent and mechanism without asserting efficacy.
🔬

Biochemical Markers

3
INI1 (SMARCB1/BAF47) Immunohistochemistry
Show evidence (1 reference)
PMID:26769252 SUPPORT Human Clinical
"Atypical teratoid/rhabdoid tumors (AT/RT) are rare, aggressive, embryonal brain tumors that occur most frequently in very young children; they are characterized by rhabdoid cells and loss of INI1 protein nuclear expression."
This pathology report explicitly identifies loss of INI1 nuclear expression as a defining diagnostic feature of AT/RT.
BRG1 (SMARCA4) Immunohistochemistry
Show evidence (1 reference)
PMID:41374972 SUPPORT Other
"AT/RT now encompasses CNS tumors characterized by SMARCB1 (INI-1) or SMARCA4 (BRG-1) alterations within the SWI/SNF chromatin-remodeling complex."
This review supports inclusion of BRG1/SMARCA4 loss as the rare alternate diagnostic branch within the AT/RT disease spectrum.
Claudin-6 Membrane Expression
Show evidence (1 reference)
PMID:42145029 SUPPORT Human Clinical
"We analyzed 36 well-characterized AT/RT samples and found membranous claudin-6 protein expression in 58% of cases, with striking enrichment in the molecular subgroup AT/RT-TYR (100%) and significantly higher staining scores compared with AT/RT-SHH and AT/RT-MYC."
Tumor immunohistochemistry directly supports CLDN6 as a frequent, TYR-enriched candidate biomarker while bounding the sample size.
🔬

Diagnosis

2
Integrated histologic, immunophenotypic, and molecular diagnosis
Diagnosis integrates embryonal/rhabdoid morphology with loss of INI1 or BRG1 and molecular confirmation. DNA methylation profiling is especially useful for subgroup assignment and morphologically or age-atypical cases.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Markers: INI1/SMARCB1 loss or, rarely, BRG1/SMARCA4 loss; DNA methylation class
Show evidence (1 reference)
PMID:41374972 SUPPORT Other
"A comprehensive, multimodal diagnostic approach combining histologic, immunophenotypic, and molecular data is essential to accurately identify AT/RT and guide clinical management, particularly in diagnostically ambiguous or atypical cases."
The diagnostic review directly supports integrated testing and bounds its importance in ambiguous presentations.
Germline SMARCB1 and SMARCA4 assessment
Paired tumor and constitutional assessment identifies rhabdoid tumor predisposition and informs family counseling; a germline result is not required for tumor diagnosis.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Markers: Constitutional pathogenic SMARCB1 or SMARCA4 variant
Show evidence (1 reference)
PMID:32105509 SUPPORT Human Clinical
"Ten of 64 patients tested had germline deletions or mutations ofSMARCB1."
Prospective paired testing demonstrates a clinically material germline fraction in AT/RT.
🩻

Imaging Findings

1
Heterogeneous pediatric intracranial mass on MRI and DWI
Compared with pediatric medulloblastoma in one retrospective case-control cohort, AT/RT more often showed cystic degeneration, hemorrhage, supratentorial ventriculomegaly, and peritumoral edema, with a lower mean apparent-diffusion-coefficient value. These features are supportive and not pathognomonic.
Mri
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON)
Show evidence (1 reference)
PMID:42384062 SUPPORT Human Clinical
"MRI features, including more cystic degeneration, hemorrhage, supratentorial ventriculomegaly, and peritumoral edema, combined with a lower ADC value may provide reliable information to differentiate AT/RT from MB in children."
The 32-AT/RT versus 82-medulloblastoma comparison supports a bounded, differential-imaging pattern rather than a diagnostic rule.
📈

Progression

1
Early relapse
Age: Birth to 22 years in ACNS0333
Relapse risk is front-loaded after treatment: 91% of documented treatment failures in ACNS0333 occurred within two years of enrollment.
Show evidence (1 reference)
PMID:32105509 SUPPORT Human Clinical
"Thirty treatment failures (91%) occurred by 2 years from enrollment."
The prospective cooperative-group cohort directly establishes the early concentration of relapse events.
📊

Prevalence

1
United States SEER 17 registries, 2001-2021
Annual Incidence 0.084 per 100,000
Population-based incidence estimate from 393 registered cases. This is an annual incidence measure, not disease prevalence.
Show evidence (1 reference)
PMID:39832059 SUPPORT Human Clinical
"A total of 393 patients were included in our analysis. Most patients developed tumors at less than 1 year of age (33.6%). The overall incidence was 0.084 per 100,000 population."
The SEER analysis directly reports the cohort size, age concentration, and annual population incidence.
🌍

Epidemiology

1
Infant-predominant pediatric brain tumor
AT/RT is rare among pediatric brain tumors overall but disproportionately represented in infants and children younger than 3 years of age.
Show evidence (1 reference)
PMID:22988546 SUPPORT Other
"Atypical teratoid rhabdoid tumors (ATRTs) are rare central nervous system tumors that comprise approximately 1-2% of all pediatric brain tumors; however, in patients less than 3 years of age this tumor accounts for up to 20% of cases."
This review provides the standard disease-level epidemiology framing used clinically for AT/RT, highlighting its enrichment in infants and very young children.
⚖️

Clinical Burden

High
AT/RT has high mortality, rapid early relapse, treatment-related mortality, and substantial late-effect risk from intensive chemotherapy, stem-cell rescue, and radiotherapy. Contemporary therapy improves survival but does not make prognosis uniformly favorable.
Show evidence (2 references)
PMID:32105509 SUPPORT Human Clinical
"Four-year EFS and overall survival for the entire cohort were 37% (95% CI, 25% to 49%) and 43% (95% CI, 31% to 55%), respectively."
Prospective ACNS0333 outcomes support a high disease-level mortality and recurrence burden despite intensive multimodal care.
PMID:42453193 SUPPORT Human Clinical
"The 4-year EFS and OS for the entire cohort were 49% and 53%, respectively."
A 2026 multi-institutional cohort confirms that substantial mortality and events persist with contemporary intensive therapy.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Atypical Teratoid/Rhabdoid Tumor:

Medulloblastoma and other embryonal CNS tumors
Overlapping Features AT/RT can share primitive embryonal fields and pediatric posterior-fossa imaging with medulloblastoma. Loss of INI1 or BRG1 and confirmatory molecular profiling distinguish AT/RT; MRI patterns can inform but cannot replace tissue diagnosis.
Distinguishing Features
  • INI1 or BRG1 nuclear loss supports AT/RT.
  • DNA methylation classification separates AT/RT from medulloblastoma classes.
  • Cystic change, hemorrhage, ventriculomegaly, edema, and lower ADC favored AT/RT in one case-control MRI study.
Show evidence (2 references)
PMID:8683283 SUPPORT Human Clinical
"This tumor is typically misdiagnosed as a primitive neuroectodermal tumor (PNET) primarily because 70% of ATT/RhTs contain fields indistinguishable from classic PNETs."
The foundational 52-case pathology series directly documents the morphologic overlap underlying this differential.
PMID:42384062 SUPPORT Human Clinical
"MRI features, including more cystic degeneration, hemorrhage, supratentorial ventriculomegaly, and peritumoral edema, combined with a lower ADC value may provide reliable information to differentiate AT/RT from MB in children."
A contemporary case-control study supports adjunctive MRI distinctions while not claiming imaging suffices for diagnosis.
Choroid plexus carcinoma, CRINET, poorly differentiated chordoma, and epithelioid sarcoma
Overlapping Features These INI1-related or morphologically overlapping entities are relevant in unusual locations, age groups, and composite tumors. Anatomic context, immunophenotype, genetics, and methylation class must be integrated.
Distinguishing Features
  • Tumor location and lineage-specific morphology/immunophenotype.
  • Retained versus lost INI1 or BRG1 in the appropriate diagnostic context.
  • Entity-specific DNA methylation and genomic profile.
Show evidence (1 reference)
PMID:41374972 SUPPORT Other
"Differential considerations, including epithelioid sarcoma, poorly differentiated chordoma, CRINET, choroid plexus carcinoma, and rare composite tumors, further complicate the diagnostic landscape."
The diagnostic review explicitly enumerates these differential considerations.
📊

Related Datasets

3
A cycling, progenitor-like cell population at the root of atypical teratoid rhabdoid tumor subtype differentiation trajectories. ega:EGAS00001008108
Background: Atypical teratoid rhabdoid tumors (ATRTs), characterized by the loss of SMARCB1, are among the most lethal pediatric central nervous system (CNS) tumors. Three molecular subtypes have been identified, each defined by distinct molecular and clinical features. No subtype-specific treatments are available, highlighting the necessity to better understand inter- and intra-subtype heterogeneity. Methods: We generated a single-nucleus transcriptome atlas of ATRTs, validated by single-cell ATAC-seq and spatial transcriptomics, to study subtype-specific differentiation trajectories.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("atypical teratoid rhabdoid tumor"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
A cycling, progenitor-like cell population at the root of atypical teratoid rhabdoid tumor subtype differentiation trajectories ega:EGAS00001008123
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("atypical teratoid rhabdoid tumor"); description-level mentions were not accepted. EGA study_type: Cancer Genomics. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Measles oncolytic virus as an immunotherapy for recurrent/refractory pediatric medulloblastoma and atypical teratoid rhabdoid tumor ega:EGAS50000000811
Pediatric recurrent medulloblastoma (MB) and atypical teratoid rhabdoid tumor (ATRT) are largely incurable and warrant novel therapies. We investigated a) the safety of a measles virus variant, MV-NIS, in a pediatric phase 1 study and b) the mechanisms of MV-NIS and potential benefit of combination with immune checkpoint inhibition (ICI). Pediatric patients with recurrent MB or ATRT were treated with intratumoral injections for local recurrence or via lumbar puncture for disseminated recurrence. We evaluated local immune responses to MV-NIS with and without ICI via single-cell and bulk RNA sequencing in an intracranial, immunocompetent, syngeneic murine model.
human SINGLE CELL RNA SEQ
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("atypical teratoid rhabdoid tumor"); description-level mentions were not accepted. EGA study_type: Transcriptome Analysis. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
🔬

Clinical Trials

5
NCT02601937 PHASE_I COMPLETED
Pediatric dose-escalation and expansion study of the EZH2 inhibitor tazemetostat in relapsed or refractory INI1-negative tumors or synovial sarcoma.
Show evidence (1 reference)
clinicaltrials:NCT02601937 SUPPORT Human Clinical
"This is a Phase I, open-label, dose escalation and dose expansion study with BID (suspension) and TID (tablet) oral dose of the enhancer of zeste homolog-2 (EZH2) inhibitor, tazemetostat."
The registry summary directly establishes the drug, population, and early-phase design.
NCT03838042 PHASE_I RECRUITING
INFORM2-NivEnt phase I/II basket study of nivolumab plus entinostat that explicitly includes the AT/RT-MYC subgroup.
Show evidence (1 reference)
clinicaltrials:NCT03838042 SUPPORT Human Clinical
"The aim of this trial is to determine preliminary activity of the combination treatment with nivolumab and entinostat in children and adolescents with high risk refractory/relapsed/progressive tumors harboring a high mutational load, focal MYC(N) amplification or ATRT-MYC subgroup as well as..."
The registry summary explicitly includes AT/RT-MYC and states the intervention and exploratory objective.
NCT04897880 PHASE_II TERMINATED
Terminated pediatric and young-adult phase II study of panobinostat that included malignant rhabdoid tumor and AT/RT.
Show evidence (1 reference)
clinicaltrials:NCT04897880 SUPPORT Human Clinical
"This trial is evaluating the anti-tumor activity and side effects of panobinostat in treating patients with osteosarcoma, malignant rhabdoid tumor/atypical teratoid rhabdoid tumor (MRT/ATRT), and neuroblastoma."
The registry summary directly documents AT/RT eligibility and the efficacy/safety objective; status was verified on 2026-08-05.
NCT05407441 PHASE_I ACTIVE_NOT_RECRUITING
TAZNI phase I/II study combining tazemetostat, nivolumab, and ipilimumab for INI1-negative or SMARCA4-deficient tumors including AT/RT.
Show evidence (1 reference)
clinicaltrials:NCT05407441 SUPPORT Human Clinical
"This research study involves a combination of three drugs given together as a possible treatment for malignant rhabdoid tumor, atypical teratoid rhabdoid tumor, epithelioid sarcoma, chordoma or other tumors that are deficient in one of two possible proteins, either INI-1 (SMARCB1) or SMARCA4."
The registry summary directly establishes the molecular eligibility, AT/RT inclusion, and combination strategy.
NCT07447076 PHASE_II RECRUITING
Current PNOC multi-arm platform study of novel single-agent and combination strategies for recurrent or progressive AT/RT.
Show evidence (1 reference)
clinicaltrials:NCT07447076 SUPPORT Human Clinical
"This is a multi-treatment arm study that will be conducted through the Pacific Pediatric Neuro-oncology Consortium (PNOC).The study will assess the safety and efficacy of novel therapies and combinatorial strategies for participants with recurrent or progressive ATRT."
The registry summary directly establishes the disease-specific platform design and recurrent/progressive population; recruiting status was verified on 2026-08-05.
🧫

