Anaplastic ependymoma

Summary

Anaplastic ependymoma (MONDO:0016700) is a disease with 3 cohort genes and 15 clinical trials. Molecularly, KANK1::NTRK2 Fusion confers sensitivity to Larotrectinib in Anaplastic Ependymoma (CIViC Level C). Top therapeutic interventions include 2-mercaptoethanesulfonic acid, imetelstat sodium, and sonidegib.

At a glance

• Prevalence: <1 / 1 000 000 (United States) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 3
• Clinical trials: 15
• Precision-medicine evidence (CIViC): 1 subtype–drug association

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000	0.04	United States	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	anaplastic ependymoma
Mondo ID	MONDO:0016700
Orphanet	251646
DOID	DOID:5074, DOID:5889
NCIT	C4049
UMLS	C0280788
MedGen	128891
GARD	0010634
MedDRA	10014968
Is cancer (heuristic)	no

Also known as: anaplastic ependymal neoplasm · anaplastic ependymal tumor · anaplastic ependymal tumour · anaplastic ependymoma · ependymal tumors · ependymal tumours · ependymoma, anaplastic, malignant · ependymoma, malignant · high-grade ependymoma · malignant ependymoma · undifferentiated ependymal neoplasm · undifferentiated ependymal tumor · undifferentiated ependymal tumour · undifferentiated ependymoma · WHO grade III ependymal neoplasm · WHO grade III ependymal tumor · WHO grade III ependymal tumour

Data availability: 3 ClinVar variants.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › nervous system neoplasm › neuroepithelial neoplasm › glioma › ependymal tumor › anaplastic ependymoma

Related subtypes (5): ependymal tumor of brain, ependymoma, myxopapillary ependymoma, ependymal tumor of spinal cord, RELA fusion-positive ependymoma

Subtypes (3): adult anaplastic ependymoma, posterior fossa ependymoma, supratentorial ependymoma

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

3 retrieved; paginated sample, class counts are floors:

1 benign, 1 likely benign, 1 other

ClinVar	Variant (HGVS)	Gene	Classification	Review
438786	NM_001256071.3(RNF213):c.12841C>T (p.Arg4281Trp)	RNF213	other	no assertion criteria provided
126726	NM_024675.4(PALB2):c.3249G>C (p.Glu1083Asp)	PALB2	Benign	reviewed by expert panel
239044	NM_001754.5(RUNX1):c.155T>A (p.Met52Lys)	RUNX1	Likely benign	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RUNX1	Orphanet:102724	Acute myeloid leukemia with t(8;21)(q22;q22) translocation
RUNX1	Orphanet:521	Chronic myeloid leukemia
RUNX1	Orphanet:71290	Familial platelet disorder with associated myeloid malignancy
RUNX1	Orphanet:98850	Aggressive systemic mastocytosis
RNF213	Orphanet:2573	Moyamoya disease
PALB2	Orphanet:1333	Familial pancreatic carcinoma
PALB2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
PALB2	Orphanet:178	Chordoma
PALB2	Orphanet:227535	Hereditary breast cancer
PALB2	Orphanet:84	Fanconi anemia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RUNX1	HGNC:10471	ENSG00000159216	Q01196	Runt-related transcription factor 1	clinvar
RNF213	HGNC:14539	ENSG00000173821	Q63HN8	E3 ubiquitin-protein ligase RNF213	clinvar
PALB2	HGNC:26144	ENSG00000083093	Q86YC2	Partner and localizer of BRCA2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RUNX1	Runt-related transcription factor 1	Forms the heterodimeric complex core-binding factor (CBF) with CBFB.
RNF213	E3 ubiquitin-protein ligase RNF213	Atypical E3 ubiquitin ligase that can catalyze ubiquitination of both proteins and lipids, and which is involved in various processes, such as lipid metabolism, angiogenesis and cell-autonomous immunity.
PALB2	Partner and localizer of BRCA2	Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks.

Protein-family classification

Druggable: 0 · Difficult: 3 · Unknown: 0 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	2	5.5×	0.081
Scaffold/PPI	1	5.8×	0.164

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RUNX1	Transcription factor	no		AML1_Runt, p53-like_TF_DNA-bd_sf, p53/RUNT-type_