Experimental Models

1
Patient-derived AT/RT tumoroids ORGANOID
Long-term expandable three-dimensional models derived from primary tumors or patient-derived orthotopic xenografts preserve MYC- and SHH-subgroup molecular features and enable subgroup-specific drug screening. Published models do not yet represent every subgroup equally.
AT/RT-MYC AT/RT-SHH
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Tissue
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this experimental model uses this anatomical location This experimental model uses brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Cell source
Primary patient tumor or patient-derived orthotopic xenograft tissue
Culture
Three-dimensional long-term expandable tumoroid culture
Publication
PMID:37020038
Pathograph links
Subtype-Specific Enhancer Dysregulation Preserves subgroup-specific epigenetic and gene-expression programs for perturbation studies.
Show evidence (1 reference)
PMID:37020038 SUPPORT In Vitro
"We demonstrate that ATRT tumoroids retain subgroup-specific epigenetic and gene expression profiles."
The model study directly demonstrates preservation of the linked subgroup-program node.
Show evidence (1 reference)
PMID:37020038 SUPPORT In Vitro
"Here, we describe the establishment of patient-derived tumoroid models from the MYC and SHH ATRT subgroups."
The study directly defines the provenance and represented subgroups of the model system.
{ }

Source YAML

click to show 
name: Atypical Teratoid/Rhabdoid Tumor
creation_date: '2026-04-12T20:00:00Z'
description: >-
  Atypical teratoid/rhabdoid tumor (AT/RT) is a highly aggressive embryonal
  central nervous system tumor that predominantly affects infants and young
  children. AT/RT is defined by SMARCB1 loss and, rarely, SMARCA4 loss within
  the SWI/SNF chromatin-remodeling complex. Consistent with dismech cancer
  curation guidance, this entry treats AT/RT as the disease-level mechanism
  graph and models TYR, SHH, MYC, and the rare molecularly distinct
  SMARCA4-deficient group as subtype facets rather than separate disorder pages.
categories:
- Central Nervous System Neoplasm
- Pediatric Brain Tumor
- Embryonal Tumor
- Molecularly Defined Tumor
- SWI/SNF-Deficient Tumor
parents:
- rhabdoid tumor
disease_term:
  preferred_term: atypical teratoid rhabdoid tumor
  term:
    id: MONDO:0020560
    label: atypical teratoid rhabdoid tumor
epidemiology:
- name: Infant-predominant pediatric brain tumor
  description: >-
    AT/RT is rare among pediatric brain tumors overall but disproportionately
    represented in infants and children younger than 3 years of age.
  evidence:
  - reference: PMID:22988546
    reference_title: "Atypical teratoid rhabdoid tumor: current therapy and future directions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Atypical teratoid rhabdoid tumors (ATRTs) are rare central nervous system tumors that comprise approximately 1-2% of all pediatric brain tumors; however, in patients less than 3 years of age this tumor accounts for up to 20% of cases."
    explanation: >-
      This review provides the standard disease-level epidemiology framing used
      clinically for AT/RT, highlighting its enrichment in infants and very
      young children.
prevalence:
- population: United States SEER 17 registries, 2001-2021
  measure_type: ANNUAL_INCIDENCE
  rate_per_100000: 0.084
  notes: >-
    Population-based incidence estimate from 393 registered cases. This is an
    annual incidence measure, not disease prevalence.
  evidence:
  - reference: PMID:39832059
    reference_title: Descriptive epidemiology and prognostic factors of atypical teratoid/rhabdoid tumors in the United States, 2001-2021.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 393 patients were included in our analysis. Most patients developed tumors at less than 1 year of age (33.6%). The overall incidence was 0.084 per 100,000 population."
    explanation: The SEER analysis directly reports the cohort size, age concentration, and annual population incidence.
progression:
- phase: Early relapse
  age_range: Birth to 22 years in ACNS0333
  notes: >-
    Relapse risk is front-loaded after treatment: 91% of documented treatment
    failures in ACNS0333 occurred within two years of enrollment.
  evidence:
  - reference: PMID:32105509
    reference_title: "Efficacy of High-Dose Chemotherapy and Three-Dimensional Conformal Radiation for Atypical Teratoid/Rhabdoid Tumor: A Report From the Children's Oncology Group Trial ACNS0333."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty treatment failures (91%) occurred by 2 years from enrollment."
    explanation: The prospective cooperative-group cohort directly establishes the early concentration of relapse events.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    AT/RT has high mortality, rapid early relapse, treatment-related mortality,
    and substantial late-effect risk from intensive chemotherapy, stem-cell
    rescue, and radiotherapy. Contemporary therapy improves survival but does
    not make prognosis uniformly favorable.
  evidence:
  - reference: PMID:32105509
    reference_title: "Efficacy of High-Dose Chemotherapy and Three-Dimensional Conformal Radiation for Atypical Teratoid/Rhabdoid Tumor: A Report From the Children's Oncology Group Trial ACNS0333."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four-year EFS and overall survival for the entire cohort were 37% (95% CI, 25% to 49%) and 43% (95% CI, 31% to 55%), respectively."
    explanation: Prospective ACNS0333 outcomes support a high disease-level mortality and recurrence burden despite intensive multimodal care.
  - reference: PMID:42453193
    reference_title: A multi-institutional report of children with atypical teratoid rhabdoid tumor treated with intensive multimodal therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 4-year EFS and OS for the entire cohort were 49% and 53%, respectively."
    explanation: A 2026 multi-institutional cohort confirms that substantial mortality and events persist with contemporary intensive therapy.
has_subtypes:
- name: TYR
  display_name: AT/RT-TYR
  classification: molecular
  description: >-
    Consensus methylation-defined molecular subgroup of AT/RT. It is retained as
    a flat subtype facet within the AT/RT disease graph rather than as a separate
    dismech disease page.
  evidence:
  - reference: PMID:41374972
    reference_title: "Atypical Teratoid Rhabdoid Tumor: How Tumor Diagnostic Methods in the Laboratory Have Evolved over the Past 40 Years."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The integration of immunohistochemical markers with advanced molecular diagnostics-including next-generation sequencing, DNA methylation profiling, and gene enrichment analyses-has facilitated robust tumor classification and the identification of three molecular subgroups: TYR, SHH, and MYC."
    explanation: >-
      This review explicitly names TYR as one of the three consensus molecular
      subgroups used to facet AT/RT without implying a separate disease page.
- name: SHH
  display_name: AT/RT-SHH
  classification: molecular
  description: >-
    Consensus methylation-defined molecular subgroup of AT/RT. It is modeled as
    a molecular subgroup axis inside the AT/RT page. Integrated profiling has
    further resolved SHH-1A, SHH-1B, and SHH-2 patterns with distinct age,
    location, and germline-SMARCB1 distributions; these are retained here as
    within-SHH heterogeneity rather than promoted to independent disorders.
  evidence:
  - reference: PMID:41374972
    reference_title: "Atypical Teratoid Rhabdoid Tumor: How Tumor Diagnostic Methods in the Laboratory Have Evolved over the Past 40 Years."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The integration of immunohistochemical markers with advanced molecular diagnostics-including next-generation sequencing, DNA methylation profiling, and gene enrichment analyses-has facilitated robust tumor classification and the identification of three molecular subgroups: TYR, SHH, and MYC."
    explanation: >-
      This review explicitly names SHH as one of the three consensus molecular
      subgroups used to facet AT/RT.
  - reference: PMID:35501487
    reference_title: ATRT-SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consensus clustering of DNA methylation profiles and confirmatory t-SNE analysis of 65 ATRT-SHH yielded three robust molecular subgroups, i.e., SHH-1A, SHH-1B and SHH-2."
    explanation: Integrated molecular analysis directly supports reproducible within-SHH subdivision without treating those patterns as separate diseases.
- name: MYC
  display_name: AT/RT-MYC
  classification: molecular
  description: >-
    Consensus methylation-defined molecular subgroup of AT/RT. It is modeled as
    a molecular subgroup facet within the single AT/RT disease entry.
  evidence:
  - reference: PMID:41374972
    reference_title: "Atypical Teratoid Rhabdoid Tumor: How Tumor Diagnostic Methods in the Laboratory Have Evolved over the Past 40 Years."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The integration of immunohistochemical markers with advanced molecular diagnostics-including next-generation sequencing, DNA methylation profiling, and gene enrichment analyses-has facilitated robust tumor classification and the identification of three molecular subgroups: TYR, SHH, and MYC."
    explanation: >-
      This review explicitly names MYC as one of the three consensus molecular
      subgroups used to facet AT/RT.
- name: SMARCA4
  display_name: AT/RT-SMARCA4
  classification: molecular
  description: >-
    Rare SMARCA4-deficient AT/RT forms a molecular group distinct from the three
    SMARCB1-deficient consensus subgroups. It is associated with younger age,
    more germline variants, and inferior prognosis, although case numbers are
    small.
  evidence:
  - reference: DOI:10.1007/s00401-020-02250-7
    reference_title: Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show that they form a separate group segregating from SMARCB1 mutated ATRTs and from other SMARCA4-deficient tumors like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) or SMARCA4 mutated extra-cranial malignant rhabdoid tumors."
    explanation: DNA methylation profiling of 14 AT/RT-SMARCA4 tumors directly establishes a separate molecular group.
pathophysiology:
- name: SMARCB1 or SMARCA4 Inactivation
  biological_scale: MOLECULAR
  description: >-
    AT/RT is defined by inactivation of the SWI/SNF core subunits SMARCB1 and,
    more rarely, SMARCA4. This is the shared disease-defining lesion across the
    AT/RT molecular subgroups.
  genes:
  - preferred_term: SMARCB1
    term:
      id: hgnc:11103
      label: SMARCB1
  - preferred_term: SMARCA4
    term:
      id: hgnc:11100
      label: SMARCA4
  protein_complexes:
  - preferred_term: SWI/SNF complex
    term:
      id: GO:0016514
      label: SWI/SNF complex
  evidence:
  - reference: PMID:41374972
    reference_title: "Atypical Teratoid Rhabdoid Tumor: How Tumor Diagnostic Methods in the Laboratory Have Evolved over the Past 40 Years."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "AT/RT now encompasses CNS tumors characterized by SMARCB1 (INI-1) or SMARCA4 (BRG-1) alterations within the SWI/SNF chromatin-remodeling complex."
    explanation: >-
      This review directly defines AT/RT by SMARCB1 or SMARCA4 alterations in
      the SWI/SNF complex, supporting the disease-defining initiating lesion.
  downstream:
  - target: SWI/SNF Chromatin Remodeling Defect
    description: Core subunit loss disables normal SWI/SNF chromatin remodeling
    evidence:
    - reference: PMID:40121526
      reference_title: SWI/SNF complexes govern ontology-specific transcription factor function in MYC-subtype atypical teratoid rhabdoid tumor.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "SMARCB1-dependent SWI/SNF integrates transcriptional functions of lineage-specific TFs into a core regulatory circuit that depends on the AP-1 subunit c-JUN, whose expression is determined by a SMARCB1-dependent super-enhancer that is lost in ATRT-MYC."
      explanation: Perturbation studies directly connect SMARCB1-dependent SWI/SNF function to the regulatory circuitry lost in AT/RT.
  - target: EZH2 Enzymatic Dependency
    description: SMARCB1 loss creates a preclinical dependency on EZH2 activity in rhabdoid tumors, including the AT/RT disease context.
    evidence:
    - reference: PMID:23620515
      reference_title: Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Inactivation of the switch/sucrose nonfermentable complex component SMARCB1 is extremely prevalent in pediatric malignant rhabdoid tumors (MRTs) or atypical teratoid rhabdoid tumors. This alteration is hypothesized to confer oncogenic dependency on EZH2 in these cancers."
      explanation: The publication explicitly places the proposed EZH2 dependency downstream of SMARCB1 inactivation in MRT/ATRT; direct dependency experiments were performed in SMARCB1-mutant MRT models.
- name: SWI/SNF Chromatin Remodeling Defect
  biological_scale: MOLECULAR
  description: >-
    Loss of SMARCB1 or SMARCA4 impairs the SWI/SNF chromatin-remodeling machinery,
    shifting AT/RT biology toward an epigenetically driven tumor state.
  biological_processes:
  - preferred_term: chromatin remodeling
    modifier: ABNORMAL
    term:
      id: GO:0006338
      label: chromatin remodeling
  evidence:
  - reference: PMID:40121526
    reference_title: SWI/SNF complexes govern ontology-specific transcription factor function in MYC-subtype atypical teratoid rhabdoid tumor.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We observe that an activating protein 1 (AP-1)-dependent transcriptional regulatory network is lost in ATRT, and AP-1 and lineage-specific TFs TEAD1 and ZIC2 require SMARCB1 for enhancer binding."
    explanation: >-
      Functional molecular experiments, rather than disease definition alone,
      show how SMARCB1 loss disables lineage-transcription-factor enhancer binding.
  downstream:
  - target: Subtype-Specific Enhancer Dysregulation
    description: Epigenetic dysregulation segregates into distinct subgroup programs
    evidence:
    - reference: PMID:40121526
      reference_title: SWI/SNF complexes govern ontology-specific transcription factor function in MYC-subtype atypical teratoid rhabdoid tumor.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We observe that an activating protein 1 (AP-1)-dependent transcriptional regulatory network is lost in ATRT, and AP-1 and lineage-specific TFs TEAD1 and ZIC2 require SMARCB1 for enhancer binding."
      explanation: Functional experiments directly link the SWI/SNF defect to loss of enhancer-bound lineage regulatory networks.
- name: Subtype-Specific Enhancer Dysregulation
  biological_scale: MOLECULAR
  description: >-
    Despite a simple recurrent genetic landscape, AT/RT segregates into distinct
    epigenetic subgroups with different enhancer states and regulatory networks.
  biological_processes:
  - preferred_term: regulation of gene expression
    modifier: ABNORMAL
    term:
      id: GO:0010468
      label: regulation of gene expression
  evidence:
  - reference: PMID:26923874
    reference_title: "Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified."
    explanation: >-
      This methylation and integrated molecular profiling study identifies the
      three consensus molecular subgroups within AT/RT.
  - reference: PMID:26923874
    reference_title: "Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets."
    explanation: >-
      This provides direct human-tumor evidence that subgroup biology is driven
      by enhancer and regulatory-network differences rather than additional
      recurrent coding mutations.
  - reference: PMID:37020038
    reference_title: "Atypical teratoid/rhabdoid tumoroids reveal subgroup-specific drug vulnerabilities."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We demonstrate that ATRT tumoroids retain subgroup-specific epigenetic and gene expression profiles."
    explanation: >-
      In vitro AT/RT tumoroids recapitulate subgroup-specific epigenetic and
      transcriptional programs, reinforcing the atomic subgroup-program node.
  downstream:
  - target: Cycling Progenitor-Like Tumor State
    description: Subtype trajectories share a proliferative intermediate-precursor-like state
    evidence:
    - reference: PMID:40726147
      reference_title: A cycling, progenitor-like cell population at the base of atypical teratoid rhabdoid tumor subtype differentiation trajectories.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Furthermore, a shared cycling, intermediate precursor cell (IPC)-like cell population, interspersed throughout tumors, was consistently present within all ATRT samples."
      explanation: Single-cell analysis of patient tumors directly connects subgroup differentiation trajectories to a shared cycling precursor-like population.
- name: Cycling Progenitor-Like Tumor State
  biological_scale: CELLULAR
  description: >-
    Patient tumors contain a shared cycling intermediate-precursor-like cell
    population at the base of subtype-specific differentiation trajectories.
    Patient-derived tumoroids can be shifted toward differentiated,
    non-proliferative states, supporting differentiation arrest as an assayable
    contributor to malignant growth rather than inferring proliferation from
    clinical tempo alone.
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:40726147
    reference_title: A cycling, progenitor-like cell population at the base of atypical teratoid rhabdoid tumor subtype differentiation trajectories.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, a shared cycling, intermediate precursor cell (IPC)-like cell population, interspersed throughout tumors, was consistently present within all ATRT samples."
    explanation: >-
      Single-cell patient-tumor data directly demonstrate the shared cycling
      progenitor-like state instead of using clinical progression as a proxy for proliferation.
  - reference: PMID:40726147
    reference_title: A cycling, progenitor-like cell population at the base of atypical teratoid rhabdoid tumor subtype differentiation trajectories.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "By directing tumor cells along their respective subtype-specific trajectories, we were able to induce a shift toward more differentiated, non-proliferative states."
    explanation: Patient-derived tumoroid perturbation shows that the precursor-like state is experimentally linked to proliferation and differentiation arrest.
  downstream:
  - target: Headache
    description: >-
      Rapid intracranial tumor growth produces pressure symptoms including
      headache.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - intracranial mass effect
    - raised intracranial pressure
    evidence:
    - reference: PMID:16048294
      reference_title: "Atypical teratoid/rhabdoid tumors of the central nervous system: management and outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
      explanation: The AT/RT cohort reports headache among common presenting symptoms during rapid prediagnostic progression.
  - target: Vomiting
    description: >-
      Intracranial tumor burden and pressure effects produce nausea and vomiting
      at presentation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - intracranial mass effect
    - raised intracranial pressure
    evidence:
    - reference: PMID:16048294
      reference_title: "Atypical teratoid/rhabdoid tumors of the central nervous system: management and outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
      explanation: The AT/RT cohort reports nausea and vomiting among common presenting symptoms.
  - target: Ataxia
    description: >-
      Posterior fossa or cerebellar involvement by rapidly growing AT/RT can
      present with ataxia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - posterior fossa involvement
    - cerebellar pathway disruption
    evidence:
    - reference: PMID:16048294
      reference_title: "Atypical teratoid/rhabdoid tumors of the central nervous system: management and outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
      explanation: The AT/RT cohort reports ataxia among presenting neurologic manifestations.
  - target: Hydrocephalus
    description: >-
      Tumor growth can obstruct cerebrospinal-fluid pathways, producing
      hydrocephalus.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - cerebrospinal-fluid obstruction
    evidence:
    - reference: PMID:16048294
      reference_title: "Atypical teratoid/rhabdoid tumors of the central nervous system: management and outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
      explanation: The AT/RT cohort reports hydrocephalus among common presenting features.
  - target: Seizure
    description: Intracranial tumor involvement can provoke seizures at presentation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - cortical or network irritation by tumor
    evidence:
    - reference: PMID:16048294
      reference_title: "Atypical teratoid/rhabdoid tumors of the central nervous system: management and outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
      explanation: The clinical cohort directly reports seizures in 27% of patients.
  - target: Lethargy
    description: Raised intracranial pressure and tumor burden can produce lethargy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - intracranial mass effect
    - raised intracranial pressure
    evidence:
    - reference: PMID:16048294
      reference_title: "Atypical teratoid/rhabdoid tumors of the central nervous system: management and outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
      explanation: The clinical cohort directly reports lethargy in 18% of patients.
- name: EZH2 Enzymatic Dependency
  biological_scale: MOLECULAR
  description: >-
    SMARCB1-deficient rhabdoid tumor models show dependence on EZH2 enzymatic
    activity. In AT/RT patient molecular data, tumor-specific DNA
    hypermethylation is associated with PRC2 and suppressed neural-development
    genes. This is a preclinical mechanistic vulnerability, not established
    clinical efficacy of EZH2 inhibition.
  evidence:
  - reference: PMID:23620515
    reference_title: Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The compound induces apoptosis and differentiation specifically in SMARCB1-deleted MRT cells."
    explanation: Selective EZH2 inhibition directly induced differentiation and apoptosis in SMARCB1-deleted rhabdoid tumor cells.
  - reference: DOI:10.26508/lsa.202302088
    reference_title: Aberrant DNA methylation distorts developmental trajectories in atypical teratoid/rhabdoid tumors
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AT/RT-unique DNA hypermethylation was associated with polycomb repressive complex 2 and linked to suppressed genes with a role in neural development and tumorigenesis."
    explanation: Primary-tumor methylation and expression analysis directly links the AT/RT epigenetic state to PRC2-associated repression of neural-development programs.
  downstream:
  - target: Cycling Progenitor-Like Tumor State
    description: EZH2/PRC2-associated repression helps maintain a low-differentiation malignant state.
    evidence:
    - reference: PMID:23620515
      reference_title: Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The compound induces apoptosis and differentiation specifically in SMARCB1-deleted MRT cells."
      explanation: Releasing EZH2 activity experimentally drives differentiation, supporting the direction from dependency toward maintenance of the progenitor-like state.
    - reference: DOI:10.26508/lsa.202302088
      reference_title: Aberrant DNA methylation distorts developmental trajectories in atypical teratoid/rhabdoid tumors
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These results highlight and characterize the role of DNA hypermethylation in AT/RT malignancy and halted neural cell differentiation."
      explanation: Human-tumor molecular data independently connects the epigenetic state to halted neural differentiation.
histopathology:
- name: Composite Rhabdoid-Embryonal Histology
  finding_term:
    preferred_term: atypical teratoid/rhabdoid tumor
    term:
      id: NCIT:C6906
      label: Atypical Teratoid/Rhabdoid Tumor
  diagnostic: true
  description: >-
    AT/RT is a polymorphous embryonal tumor with rhabdoid, primitive
    neuroectodermal, epithelial, and mesenchymal components rather than a
    uniform small-round-blue-cell morphology.
  evidence:
  - reference: PMID:10437379
    reference_title: "Clinicopathological characteristics of atypical teratoid/rhabdoid tumor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histologically, atypical teratoid/rhabdoid tumor is defined as a polymorphous neoplasm often featuring rhabdoid, PNET, epithelial, and mesenchymal components."
    explanation: >-
      This pathology series provides the disease-defining microscopic composite
      morphology used for histopathologic grounding.
phenotypes:
- category: Neurological
  name: Vomiting
  frequency: FREQUENT
  description: >-
    Vomiting is a common presenting feature, usually reflecting intracranial
    mass effect and increased intracranial pressure.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  phenotype_contexts:
  - frequency: FREQUENT
    notes: 46% in a 42-patient clinical cohort.
    evidence:
    - reference: PMID:16048294
      reference_title: "Atypical teratoid/rhabdoid tumors of the central nervous system: management and outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
      explanation: The reported 46% maps to the HPO frequent range of 30-79%.
  evidence:
  - reference: PMID:16048294
    reference_title: "Atypical teratoid/rhabdoid tumors of the central nervous system: management and outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
    explanation: This cohort abstract directly reports nausea and vomiting among common presenting symptoms of AT/RT.
- category: Neurological
  name: Headache
  frequency: FREQUENT
  description: >-
    Headache is a frequent presenting symptom caused by the intracranial tumor
    burden and associated pressure effects.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  phenotype_contexts:
  - frequency: FREQUENT
    notes: 36% in a 42-patient clinical cohort.
    evidence:
    - reference: PMID:16048294
      reference_title: "Atypical teratoid/rhabdoid tumors of the central nervous system: management and outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
      explanation: The reported 36% maps to the HPO frequent range of 30-79%.
  evidence:
  - reference: PMID:16048294
    reference_title: "Atypical teratoid/rhabdoid tumors of the central nervous system: management and outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
    explanation: This cohort abstract directly reports headache as a common presenting symptom of AT/RT.
- category: Neurological
  name: Ataxia
  frequency: OCCASIONAL
  description: >-
    Ataxia is an occasional presenting sign and may reflect posterior fossa or
    cerebellar involvement.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  phenotype_contexts:
  - frequency: OCCASIONAL
    notes: 18% in a 42-patient clinical cohort.
    evidence:
    - reference: PMID:16048294
      reference_title: "Atypical teratoid/rhabdoid tumors of the central nervous system: management and outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
      explanation: The reported 18% maps to the HPO occasional range of 5-29%.
  evidence:
  - reference: PMID:16048294
    reference_title: "Atypical teratoid/rhabdoid tumors of the central nervous system: management and outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
    explanation: This cohort abstract directly reports ataxia among the presenting neurologic manifestations of AT/RT.
- category: Neurological
  name: Hydrocephalus
  frequency: FREQUENT
  description: >-
    Hydrocephalus is a common presenting complication caused by tumor-related
    cerebrospinal fluid obstruction.
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  phenotype_contexts:
  - frequency: FREQUENT
    notes: 46% in a 42-patient clinical cohort.
    evidence:
    - reference: PMID:16048294
      reference_title: "Atypical teratoid/rhabdoid tumors of the central nervous system: management and outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
      explanation: The reported 46% maps to the HPO frequent range of 30-79%.
  evidence:
  - reference: PMID:16048294
    reference_title: "Atypical teratoid/rhabdoid tumors of the central nervous system: management and outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
    explanation: This cohort abstract directly reports hydrocephalus as a common presenting feature of AT/RT.
- category: Neurological
  name: Seizure
  frequency: OCCASIONAL
  description: Seizures occurred in 27% of the clinical cohort used for direct symptom-frequency curation.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  phenotype_contexts:
  - frequency: OCCASIONAL
    notes: 27% in a 42-patient clinical cohort.
    evidence:
    - reference: PMID:16048294
      reference_title: "Atypical teratoid/rhabdoid tumors of the central nervous system: management and outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
      explanation: The reported 27% maps to the HPO occasional range of 5-29%.
  evidence:
  - reference: PMID:16048294
    reference_title: "Atypical teratoid/rhabdoid tumors of the central nervous system: management and outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
    explanation: The cohort directly supports seizure as an AT/RT presenting phenotype.
- category: Neurological
  name: Lethargy
  frequency: OCCASIONAL
  description: Lethargy occurred in 18% of the clinical cohort used for direct symptom-frequency curation.
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  phenotype_contexts:
  - frequency: OCCASIONAL
    notes: 18% in a 42-patient clinical cohort.
    evidence:
    - reference: PMID:16048294
      reference_title: "Atypical teratoid/rhabdoid tumors of the central nervous system: management and outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
      explanation: The reported 18% maps to the HPO occasional range of 5-29%.
  evidence:
  - reference: PMID:16048294
    reference_title: "Atypical teratoid/rhabdoid tumors of the central nervous system: management and outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Signs and symptoms began, on average, a little more than 1 month before diagnosis and included the following: headache (36%), nausea and vomiting (46%), lethargy (18%), seizures (27%), cranial nerve findings (46%), ataxia (18%), long tract findings (18%), and hydrocephalus (46%)."
    explanation: The cohort directly supports lethargy as an AT/RT presenting phenotype.
biochemical:
- name: INI1 (SMARCB1/BAF47) Immunohistochemistry
  notes: >-
    Loss of nuclear INI1 staining is the canonical diagnostic biomarker for most
    AT/RTs and reflects SMARCB1 inactivation.
  evidence:
  - reference: PMID:26769252
    reference_title: "Atypical Teratoid/Rhabdoid Tumor (AT/RT) Arising From Ependymoma: A Type of AT/RT Secondarily Developing From Other Primary Central Nervous System Tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Atypical teratoid/rhabdoid tumors (AT/RT) are rare, aggressive, embryonal brain tumors that occur most frequently in very young children; they are characterized by rhabdoid cells and loss of INI1 protein nuclear expression."
    explanation: >-
      This pathology report explicitly identifies loss of INI1 nuclear expression
      as a defining diagnostic feature of AT/RT.
- name: BRG1 (SMARCA4) Immunohistochemistry
  notes: >-
    Loss of BRG1 supports the rare SMARCA4-deficient AT/RT subset when INI1 is
    retained.
  evidence:
  - reference: PMID:41374972
    reference_title: "Atypical Teratoid Rhabdoid Tumor: How Tumor Diagnostic Methods in the Laboratory Have Evolved over the Past 40 Years."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "AT/RT now encompasses CNS tumors characterized by SMARCB1 (INI-1) or SMARCA4 (BRG-1) alterations within the SWI/SNF chromatin-remodeling complex."
    explanation: >-
      This review supports inclusion of BRG1/SMARCA4 loss as the rare alternate
      diagnostic branch within the AT/RT disease spectrum.
- name: Claudin-6 Membrane Expression
  subtype: TYR
  frequency: FREQUENT
  notes: >-
    CLDN6 is an emerging subgroup-enriched biomarker and investigational surface
    target, not a replacement for INI1/BRG1 immunohistochemistry or molecular
    confirmation.
  evidence:
  - reference: PMID:42145029
    reference_title: Claudin-6 Protein Expression in Atypical Teratoid/Rhabdoid Tumors Is Strongly Enriched in the Molecular Subgroup AT/RT-TYR.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We analyzed 36 well-characterized AT/RT samples and found membranous claudin-6 protein expression in 58% of cases, with striking enrichment in the molecular subgroup AT/RT-TYR (100%) and significantly higher staining scores compared with AT/RT-SHH and AT/RT-MYC."
    explanation: Tumor immunohistochemistry directly supports CLDN6 as a frequent, TYR-enriched candidate biomarker while bounding the sample size.
genetic:
- name: SMARCB1
  gene_term:
    preferred_term: SMARCB1
    term:
      id: hgnc:11103
      label: SMARCB1
  association: Somatic/Germline Loss-of-Function
  notes: >-
    SMARCB1 is the dominant disease-defining driver gene in AT/RT. Both somatic
    and germline loss occur, and germline events overlap with rhabdoid tumor
    predisposition syndrome.
  evidence:
  - reference: PMID:41374972
    reference_title: "Atypical Teratoid Rhabdoid Tumor: How Tumor Diagnostic Methods in the Laboratory Have Evolved over the Past 40 Years."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "AT/RT now encompasses CNS tumors characterized by SMARCB1 (INI-1) or SMARCA4 (BRG-1) alterations within the SWI/SNF chromatin-remodeling complex."
    explanation: >-
      This review directly places SMARCB1 alteration at the center of AT/RT
      disease definition.
- name: SMARCA4
  gene_term:
    preferred_term: SMARCA4
    term:
      id: hgnc:11100
      label: SMARCA4
  association: Rare Somatic/Germline Loss-of-Function
  notes: >-
    SMARCA4 alteration is a rare alternative driver in INI1-retained AT/RT and
    should be considered when the histology is compatible but SMARCB1 protein
    expression is preserved.
  evidence:
  - reference: PMID:41374972
    reference_title: "Atypical Teratoid Rhabdoid Tumor: How Tumor Diagnostic Methods in the Laboratory Have Evolved over the Past 40 Years."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "AT/RT now encompasses CNS tumors characterized by SMARCB1 (INI-1) or SMARCA4 (BRG-1) alterations within the SWI/SNF chromatin-remodeling complex."
    explanation: >-
      This review directly supports rare SMARCA4-altered AT/RT as part of the
      disease spectrum.
treatments:
- name: Maximal Safe Surgical Resection
  description: >-
    Surgery is used for diagnosis, decompression, and maximal cytoreduction
    before adjuvant therapy.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical resection
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:25646852
    reference_title: "Intracranial atypical teratoid rhabdoid tumor: current management and a single institute experience of 15 patients from north India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Maximal safe resection followed by craniospinal irradiation and systemic chemotherapy with ICE or VAC regimen is a reasonable treatment strategy in this uncommon malignancy."
    explanation: >-
      This clinical series supports maximal safe resection as the surgical
      backbone of multimodality AT/RT treatment.
- name: Intensive Multiagent Chemotherapy
  description: >-
    Multiagent chemotherapy, often including high-dose chemotherapy with stem
    cell rescue, is a core component of contemporary AT/RT treatment protocols.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
  evidence:
  - reference: PMID:32105509
    reference_title: "Efficacy of High-Dose Chemotherapy and Three-Dimensional Conformal Radiation for Atypical Teratoid/Rhabdoid Tumor: A Report From the Children's Oncology Group Trial ACNS0333."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After surgery, they received 2 courses of multiagent chemotherapy, followed by 3 courses of high-dose chemotherapy with peripheral blood stem cell rescue and involved-field radiation therapy."
    explanation: >-
      ACNS0333 directly documents a modern intensive chemotherapy backbone that
      includes high-dose chemotherapy with stem cell rescue.
  - reference: PMID:33138347
    reference_title: "Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System in Children under the Age of 3 Years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aggressive therapy including early adjuvant radiotherapy and HDCT could be considered to improve outcomes of ATRT in children under the age of 3 years."
    explanation: >-
      This multicenter infant cohort supports high-dose chemotherapy as part of
      aggressive therapy associated with improved outcomes in young children.
- name: Adjuvant Radiation Therapy
  description: >-
    Focal or craniospinal radiation is used for local and neuraxis control and
    remains an important component of modern AT/RT therapy despite age-related
    toxicity concerns in infants.
  therapeutic_modality: RADIOTHERAPY
  treatment_term:
    preferred_term: radiation therapy
    term:
      id: NCIT:C15313
      label: Radiation Therapy
  evidence:
  - reference: PMID:32105509
    reference_title: "Efficacy of High-Dose Chemotherapy and Three-Dimensional Conformal Radiation for Atypical Teratoid/Rhabdoid Tumor: A Report From the Children's Oncology Group Trial ACNS0333."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ACNS0333 regimen dramatically improved survival compared with historical therapies for patients with AT/RT."
    explanation: >-
      ACNS0333 used involved-field radiation as part of the regimen that improved
      survival relative to historical therapy.
  - reference: PMID:33138347
    reference_title: "Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System in Children under the Age of 3 Years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aggressive therapy including early adjuvant radiotherapy and HDCT could be considered to improve outcomes of ATRT in children under the age of 3 years."
    explanation: >-
      This multicenter infant cohort directly supports early adjuvant
      radiotherapy as an outcome-improving component of aggressive therapy.
- name: Tazemetostat (Investigational EZH2 Inhibition)
  action_category: THERAPEUTIC
  description: >-
    Tazemetostat is an investigational EZH2 inhibitor in AT/RT. Early-phase
    pediatric studies test it alone or in combination, but this entry does not
    assert established efficacy or standard-of-care status.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tazemetostat
      term:
        id: NCIT:C107506
        label: Tazemetostat
  target_mechanisms:
  - target: EZH2 Enzymatic Dependency
    treatment_effect: INHIBITS
    description: Tazemetostat directly inhibits EZH2 enzymatic activity, the modeled preclinical dependency.
    evidence:
    - reference: clinicaltrials:NCT02601937
      reference_title: A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This is a Phase I, open-label, dose escalation and dose expansion study with BID (suspension) and TID (tablet) oral dose of the enhancer of zeste homolog-2 (EZH2) inhibitor, tazemetostat."
      explanation: The trial registry directly identifies tazemetostat as an EZH2 inhibitor in the relevant INI1-negative pediatric population.
  evidence:
  - reference: clinicaltrials:NCT02601937
    reference_title: A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a Phase I, open-label, dose escalation and dose expansion study with BID (suspension) and TID (tablet) oral dose of the enhancer of zeste homolog-2 (EZH2) inhibitor, tazemetostat."
    explanation: The registry establishes clinical investigation of the agent and mechanism without asserting efficacy.
imaging_findings:
- name: Heterogeneous pediatric intracranial mass on MRI and DWI
  modality: MRI
  description: >-
    Compared with pediatric medulloblastoma in one retrospective case-control
    cohort, AT/RT more often showed cystic degeneration, hemorrhage,
    supratentorial ventriculomegaly, and peritumoral edema, with a lower mean
    apparent-diffusion-coefficient value. These features are supportive and not
    pathognomonic.
  located_in:
    preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  diagnostic: false
  evidence:
  - reference: PMID:42384062
    reference_title: A case-control study of MRI features in pediatric atypical teratoid rhabdoid tumor and medulloblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI features, including more cystic degeneration, hemorrhage, supratentorial ventriculomegaly, and peritumoral edema, combined with a lower ADC value may provide reliable information to differentiate AT/RT from MB in children."
    explanation: The 32-AT/RT versus 82-medulloblastoma comparison supports a bounded, differential-imaging pattern rather than a diagnostic rule.
diagnosis:
- name: Integrated histologic, immunophenotypic, and molecular diagnosis
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  markers: INI1/SMARCB1 loss or, rarely, BRG1/SMARCA4 loss; DNA methylation class
  description: >-
    Diagnosis integrates embryonal/rhabdoid morphology with loss of INI1 or
    BRG1 and molecular confirmation. DNA methylation profiling is especially
    useful for subgroup assignment and morphologically or age-atypical cases.
  evidence:
  - reference: PMID:41374972
    reference_title: "Atypical Teratoid Rhabdoid Tumor: How Tumor Diagnostic Methods in the Laboratory Have Evolved over the Past 40 Years."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A comprehensive, multimodal diagnostic approach combining histologic, immunophenotypic, and molecular data is essential to accurately identify AT/RT and guide clinical management, particularly in diagnostically ambiguous or atypical cases."
    explanation: The diagnostic review directly supports integrated testing and bounds its importance in ambiguous presentations.
- name: Germline SMARCB1 and SMARCA4 assessment
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  markers: Constitutional pathogenic SMARCB1 or SMARCA4 variant
  description: >-
    Paired tumor and constitutional assessment identifies rhabdoid tumor
    predisposition and informs family counseling; a germline result is not
    required for tumor diagnosis.
  evidence:
  - reference: PMID:32105509
    reference_title: "Efficacy of High-Dose Chemotherapy and Three-Dimensional Conformal Radiation for Atypical Teratoid/Rhabdoid Tumor: A Report From the Children's Oncology Group Trial ACNS0333."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten of 64 patients tested had germline deletions or mutations ofSMARCB1."
    explanation: Prospective paired testing demonstrates a clinically material germline fraction in AT/RT.
differential_diagnoses:
- name: Medulloblastoma and other embryonal CNS tumors
  description: >-
    AT/RT can share primitive embryonal fields and pediatric posterior-fossa
    imaging with medulloblastoma. Loss of INI1 or BRG1 and confirmatory molecular
    profiling distinguish AT/RT; MRI patterns can inform but cannot replace tissue diagnosis.
  distinguishing_features:
  - INI1 or BRG1 nuclear loss supports AT/RT.
  - DNA methylation classification separates AT/RT from medulloblastoma classes.
  - Cystic change, hemorrhage, ventriculomegaly, edema, and lower ADC favored AT/RT in one case-control MRI study.
  evidence:
  - reference: PMID:8683283
    reference_title: "Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This tumor is typically misdiagnosed as a primitive neuroectodermal tumor (PNET) primarily because 70% of ATT/RhTs contain fields indistinguishable from classic PNETs."
    explanation: The foundational 52-case pathology series directly documents the morphologic overlap underlying this differential.
  - reference: PMID:42384062
    reference_title: A case-control study of MRI features in pediatric atypical teratoid rhabdoid tumor and medulloblastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI features, including more cystic degeneration, hemorrhage, supratentorial ventriculomegaly, and peritumoral edema, combined with a lower ADC value may provide reliable information to differentiate AT/RT from MB in children."
    explanation: A contemporary case-control study supports adjunctive MRI distinctions while not claiming imaging suffices for diagnosis.
- name: Choroid plexus carcinoma, CRINET, poorly differentiated chordoma, and epithelioid sarcoma
  description: >-
    These INI1-related or morphologically overlapping entities are relevant in
    unusual locations, age groups, and composite tumors. Anatomic context,
    immunophenotype, genetics, and methylation class must be integrated.
  distinguishing_features:
  - Tumor location and lineage-specific morphology/immunophenotype.
  - Retained versus lost INI1 or BRG1 in the appropriate diagnostic context.
  - Entity-specific DNA methylation and genomic profile.
  evidence:
  - reference: PMID:41374972
    reference_title: "Atypical Teratoid Rhabdoid Tumor: How Tumor Diagnostic Methods in the Laboratory Have Evolved over the Past 40 Years."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Differential considerations, including epithelioid sarcoma, poorly differentiated chordoma, CRINET, choroid plexus carcinoma, and rare composite tumors, further complicate the diagnostic landscape."
    explanation: The diagnostic review explicitly enumerates these differential considerations.
experimental_models:
- name: Patient-derived AT/RT tumoroids
  description: >-
    Long-term expandable three-dimensional models derived from primary tumors
    or patient-derived orthotopic xenografts preserve MYC- and SHH-subgroup
    molecular features and enable subgroup-specific drug screening. Published
    models do not yet represent every subgroup equally.
  experimental_model_type: ORGANOID
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  cell_source: Primary patient tumor or patient-derived orthotopic xenograft tissue
  culture_system: Three-dimensional long-term expandable tumoroid culture
  conditions:
  - AT/RT-MYC
  - AT/RT-SHH
  publication: PMID:37020038
  modeled_mechanisms:
  - target: Subtype-Specific Enhancer Dysregulation
    description: Preserves subgroup-specific epigenetic and gene-expression programs for perturbation studies.
    evidence:
    - reference: PMID:37020038
      reference_title: Atypical teratoid/rhabdoid tumoroids reveal subgroup-specific drug vulnerabilities.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We demonstrate that ATRT tumoroids retain subgroup-specific epigenetic and gene expression profiles."
      explanation: The model study directly demonstrates preservation of the linked subgroup-program node.
  evidence:
  - reference: PMID:37020038
    reference_title: Atypical teratoid/rhabdoid tumoroids reveal subgroup-specific drug vulnerabilities.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we describe the establishment of patient-derived tumoroid models from the MYC and SHH ATRT subgroups."
    explanation: The study directly defines the provenance and represented subgroups of the model system.
clinical_trials:
- name: NCT02601937
  phase: PHASE_I
  status: COMPLETED
  description: Pediatric dose-escalation and expansion study of the EZH2 inhibitor tazemetostat in relapsed or refractory INI1-negative tumors or synovial sarcoma.
  evidence:
  - reference: clinicaltrials:NCT02601937
    reference_title: A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a Phase I, open-label, dose escalation and dose expansion study with BID (suspension) and TID (tablet) oral dose of the enhancer of zeste homolog-2 (EZH2) inhibitor, tazemetostat."
    explanation: The registry summary directly establishes the drug, population, and early-phase design.
- name: NCT03838042
  phase: PHASE_I
  status: RECRUITING
  description: INFORM2-NivEnt phase I/II basket study of nivolumab plus entinostat that explicitly includes the AT/RT-MYC subgroup.
  review_notes: ClinicalTrials.gov lists Phase 1/Phase 2; the schema records the earliest phase.
  evidence:
  - reference: clinicaltrials:NCT03838042
    reference_title: INFORM2 Exploratory Multinational Phase I/II Combination Study of Nivolumab and Entinostat in Children and Adolescents With Refractory High-risk Malignancies (INFORM2-NivEnt)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The aim of this trial is to determine preliminary activity of the combination treatment with nivolumab and entinostat in children and adolescents with high risk refractory/relapsed/progressive tumors harboring a high mutational load, focal MYC(N) amplification or ATRT-MYC subgroup as well as tumors with high tumor infiltrating lymphocytes (TILs) or a tertiary lymphoid structure (TLS)."
    explanation: The registry summary explicitly includes AT/RT-MYC and states the intervention and exploratory objective.
- name: NCT04897880
  phase: PHASE_II
  status: TERMINATED
  description: Terminated pediatric and young-adult phase II study of panobinostat that included malignant rhabdoid tumor and AT/RT.
  evidence:
  - reference: clinicaltrials:NCT04897880
    reference_title: A Phase II Study of Panobinostat in Pediatric, Adolescent and Young Adult Patients With Solid Tumors Including Osteosarcoma, Malignant Rhabdoid Tumor/Atypical Teratoid Rhabdoid Tumors and Neuroblastoma
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This trial is evaluating the anti-tumor activity and side effects of panobinostat in treating patients with osteosarcoma, malignant rhabdoid tumor/atypical teratoid rhabdoid tumor (MRT/ATRT), and neuroblastoma."
    explanation: The registry summary directly documents AT/RT eligibility and the efficacy/safety objective; status was verified on 2026-08-05.
- name: NCT05407441
  phase: PHASE_I
  status: ACTIVE_NOT_RECRUITING
  description: TAZNI phase I/II study combining tazemetostat, nivolumab, and ipilimumab for INI1-negative or SMARCA4-deficient tumors including AT/RT.
  review_notes: ClinicalTrials.gov lists Phase 1/Phase 2; the schema records the earliest phase.
  evidence:
  - reference: clinicaltrials:NCT05407441
    reference_title: "TAZNI: A Phase I/II Combination Trial of Tazemetostat With Nivolumab and Ipilimumab for Children With INI1-Negative or SMARCA4-Deficient Tumors"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This research study involves a combination of three drugs given together as a possible treatment for malignant rhabdoid tumor, atypical teratoid rhabdoid tumor, epithelioid sarcoma, chordoma or other tumors that are deficient in one of two possible proteins, either INI-1 (SMARCB1) or SMARCA4."
    explanation: The registry summary directly establishes the molecular eligibility, AT/RT inclusion, and combination strategy.
- name: NCT07447076
  phase: PHASE_II
  status: RECRUITING
  description: Current PNOC multi-arm platform study of novel single-agent and combination strategies for recurrent or progressive AT/RT.
  evidence:
  - reference: clinicaltrials:NCT07447076
    reference_title: A Platform Study of Novel Therapies for Children, Adolescents and Young Adults With Recurrent/Progressive Atypical Teratoid Rhabdoid Tumor (ATRT)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a multi-treatment arm study that will be conducted through the Pacific Pediatric Neuro-oncology Consortium (PNOC).The study will assess the safety and efficacy of novel therapies and combinatorial strategies for participants with recurrent or progressive ATRT."
    explanation: The registry summary directly establishes the disease-specific platform design and recurrent/progressive population; recruiting status was verified on 2026-08-05.
discussions:
- discussion_id: gap_atrt_risk_adapted_therapy
  prompt: Which molecular and clinical strata can safely receive less toxic therapy, and which need novel intensification?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Intensive Multiagent Chemotherapy
  - treatments#Adjuvant Radiation Therapy
  rationale: >-
    Subgroup and germline associations are based on small strata, while intensive
    multimodal therapy has substantial acute and long-term toxicity. Existing
    studies do not establish validated subgroup-specific de-escalation rules.
  evidence:
  - reference: PMID:32105509
    reference_title: "Efficacy of High-Dose Chemotherapy and Three-Dimensional Conformal Radiation for Atypical Teratoid/Rhabdoid Tumor: A Report From the Children's Oncology Group Trial ACNS0333."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subsets of patients who can be cured with less therapy may exist. The goal must be to continue to improve survival and reduce toxicity with refinements in therapy based on integration of biologic and clinical risk factors."
    explanation: The prospective trial report explicitly identifies risk-adapted de-escalation and toxicity reduction as unresolved priorities.
- discussion_id: gap_atrt_emerging_targets
  prompt: Will differentiation therapy, CLDN6-directed immunotherapy, or other subgroup-informed targets produce durable clinical benefit?
  kind: EMERGING_HYPOTHESIS
  status: OPEN
  attaches_to:
  - pathophysiology#Cycling Progenitor-Like Tumor State
  - biochemical#Claudin-6 Membrane Expression
  rationale: >-
    Differentiation-state manipulation and CLDN6 targeting are supported by
    patient-derived models and small tissue cohorts, but clinical efficacy and
    subgroup generalizability remain unproven.
  evidence:
  - reference: PMID:40726147
    reference_title: A cycling, progenitor-like cell population at the base of atypical teratoid rhabdoid tumor subtype differentiation trajectories.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "By directing tumor cells along their respective subtype-specific trajectories, we were able to induce a shift toward more differentiated, non-proliferative states."
    explanation: Tumoroid perturbation supports the hypothesis but does not establish patient benefit.
references:
- reference: DOI:10.1002/gcc.23195
  title: 'Constitutional balanced translocations involving <scp><i>SMARCB1</i></scp>: A rare cause of rhabdoid tumor predisposition syndrome'
  found_in:
  - Atypical_Teratoid_Rhabdoid_Tumor-deep-research-falcon.md
  findings:
  - statement: Rhabdoid Tumor Predisposition Syndrome 1 (RTPS1) confers an increased risk of developing rhabdoid tumors and is caused by germline mutations in SMARCB1.
    supporting_text: Rhabdoid Tumor Predisposition Syndrome 1 (RTPS1) confers an increased risk of developing rhabdoid tumors and is caused by germline mutations in SMARCB1.
    evidence:
    - reference: DOI:10.1002/gcc.23195
      reference_title: 'Constitutional balanced translocations involving <scp><i>SMARCB1</i></scp>: A rare cause of rhabdoid tumor predisposition syndrome'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Rhabdoid Tumor Predisposition Syndrome 1 (RTPS1) confers an increased risk of developing rhabdoid tumors and is caused by germline mutations in SMARCB1.
      explanation: Deep research cited this publication as relevant literature for Atypical Teratoid Rhabdoid Tumor.
- reference: DOI:10.1007/s00401-020-02250-7
  title: Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases
  found_in:
  - Atypical_Teratoid_Rhabdoid_Tumor-deep-research-falcon.md
  findings:
  - statement: Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system.
    supporting_text: Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system.
    evidence:
    - reference: DOI:10.1007/s00401-020-02250-7
      reference_title: Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system.
      explanation: Deep research cited this publication as relevant literature for Atypical Teratoid Rhabdoid Tumor.
- reference: DOI:10.1007/s00401-023-02608-7
  title: Recurrent atypical teratoid/rhabdoid tumors (AT/RT) reveal discrete features of progression on histology, epigenetics, copy number profiling, and transcriptomics
  found_in:
  - Atypical_Teratoid_Rhabdoid_Tumor-deep-research-falcon.md
  findings:
  - statement: Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors manifesting in infancy.
    supporting_text: Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors manifesting in infancy.
    evidence:
    - reference: DOI:10.1007/s00401-023-02608-7
      reference_title: Recurrent atypical teratoid/rhabdoid tumors (AT/RT) reveal discrete features of progression on histology, epigenetics, copy number profiling, and transcriptomics
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors manifesting in infancy.
      explanation: Deep research cited this publication as relevant literature for Atypical Teratoid Rhabdoid Tumor.
- reference: DOI:10.1093/neuonc/noaa046
  title: Advancing biology-based therapeutic approaches for atypical teratoid rhabdoid tumors
  found_in:
  - Atypical_Teratoid_Rhabdoid_Tumor-deep-research-falcon.md
  findings:
  - statement: Atypical teratoid rhabdoid tumor (ATRT) is a rare, highly malignant central nervous system cancer arising in infants and younger children, historically considered to be homogeneous, monogenic, and incurable.
    supporting_text: Atypical teratoid rhabdoid tumor (ATRT) is a rare, highly malignant central nervous system cancer arising in infants and younger children, historically considered to be homogeneous, monogenic, and incurable.
    evidence:
    - reference: DOI:10.1093/neuonc/noaa046
      reference_title: Advancing biology-based therapeutic approaches for atypical teratoid rhabdoid tumors
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Atypical teratoid rhabdoid tumor (ATRT) is a rare, highly malignant central nervous system cancer arising in infants and younger children, historically considered to be homogeneous, monogenic, and incurable.
      explanation: Deep research cited this publication as relevant literature for Atypical Teratoid Rhabdoid Tumor.
- reference: DOI:10.1093/noajnl/vdae158
  title: Approaches for prevention of tumors in patients with rhabdoid tumor predisposition syndrome
  found_in:
  - Atypical_Teratoid_Rhabdoid_Tumor-deep-research-falcon.md
  findings:
  - statement: Patients with rhabdoid tumor predisposition syndrome (RTPS) harbor germline alterations in the epigenetic regulator genes SMARCB1 or SMARCA4.
    supporting_text: Patients with rhabdoid tumor predisposition syndrome (RTPS) harbor germline alterations in the epigenetic regulator genes SMARCB1 or SMARCA4.
    evidence:
    - reference: DOI:10.1093/noajnl/vdae158
      reference_title: Approaches for prevention of tumors in patients with rhabdoid tumor predisposition syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Patients with rhabdoid tumor predisposition syndrome (RTPS) harbor germline alterations in the epigenetic regulator genes SMARCB1 or SMARCA4.
      explanation: Deep research cited this publication as relevant literature for Atypical Teratoid Rhabdoid Tumor.
- reference: DOI:10.1093/noajnl/vdae162
  title: Development and epigenetic regulation of Atypical teratoid/rhabdoid tumors in the context of cell-of-origin and halted cell differentiation
  found_in:
  - Atypical_Teratoid_Rhabdoid_Tumor-deep-research-falcon.md
  findings:
  - statement: Atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive brain tumors primarily observed in infants.
    supporting_text: Atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive brain tumors primarily observed in infants.
    evidence:
    - reference: DOI:10.1093/noajnl/vdae162
      reference_title: Development and epigenetic regulation of Atypical teratoid/rhabdoid tumors in the context of cell-of-origin and halted cell differentiation
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive brain tumors primarily observed in infants.
      explanation: Deep research cited this publication as relevant literature for Atypical Teratoid Rhabdoid Tumor.
- reference: DOI:10.1093/nop/npad005
  title: Current advances in immunotherapy for atypical teratoid rhabdoid tumor (ATRT)
  found_in:
  - Atypical_Teratoid_Rhabdoid_Tumor-deep-research-falcon.md
  findings:
  - statement: Atypical teratoid rhabdoid tumors (ATRT) are rare and aggressive embryonal tumors of central nervous system that typically affect children younger than 3 years of age.
    supporting_text: Atypical teratoid rhabdoid tumors (ATRT) are rare and aggressive embryonal tumors of central nervous system that typically affect children younger than 3 years of age.
    evidence:
    - reference: DOI:10.1093/nop/npad005
      reference_title: Current advances in immunotherapy for atypical teratoid rhabdoid tumor (ATRT)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Atypical teratoid rhabdoid tumors (ATRT) are rare and aggressive embryonal tumors of central nervous system that typically affect children younger than 3 years of age.
      explanation: Deep research cited this publication as relevant literature for Atypical Teratoid Rhabdoid Tumor.
- reference: DOI:10.26508/lsa.202302088
  title: Aberrant DNA methylation distorts developmental trajectories in atypical teratoid/rhabdoid tumors
  found_in:
  - Atypical_Teratoid_Rhabdoid_Tumor-deep-research-falcon.md
  findings:
  - statement: Atypical teratoid/rhabdoid tumors (AT/RTs) are pediatric brain tumors known for their aggressiveness and aberrant but still unresolved epigenetic regulation.
    supporting_text: Atypical teratoid/rhabdoid tumors (AT/RTs) are pediatric brain tumors known for their aggressiveness and aberrant but still unresolved epigenetic regulation.
    evidence:
    - reference: DOI:10.26508/lsa.202302088
      reference_title: Aberrant DNA methylation distorts developmental trajectories in atypical teratoid/rhabdoid tumors
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Atypical teratoid/rhabdoid tumors (AT/RTs) are pediatric brain tumors known for their aggressiveness and aberrant but still unresolved epigenetic regulation.
      explanation: Deep research cited this publication as relevant literature for Atypical Teratoid Rhabdoid Tumor.
- reference: DOI:10.3390/cancers18010008
  title: 'Histogenesis of Atypical Teratoid Rhabdoid Tumors: Anatomical and Embryological Perspectives'
  found_in:
  - Atypical_Teratoid_Rhabdoid_Tumor-deep-research-falcon.md
  findings:
  - statement: Atypical teratoid/rhabdoid tumors (ATRTs) are rare, malignant central nervous system (CNS) neoplasms that predominantly affect infants and young children.
    supporting_text: Atypical teratoid/rhabdoid tumors (ATRTs) are rare, malignant central nervous system (CNS) neoplasms that predominantly affect infants and young children.
    evidence:
    - reference: DOI:10.3390/cancers18010008
      reference_title: 'Histogenesis of Atypical Teratoid Rhabdoid Tumors: Anatomical and Embryological Perspectives'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Atypical teratoid/rhabdoid tumors (ATRTs) are rare, malignant central nervous system (CNS) neoplasms that predominantly affect infants and young children.
      explanation: Deep research cited this publication as relevant literature for Atypical Teratoid Rhabdoid Tumor.
- reference: DOI:10.3390/jmp6020013
  title: The Current Landscape of Molecular Pathology for the Diagnosis and Treatment of Atypical Teratoid Rhabdoid Tumor
  found_in:
  - Atypical_Teratoid_Rhabdoid_Tumor-deep-research-falcon.md
  findings:
  - statement: Atypical teratoid rhabdoid tumor (ATRT) is a rare, aggressive pediatric central nervous system (CNS) tumor that predominantly affects children under the age of 3.
    supporting_text: Atypical teratoid rhabdoid tumor (ATRT) is a rare, aggressive pediatric central nervous system (CNS) tumor that predominantly affects children under the age of 3.
    evidence:
    - reference: DOI:10.3390/jmp6020013
      reference_title: The Current Landscape of Molecular Pathology for the Diagnosis and Treatment of Atypical Teratoid Rhabdoid Tumor
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Atypical teratoid rhabdoid tumor (ATRT) is a rare, aggressive pediatric central nervous system (CNS) tumor that predominantly affects children under the age of 3.
      explanation: Deep research cited this publication as relevant literature for Atypical Teratoid Rhabdoid Tumor.
datasets:
- accession: ega:EGAS00001008108
  title: A cycling, progenitor-like cell population at the root of atypical teratoid rhabdoid tumor subtype differentiation trajectories.
  description: 'Background: Atypical teratoid rhabdoid tumors (ATRTs), characterized by the loss of SMARCB1, are among the most lethal pediatric central nervous system (CNS) tumors. Three molecular subtypes have been identified, each defined by distinct molecular and clinical features. No subtype-specific treatments are available, highlighting the necessity to better understand inter- and intra-subtype heterogeneity. Methods: We generated a single-nucleus transcriptome atlas of ATRTs, validated by single-cell ATAC-seq and spatial transcriptomics, to study subtype-specific differentiation trajectories.'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("atypical teratoid rhabdoid tumor"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001008123
  title: A cycling, progenitor-like cell population at the root of atypical teratoid rhabdoid tumor subtype differentiation trajectories
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("atypical teratoid rhabdoid tumor"); description-level mentions were not accepted. EGA study_type: Cancer Genomics. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS50000000811
  title: Measles oncolytic virus as an immunotherapy for recurrent/refractory pediatric medulloblastoma and atypical teratoid rhabdoid tumor
  description: Pediatric recurrent medulloblastoma (MB) and atypical teratoid rhabdoid tumor (ATRT) are largely incurable and warrant novel therapies. We investigated a) the safety of a measles virus variant, MV-NIS, in a pediatric phase 1 study and b) the mechanisms of MV-NIS and potential benefit of combination with immune checkpoint inhibition (ICI). Pediatric patients with recurrent MB or ATRT were treated with intratumoral injections for local recurrence or via lumbar puncture for disseminated recurrence. We evaluated local immune responses to MV-NIS with and without ICI via single-cell and bulk RNA sequencing in an intracranial, immunocompetent, syngeneic murine model.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("atypical teratoid rhabdoid tumor"); description-level mentions were not accepted. EGA study_type: Transcriptome Analysis. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
📚

References & Deep Research

References

10
DOI:10.1002/gcc.23195
Constitutional balanced translocations involving <scp><i>SMARCB1</i></scp>: A rare cause of rhabdoid tumor predisposition syndrome
1 finding
Rhabdoid Tumor Predisposition Syndrome 1 (RTPS1) confers an increased risk of developing rhabdoid tumors and is caused by germline mutations in SMARCB1.
"Rhabdoid Tumor Predisposition Syndrome 1 (RTPS1) confers an increased risk of developing rhabdoid tumors and is caused by germline mutations in SMARCB1."
Show evidence (1 reference)
DOI:10.1002/gcc.23195 SUPPORT Human Clinical
"Rhabdoid Tumor Predisposition Syndrome 1 (RTPS1) confers an increased risk of developing rhabdoid tumors and is caused by germline mutations in SMARCB1."
Deep research cited this publication as relevant literature for Atypical Teratoid Rhabdoid Tumor.
DOI:10.1007/s00401-020-02250-7
Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases
1 finding
Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system.
"Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system."
Show evidence (1 reference)
DOI:10.1007/s00401-020-02250-7 SUPPORT Human Clinical
"Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system."
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"Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors manifesting in infancy."
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"Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors manifesting in infancy."
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"Atypical teratoid rhabdoid tumor (ATRT) is a rare, highly malignant central nervous system cancer arising in infants and younger children, historically considered to be homogeneous, monogenic, and incurable."
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Patients with rhabdoid tumor predisposition syndrome (RTPS) harbor germline alterations in the epigenetic regulator genes SMARCB1 or SMARCA4.
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"Atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive brain tumors primarily observed in infants."
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"Atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive brain tumors primarily observed in infants."
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"Atypical teratoid rhabdoid tumors (ATRT) are rare and aggressive embryonal tumors of central nervous system that typically affect children younger than 3 years of age."
Show evidence (1 reference)
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"Atypical teratoid rhabdoid tumors (ATRT) are rare and aggressive embryonal tumors of central nervous system that typically affect children younger than 3 years of age."
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Atypical teratoid/rhabdoid tumors (AT/RTs) are pediatric brain tumors known for their aggressiveness and aberrant but still unresolved epigenetic regulation.
"Atypical teratoid/rhabdoid tumors (AT/RTs) are pediatric brain tumors known for their aggressiveness and aberrant but still unresolved epigenetic regulation."
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Atypical teratoid/rhabdoid tumors (ATRTs) are rare, malignant central nervous system (CNS) neoplasms that predominantly affect infants and young children.
"Atypical teratoid/rhabdoid tumors (ATRTs) are rare, malignant central nervous system (CNS) neoplasms that predominantly affect infants and young children."
Show evidence (1 reference)
DOI:10.3390/cancers18010008 SUPPORT Other
"Atypical teratoid/rhabdoid tumors (ATRTs) are rare, malignant central nervous system (CNS) neoplasms that predominantly affect infants and young children."
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1 finding
Atypical teratoid rhabdoid tumor (ATRT) is a rare, aggressive pediatric central nervous system (CNS) tumor that predominantly affects children under the age of 3.
"Atypical teratoid rhabdoid tumor (ATRT) is a rare, aggressive pediatric central nervous system (CNS) tumor that predominantly affects children under the age of 3."
Show evidence (1 reference)
DOI:10.3390/jmp6020013 SUPPORT Other
"Atypical teratoid rhabdoid tumor (ATRT) is a rare, aggressive pediatric central nervous system (CNS) tumor that predominantly affects children under the age of 3."
Deep research cited this publication as relevant literature for Atypical Teratoid Rhabdoid Tumor.

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1. Disease Information
Edison Scientific Literature 49 citations 2026-05-08T07:42:05.099940

1. Disease Information

Overview / current understanding

ATRT is a rare, highly aggressive embryonal tumor of the CNS that predominantly affects infants and very young children. A 2023 review summarizes: “Atypical teratoid rhabdoid tumors (ATRT) are rare and aggressive embryonal tumors of central nervous system that typically affect children younger than 3 years of age.” (Tran 2023-01, Neuro-Oncology Practice; https://doi.org/10.1093/nop/npad005) (tran2023currentadvancesin pages 1-2).

ATRT is now understood as a molecularly defined, epigenetically driven tumor entity with marked subgroup heterogeneity despite relatively low recurrent mutational burden beyond SWI/SNF genes (SMARCB1/SMARCA4). The tumor is genetically “defined by alterations in the SWI/SNF chromatin remodeling complex members SMARCB1 or SMARCA4” (Paassen 2023-04, Oncogene; https://doi.org/10.1038/s41388-023-02681-y) (reddy2020efficacyofhighdose pages 1-2).

Synonyms / alternative names

  • Atypical teratoid/rhabdoid tumor; AT/RT; ATRT (tran2023currentadvancesin pages 1-2, reddy2020efficacyofhighdose pages 1-2)
  • Extracranial counterpart: malignant rhabdoid tumor (MRT) (holdhof2021atypicalteratoidrhabdoidtumors pages 1-2)
  • Predisposition context: rhabdoid tumor predisposition syndrome (RTPS) (childress2025thecurrentlandscape pages 7-8, tomita2025histogenesisofatypical pages 14-15)

Evidence type note

Most information here is aggregated from cooperative-group clinical trials, multicenter molecular cohorts, and contemporary reviews (reddy2020efficacyofhighdose pages 1-2, tran2023currentadvancesin pages 1-2, holdhof2021atypicalteratoidrhabdoidtumors pages 1-2). Case reports exist but are not the basis for the core disease definition in this report.

2. Etiology

Primary causal factors (genetic/mechanistic)

Core genetic cause: biallelic inactivation of SWI/SNF chromatin-remodeling genes. - SMARCB1 loss is the dominant lesion; SMARCA4 loss is rare. A 2021 Acta Neuropathologica study states: “The underlying genetic cause are inactivating bi-allelic mutations in SMARCB1 or (rarely) in SMARCA4.” (Holdhof 2021-12; https://doi.org/10.1007/s00401-020-02250-7) (holdhof2021atypicalteratoidrhabdoidtumors pages 1-2). - A 2024 review reiterates: “The only characteristic, recurrent genetic aberration of AT/RTs is biallelic inactivation of SMARCB1 (or SMARCA4).” (Huhtala 2024-09, Neuro-Oncology Advances; https://doi.org/10.1093/noajnl/vdae162) (huhtala2024developmentandepigenetic pages 1-2).

Epigenetic dysregulation as an etiologic driver: ATRT biology is dominated by epigenetic and chromatin consequences of SWI/SNF disruption. In ATRT, “aberrant DNA methylation–driven epigenetic regulation…maintains the malignant, low differentiation cell state” (Pekkarinen 2024-03, Life Science Alliance; https://doi.org/10.26508/lsa.202302088) (huhtala2024developmentandepigenetic pages 1-2).

Risk factors

  • Age: infancy/early childhood is the main demographic risk factor. ATRT comprises ~1–2% of childhood CNS tumors but is enriched in children <3 years (Tran 2023-01) (tran2023currentadvancesin pages 1-2).
  • Germline predisposition (RTPS): germline SMARCB1 or SMARCA4 alterations predispose to ATRT and other rhabdoid tumors (childress2025thecurrentlandscape pages 7-8, tomita2025histogenesisofatypical pages 14-15). A 2024 genetic-cancer paper notes: “RTPS1 confers an increased risk of developing rhabdoid tumors and is caused by germline mutations in SMARCB1… RTPS1 should be evaluated in all individuals with rhabdoid tumor…” (Blackburn 2024-08, Genes Chromosomes Cancer; https://doi.org/10.1002/gcc.23195) (childress2025thecurrentlandscape pages 7-8).

Protective factors / gene–environment interactions

No protective factors or gene–environment interactions were identified in the retrieved evidence set; ATRT is predominantly driven by genetic/epigenetic mechanisms (huhtala2024developmentandepigenetic pages 1-2, holdhof2021atypicalteratoidrhabdoidtumors pages 1-2).

3. Phenotypes (clinical presentation)

Typical presenting features (symptoms/signs)

ATRT presentation reflects rapid tumor growth, mass effect, and location-dependent neurologic deficits. A 2020 cooperative-group trial paper describes ATRT as “an aggressive, early-childhood brain tumor” (Reddy 2020-04, J Clin Oncol; https://doi.org/10.1200/JCO.19.01776) (reddy2020efficacyofhighdose pages 1-2).

The 2026 case series (not required by the user’s priority years but consistent with core phenotype) describes intracranial hypertension and seizures in lateral-ventricle ATRT (not cited here because not extracted as evidence in this run).

Phenotype frequency / metastatic dissemination

  • Metastatic disease at diagnosis is commonly reported at ~20–40% (review summary) (childress2025thecurrentlandscape pages 7-8).
  • One review described M1 (tumor cells in CSF) at diagnosis around ~38% (smith2025atypicalteratoidrhabdoid pages 2-4).

Suggested HPO terms (examples; for curation)

The following HPO mappings are suggested based on typical CNS tumor presentation; precise frequency-by-term was not available in the retrieved evidence: - HP:0001298 Encephalopathy / impaired consciousness (mass effect) - HP:0002315 Headache - HP:0002013 Vomiting - HP:0001250 Seizures - HP:0001263 Developmental regression (common in infant brain tumors) - HP:0001270 Motor delay / weakness - HP:0000252 Microcephaly (treatment-related; not extracted here)

(These HPO codes are suggested for structuring and should be validated against clinical series for ATRT-specific frequencies; no citable evidence in this run provides per-HPO frequencies.)

4. Genetic / molecular information

Causal genes

  • SMARCB1 (INI1/BAF47/SNF5): defining tumor suppressor gene; loss is a diagnostic hallmark (smith2025atypicalteratoidrhabdoid pages 4-7, holdhof2021atypicalteratoidrhabdoidtumors pages 1-2).
  • SMARCA4 (BRG1): rare ATRT subset; molecularly distinct and often very early onset (holdhof2021atypicalteratoidrhabdoidtumors pages 1-2, tomita2025histogenesisofatypical pages 14-15).

Pathogenic variants (general classes)

Commonly involve loss-of-function events: deletions, truncating variants, copy-number loss, and structural events. - Structural-variant etiology in predisposition: constitutional balanced translocations disrupting SMARCB1 were reported as a rare RTPS1 cause (Blackburn 2024-08) (childress2025thecurrentlandscape pages 7-8).

Epigenetic subgrouping

A widely accepted methylation/transcriptomic stratification includes: - ATRT-TYR, ATRT-SHH, ATRT-MYC (SMARCB1-mutant majority) (tran2023currentadvancesin pages 1-2, holdhof2021atypicalteratoidrhabdoidtumors pages 1-2) - ATRT-SMARCA4 as a distinct methylation-defined group (holdhof2021atypicalteratoidrhabdoidtumors pages 1-2, johann2023recurrentatypicalteratoidrhabdoid pages 1-2)

Clinical correlates include distinct age and anatomic predilections (Tran 2023-01; Holdhof 2021-12) (tran2023currentadvancesin pages 1-2, holdhof2021atypicalteratoidrhabdoidtumors pages 1-2).

Suggested GO terms (mechanistically relevant)

Based on SWI/SNF and epigenetic-differentiation blockade (conceptual mapping; validate in GO): - GO:0016585 chromatin remodeling - GO:0006355 regulation of transcription, DNA-templated - GO:0045893 positive regulation of transcription, DNA-templated (developmental programs suppressed) - GO:0045165 cell fate commitment / differentiation processes (blocked) (huhtala2024developmentandepigenetic pages 1-2)

5. Environmental information

No environmental, lifestyle, or infectious causal factors were identified in the retrieved evidence set; ATRT is primarily a genetically and epigenetically driven pediatric cancer (huhtala2024developmentandepigenetic pages 1-2, holdhof2021atypicalteratoidrhabdoidtumors pages 1-2).

6. Mechanism / pathophysiology

Core mechanism: SWI/SNF loss → epigenetic dysregulation → differentiation blockade → aggressive embryonal tumor

  • ATRT’s recurrent genetic lesion is SWI/SNF disruption: “biallelic inactivation of SMARCB1 (or SMARCA4)” (Huhtala 2024-09) (huhtala2024developmentandepigenetic pages 1-2).
  • A 2024 study links ATRT malignancy to hypermethylation and PRC2-associated repression, concluding: “These results highlight and characterize the role of DNA hypermethylation in AT/RT malignancy and halted neural cell differentiation.” (Pekkarinen 2024-03) (huhtala2024developmentandepigenetic pages 1-2).

Recurrence biology (2023)

A matched primary–recurrence cohort found progression-associated but relatively subtle molecular changes. Key reported recurrence-associated copy-number alterations included chromosome 1q gains and chromosome 10 losses, enriched in recurrences compared with primaries (Johann 2023-07, Acta Neuropathologica; https://doi.org/10.1007/s00401-023-02608-7) (johann2023recurrentatypicalteratoidrhabdoid pages 1-2).

Preclinical models and subgroup-specific vulnerabilities (2023)

A 2023 organoid/tumoroid model paper reported subgroup-specific vulnerabilities: “High throughput drug screens…revealed distinct drug sensitivities… Whereas ATRT-MYC universally displayed high sensitivity to multi-targeted tyrosine kinase inhibitors, ATRT-SHH showed a more heterogeneous response with a subset showing high sensitivity to NOTCH inhibitors…” (Paassen 2023-04) (reddy2020efficacyofhighdose pages 1-2). This supports subgroup-aware treatment development.

Immune microenvironment (2023 review)

ATRT immune profiles differ by subgroup; ATRT-MYC is described as having higher CD8+ tumor-infiltrating lymphocytes and possible immunogenic potential (Tran 2023-01) (tran2023currentadvancesin pages 1-2).

Suggested Cell Ontology (CL) terms (conceptual)

No single-cell dataset was retrieved in this run; however, based on immune infiltration discussions: - CL:0000623 CD8-positive, alpha-beta T cell (ATRT-MYC enriched) (tran2023currentadvancesin pages 1-2) - CL:0000540 neuron / CL:0000127 astrocyte lineage cells (developmental programs implicated) (huhtala2024developmentandepigenetic pages 1-2)

7. Anatomical structures affected

Organ/tissue level

ATRT arises throughout the neuraxis, including supratentorial, infratentorial, pineal, and spinal compartments. A 50-patient cohort reported: 36% infratentorial, 30% supratentorial, 22% pineal region, and 12% spinal (Tomita 2025-12, Cancers; https://doi.org/10.3390/cancers18010008) (tomita2025histogenesisofatypical pages 1-2).

Suggested UBERON terms (examples)

  • UBERON:0000955 brain
  • UBERON:0002037 cerebellum (posterior fossa/infratentorial)
  • UBERON:0001954 spinal cord
  • UBERON:0002421 pineal gland / pineal region

(UBERON IDs are suggested for structuring; the retrieved evidence supports the anatomic compartments but does not provide ontology IDs.)

8. Temporal development (onset/progression)

Onset

Typical onset is pediatric, commonly <3 years; ATRT is described as most common malignant brain tumor manifesting in infancy (Johann 2023-07) (johann2023recurrentatypicalteratoidrhabdoid pages 1-2) and “typically affect[s] children younger than 3 years of age” (Tran 2023-01) (tran2023currentadvancesin pages 1-2).

Progression

ATRT is characterized by rapid progression and high recurrence risk. In ACNS0333, “91% of relapses occurred by 2 years from enrollment” (Reddy 2020-04) (reddy2020efficacyofhighdose pages 1-2).

9. Inheritance and population

Epidemiology

  • Incidence estimate cited in Germany: 1.4 per million (Holdhof 2021-12) (holdhof2021atypicalteratoidrhabdoidtumors pages 1-2).
  • Proportion of pediatric CNS tumors: ~1–2% overall, but much higher among very young children (Tran 2023-01) (tran2023currentadvancesin pages 1-2).

Inheritance (predisposition)

RTPS is inherited via germline pathogenic variants in SMARCB1 (RTPS1) or SMARCA4 (RTPS2) and confers risk for multiple rhabdoid tumors (Blackburn 2024-08; Geethadevi 2024-09) (childress2025thecurrentlandscape pages 7-8, reddy2020efficacyofhighdose media 822317c7). Structural variants such as constitutional balanced translocations can be an RTPS1 cause and may be missed without SV analysis (Blackburn 2024-08) (childress2025thecurrentlandscape pages 7-8).

10. Diagnostics

Histopathology and immunohistochemistry

A key routine diagnostic principle is nuclear loss of INI1 and/or BRG1: - “INI-1 (SMARCB1) and BRG-1 (SMARCA4) are routine surrogates — ‘As all nucleated cells should express INI-1 and BRG-1,’ and loss of nuclear expression of either should prompt AT/RT diagnosis.” (Smith 2025-11, Cancers; https://doi.org/10.3390/cancers17233768) (smith2025atypicalteratoidrhabdoid pages 4-7).

Molecular diagnostics

  • DNA methylation profiling is central for classification/subgrouping and is used for methylation-based CNS tumor classification (Johann 2023-07; Holdhof 2021-12) (johann2023recurrentatypicalteratoidrhabdoid pages 1-2, holdhof2021atypicalteratoidrhabdoidtumors pages 1-2).
  • NGS should detect SMARCB1/SMARCA4 variants; SMARCB1 copy-number loss (22q11.2) can be assessed by CN plots or FISH (Smith 2025-11) (smith2025atypicalteratoidrhabdoid pages 4-7).

Imaging

MRI features include restricted diffusion, cystic/necrotic change, and hemorrhage; CT lesions can be hyperdense with calcifications (Smith 2025-11) (smith2025atypicalteratoidrhabdoid pages 2-4).

Differential diagnosis

Not fully extracted in this run; however, diagnostic challenge is recognized and motivates multimodal diagnostic integration (smith2025atypicalteratoidrhabdoid pages 4-7).

11. Outcome / prognosis

Survival statistics (key data)

Children’s Oncology Group ACNS0333 (prospective cooperative-group trial): - “Four-year EFS and overall survival for the entire cohort were 37%… and 43%…” (Reddy 2020-04) (reddy2020efficacyofhighdose pages 1-2). - Regimen significantly reduced EFS events in patients <36 months vs historical cohort (hazard rate 0.43; P<.0005) (Reddy 2020-04) (reddy2020efficacyofhighdose pages 1-2).

Clinical prognostic factors (from reviews): metastatic disease at diagnosis is common (~20–40%) and often adverse; extent of resection and radiotherapy are variably associated with better outcomes (Childress 2025-06) (childress2025thecurrentlandscape pages 7-8).

12. Treatment

Standard-of-care backbone (current real-world implementation)

ATRT is treated with intensive multimodal therapy including maximal safe surgical resection, multiagent chemotherapy, radiotherapy (often focal; CSI for select metastatic cases/age contexts), and high-dose chemotherapy with autologous stem cell rescue in many protocols.

ACNS0333 protocol (widely used backbone): - Induction chemotherapy, consolidation with high-dose chemotherapy and PBSC rescue, plus involved-field radiation; reported 4-year OS 43% (Reddy 2020-04) (reddy2020efficacyofhighdose pages 1-2). - Visual evidence from the ACNS0333 paper locates regimen schema (Figure 1) and survival curves/table with the 4-year EFS/OS (Figures/Table) (reddy2020efficacyofhighdose media 8fddb41f, reddy2020efficacyofhighdose media 822317c7, reddy2020efficacyofhighdose media 8125c790).

Suggested MAXO terms (examples; validate): - Surgical tumor resection (MAXO: surgical excision) - Antineoplastic chemotherapy (multiagent chemotherapy; high-dose chemotherapy) - Radiotherapy (involved-field radiotherapy; craniospinal irradiation) - Autologous hematopoietic stem cell transplantation / stem cell rescue

Targeted/epigenetic and immunotherapy developments (2023–2024 emphasis)

Immunotherapy landscape: A 2023 review highlights immunotherapy as a response to poor outcomes and toxicity: “there is an urgent need for more novel approaches to treat ATRT, one such approach being immunotherapy.” (Tran 2023-01) (tran2023currentadvancesin pages 1-2).

EZH2 inhibition (tazemetostat) and combinations: - NCT02601937 (Phase 1; COMPLETED; results first posted 2024-10-03): pediatric tazemetostat in relapsed/refractory INI1-negative tumors including ATRT; ATRT expansion cohort regimen reported as 1200 mg/m^2 BID continuous 28-day cycles (ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT02601937) (NCT02601937 chunk 1, NCT02601937 chunk 2). - NCT05407441 (Phase I/II; ACTIVE_NOT_RECRUITING; start 2023-08-10): tazemetostat + nivolumab + ipilimumab for INI1-negative/SMARCA4-deficient tumors including ATRT (ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT05407441) (NCT05407441 chunk 1). - NCT03838042 (Phase I/II; RECRUITING): nivolumab + entinostat in biomarker-defined cohorts including ATRT-MYC (ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT03838042) (NCT03838042 chunk 1).

HDAC inhibition (panobinostat): - NCT04897880 (Phase 2; TERMINATED due to drug supply): panobinostat in pediatric solid tumors including MRT/ATRT (ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT04897880) (NCT04897880 chunk 1).

13. Prevention

Primary prevention

No established primary prevention is known for sporadic ATRT, given its early-life onset and tumor-suppressor loss mechanism.

Genetic counseling / surveillance (secondary/tertiary prevention in RTPS)

RTPS is a key context where prevention-oriented strategies are discussed. A 2024 review states: “Patients with rhabdoid tumor predisposition syndrome (RTPS) harbor germline alterations in… SMARCB1 or SMARCA4.” and proposes “maintenance or secondary prevention” approaches to reduce recurrence or additional tumors (Geethadevi 2024-09, Neuro-Oncology Advances; https://doi.org/10.1093/noajnl/vdae158) (reddy2020efficacyofhighdose media 822317c7).

14. Other species / natural disease

No naturally occurring ATRT analogs in non-human species were identified in the retrieved evidence set.

15. Model organisms / model systems

In vitro / organoid models (recent)

A 2023 study established ATRT “tumoroid models” from ATRT-MYC and ATRT-SHH that retained subgroup epigenetic/transcriptomic profiles and enabled high-throughput drug screening, revealing subgroup-specific sensitivities (Paassen 2023-04) (reddy2020efficacyofhighdose pages 1-2). This is a concrete real-world implementation of preclinical modeling for therapeutic discovery.

Expert synthesis (authoritative analysis)

  1. Definition has shifted from histology-first to molecularly anchored diagnosis. Contemporary ATRT practice relies on INI1/BRG1 immunohistochemistry and DNA methylation profiling to confirm SWI/SNF deficiency and assign molecular subgroup, as emphasized by diagnostic evolution reviews (smith2025atypicalteratoidrhabdoid pages 4-7, johann2023recurrentatypicalteratoidrhabdoid pages 1-2).
  2. Outcomes improved with intensive multimodal regimens but remain poor, especially after relapse. ACNS0333 demonstrates improved survival compared with historical cohorts but still yields ~43% 4-year OS, with most relapses within 2 years (reddy2020efficacyofhighdose pages 1-2).
  3. Subgroup heterogeneity is not academic; it is translational. Evidence of subgroup-specific immune features (ATRT-MYC CD8+ infiltration) and subgroup-specific drug vulnerabilities in tumoroids suggests rational stratified trials and combination approaches (tran2023currentadvancesin pages 1-2, reddy2020efficacyofhighdose pages 1-2).
  4. RTPS is a critical clinical-management axis. Germline SMARCB1/SMARCA4 alterations, including rare structural variants, support systematic germline testing and consideration of surveillance/maintenance strategies (childress2025thecurrentlandscape pages 7-8, reddy2020efficacyofhighdose media 822317c7).

Summary table

The following table consolidates core definitions, subgroups, diagnostics, treatments, outcomes, and 2023–2024 developments:

Topic Key details Evidence / source
Definition / classification Atypical teratoid/rhabdoid tumor (ATRT; also AT/RT) is a rare, highly aggressive embryonal CNS tumor, predominantly of infancy/early childhood; WHO-classified as an embryonal CNS neoplasm. It accounts for ~1–2% of pediatric CNS tumors overall, but ~20% of CNS tumors in children <3 years; median age at diagnosis ~16–30 months. ATRT is now understood as a molecularly heterogeneous SWI/SNF-deficient tumor family rather than a single homogeneous entity. Tran 2023, Neuro-Oncology Practice, Jan 2023, https://doi.org/10.1093/nop/npad005; Tomita 2025, Cancers, Dec 2025, https://doi.org/10.3390/cancers18010008 (tran2023currentadvancesin pages 1-2, tomita2025histogenesisofatypical pages 2-4)
Hallmark genes / protein surrogates Defining event: biallelic loss/inactivation of SMARCB1 in ~95% of cases; rare SMARCA4-mutant cases (~0.5–2%, some series up to ~4%). Routine diagnostic protein surrogates are loss of nuclear INI1/BAF47 for SMARCB1-deficient tumors and loss of BRG1 for SMARCA4-deficient tumors; all nucleated cells should normally express both. Germline pathogenic variants underlie rhabdoid tumor predisposition syndrome (RTPS1: SMARCB1; RTPS2: SMARCA4). Holdhof 2021, Acta Neuropathologica, Dec 2021, https://doi.org/10.1007/s00401-020-02250-7; Smith 2025, Cancers, Nov 2025, https://doi.org/10.3390/cancers17233768; Blackburn 2024, Genes Chromosomes Cancer, Aug 2024, https://doi.org/10.1002/gcc.23195 (holdhof2021atypicalteratoidrhabdoidtumors pages 1-2, smith2025atypicalteratoidrhabdoid pages 4-7, childress2025thecurrentlandscape pages 7-8)
Molecular subgroup: ATRT-TYR TYR subgroup: tends to occur in the youngest patients (often 0–1 year), commonly infratentorial, with overexpression of melanocytic / melanosomal genes (TYR, TYRP1, MITF, OTX2). Imaging/pathology correlations include more peripheral cysts and stronger contrast enhancement than SHH in some series. Tran 2023, https://doi.org/10.1093/nop/npad005; Smith 2025, https://doi.org/10.3390/cancers17233768 (tran2023currentadvancesin pages 1-2, smith2025atypicalteratoidrhabdoid pages 2-4)
Molecular subgroup: ATRT-SHH SHH subgroup: mixed supra- and infratentorial distribution overall; enriched for SHH/NOTCH-related programs and genes such as GLI2, BOC, PTCHD2, MYCN. Some subclass analyses show SHH-1A/1B predominantly supratentorial, while SHH-2 is largely infratentorial/pineal and enriched for germline SMARCB1 variants. Dissemination may be relatively more frequent in SHH-associated disease in some cohorts. Tran 2023, https://doi.org/10.1093/nop/npad005; Tomita 2025, https://doi.org/10.3390/cancers18010008; Smith 2025, https://doi.org/10.3390/cancers17233768 (tran2023currentadvancesin pages 1-2, tomita2025histogenesisofatypical pages 14-15, smith2025atypicalteratoidrhabdoid pages 2-4)
Molecular subgroup: ATRT-MYC MYC subgroup: often supratentorial; overexpresses MYC and HOX-related programs; a subset arises extra-axially, including along cranial nerves. Compared with other subgroups, ATRT-MYC has been reported to show higher CD8+ tumor-infiltrating lymphocytes, supporting relative immunogenicity. Tran 2023, https://doi.org/10.1093/nop/npad005; Smith 2025, https://doi.org/10.3390/cancers17233768 (tran2023currentadvancesin pages 1-2, smith2025atypicalteratoidrhabdoid pages 2-4)
Molecular subgroup: ATRT-SMARCA4 Rare, molecularly distinct subgroup defined by SMARCA4 loss rather than SMARCB1 loss; retains INI1 expression but loses BRG1. Associated with very young age, frequent germline events, and inferior prognosis versus SMARCB1-deficient ATRT. DNA methylation and RNA-seq support separation from TYR/SHH/MYC and from other SMARCA4-deficient tumors. Holdhof 2021, https://doi.org/10.1007/s00401-020-02250-7; Tomita 2025, https://doi.org/10.3390/cancers18010008 (holdhof2021atypicalteratoidrhabdoidtumors pages 1-2, tomita2025histogenesisofatypical pages 14-15)
Typical anatomy / presentation ATRT can arise anywhere along the neuraxis. In one 50-patient pediatric cohort: 36% infratentorial, 30% supratentorial, 22% pineal region, 12% spinal. Posterior fossa is common, often off-midline. Presentation often reflects rapid growth and intracranial hypertension; MRI may show restricted diffusion, cystic/necrotic change, hemorrhage, and CSF dissemination. Metastatic disease is present in ~20–40% at diagnosis; one review cited M1 CSF positivity around 38%. Tomita 2025, https://doi.org/10.3390/cancers18010008; Childress 2025, https://doi.org/10.3390/jmp6020013; Smith 2025, https://doi.org/10.3390/cancers17233768; Hoffman 2020, https://doi.org/10.1093/neuonc/noaa046 (tomita2025histogenesisofatypical pages 1-2, childress2025thecurrentlandscape pages 7-8, smith2025atypicalteratoidrhabdoid pages 2-4, hoffman2020advancingbiologybased pages 4-5)
Diagnostic modalities Modern diagnosis integrates histology + IHC + molecular testing. Core methods: (1) histopathology showing rhabdoid morphology with variable epithelial/mesenchymal/neuroectodermal elements; (2) IHC for INI1/SMARCB1 and BRG1/SMARCA4 loss; (3) genome-wide DNA methylation profiling, now considered highly informative / WHO-essential in difficult cases for subgroup assignment; (4) sequencing / CNV analysis for SMARCB1 or SMARCA4 alterations; (5) FISH / copy-number methods for 22q11.2 SMARCB1 loss when needed. Smith 2025, https://doi.org/10.3390/cancers17233768; Holdhof 2021, https://doi.org/10.1007/s00401-020-02250-7; Childress 2025, https://doi.org/10.3390/jmp6020013 (smith2025atypicalteratoidrhabdoid pages 4-7, holdhof2021atypicalteratoidrhabdoidtumors pages 1-2, childress2025thecurrentlandscape pages 10-12)
Standard therapy backbone (ACNS0333) Contemporary backbone is aggressive multimodal therapy: maximal safe resection, intensive induction chemotherapy, focal/involved-field radiotherapy, then high-dose chemotherapy with autologous stem-cell rescue. ACNS0333 schema: 2 induction cycles including vincristine, methotrexate, etoposide, cyclophosphamide, cisplatin; then 3 consolidation cycles with thiotepa + carboplatin and PBSC rescue; focal RT timing adapted by age/disease status. Gross total resection is achieved in ~30–68% across series. Reddy 2020, JCO, Apr 2020, https://doi.org/10.1200/JCO.19.01776; figure/table locations summarized from ACNS0333 visual review (reddy2020efficacyofhighdose pages 1-2, reddy2020efficacyofhighdose media 8fddb41f, childress2025thecurrentlandscape pages 7-8)
Key outcome statistics ACNS0333 (65 evaluable patients): 4-year EFS 37% (95% CI 25–49) and 4-year OS 43% (95% CI 31–55); for patients <36 months, EFS hazard ratio vs historical cohort 0.43 (P<.0005). 91% of relapses occurred within 2 years; treatment-related deaths: 4. Other cited multimodal results: Dana-Farber regimen 2-year EFS/OS 53%/70%; Head Start HDCT/ASCR 3-year EFS/OS 21%/26%. Reddy 2020, https://doi.org/10.1200/JCO.19.01776; Childress 2025, https://doi.org/10.3390/jmp6020013 (reddy2020efficacyofhighdose pages 1-2, childress2025thecurrentlandscape pages 7-8)
Representative mechanistic findings (2023–2024) Recurrence biology: recurrent ATRTs show increased mitotic activity, occasional subgroup switching, and enrichment of chromosome 1q gain and chromosome 10 loss; primary and relapse usually remain close by methylation/transcriptome, implying relative epigenetic stability with selected progression-associated changes. Epigenetic differentiation blockade: AT/RT-specific DNA hypermethylation is linked to PRC2, suppression of neural differentiation genes, impaired NEUROG/NEUROD pioneer-factor activity, and maintenance of a low-differentiation malignant state. Model systems / vulnerabilities: 2023 tumoroid models retained subgroup-specific epigenetic states; ATRT-MYC showed broad sensitivity to multi-targeted tyrosine kinase inhibitors, while a subset of ATRT-SHH was sensitive to NOTCH inhibitors. Johann 2023, Acta Neuropathologica, Jul 2023, https://doi.org/10.1007/s00401-023-02608-7; Pekkarinen 2024, Life Science Alliance, Mar 2024, https://doi.org/10.26508/lsa.202302088; Paassen 2023, Oncogene, Apr 2023, https://doi.org/10.1038/s41388-023-02681-y; Huhtala 2024, Neuro-Oncology Advances, Sep 2024, https://doi.org/10.1093/noajnl/vdae162 (johann2023recurrentatypicalteratoidrhabdoid pages 1-2, huhtala2024developmentandepigenetic pages 1-2, reddy2020efficacyofhighdose pages 1-2)
Immune microenvironment / translational rationale ATRT is epigenetically driven but immunologically nonuniform across subgroups; ATRT-MYC has relatively higher CD8+ infiltration, motivating immune-based strategies. Reviews emphasize combining immune profiling with subgrouping and epigenetic therapy to refine treatment selection. Tran 2023, https://doi.org/10.1093/nop/npad005; Childress 2025, https://doi.org/10.3390/jmp6020013 (tran2023currentadvancesin pages 1-2, childress2025thecurrentlandscape pages 10-12)
Representative clinical trials NCT02601937 — tazemetostat (EZH2 inhibitor), Phase 1, completed, pediatric relapsed/refractory INI1-negative tumors including ATRT; results posted 2024-10-03; ATRT cohort used 1200 mg/m² BID continuous 28-day cycles. NCT05407441 — tazemetostat + nivolumab + ipilimumab, Phase I/II, Active not recruiting, ATRT / INI1-negative / SMARCA4-deficient tumors. NCT04416568 — nivolumab + ipilimumab in INI1-negative cancers, Phase 2, Active not recruiting. NCT04897880 — panobinostat in pediatric solid tumors including MRT/ATRT, Phase 2, Terminated (drug supply). NCT03838042 — INFORM2 Nivolumab + entinostat, Phase I/II, Recruiting; includes biomarker-defined cohorts including ATRT-MYC. ClinicalTrials.gov records summarized from extracted trial evidence (NCT02601937, NCT05407441, NCT04416568, NCT04897880, NCT03838042) (NCT04897880 chunk 1, NCT02601937 chunk 2, NCT05407441 chunk 1, NCT02601937 chunk 1, NCT03838042 chunk 1)

Table: This table condenses the most clinically and biologically relevant facts about ATRT, including defining molecular features, subgroup correlates, diagnostics, standard therapy, outcomes, and representative recent research and trials. It is designed as a compact reference for knowledge-base curation or rapid expert review.

Key URLs (retrieved sources)

  • ACNS0333 trial publication (JCO; 2020-04): https://doi.org/10.1200/JCO.19.01776 (reddy2020efficacyofhighdose pages 1-2)
  • Immunotherapy review (Neuro-Oncology Practice; 2023-01): https://doi.org/10.1093/nop/npad005 (tran2023currentadvancesin pages 1-2)
  • Recurrence biology (Acta Neuropathologica; 2023-07): https://doi.org/10.1007/s00401-023-02608-7 (johann2023recurrentatypicalteratoidrhabdoid pages 1-2)
  • ATRT tumoroids (Oncogene; 2023-04): https://doi.org/10.1038/s41388-023-02681-y (reddy2020efficacyofhighdose pages 1-2)
  • DNA methylation differentiation blockade (Life Science Alliance; 2024-03): https://doi.org/10.26508/lsa.202302088 (huhtala2024developmentandepigenetic pages 1-2)
  • RTPS balanced translocations (Genes Chromosomes Cancer; 2024-08): https://doi.org/10.1002/gcc.23195 (childress2025thecurrentlandscape pages 7-8)
  • RTPS prevention/maintenance review (Neuro-Oncology Advances; 2024-09): https://doi.org/10.1093/noajnl/vdae158 (reddy2020efficacyofhighdose media 822317c7)
  • ClinicalTrials.gov tazemetostat pediatric INI1-negative tumors (NCT02601937; results posted 2024-10-03): https://clinicaltrials.gov/study/NCT02601937 (NCT02601937 chunk 1)
  • ClinicalTrials.gov tazemetostat + nivo/ipi (NCT05407441; started 2023-08-10): https://clinicaltrials.gov/study/NCT05407441 (NCT05407441 chunk 1)
  • ClinicalTrials.gov nivolumab + entinostat INFORM2 (NCT03838042): https://clinicaltrials.gov/study/NCT03838042 (NCT03838042 chunk 1)
  • ClinicalTrials.gov panobinostat (NCT04897880; terminated): https://clinicaltrials.gov/study/NCT04897880 (NCT04897880 chunk 1)

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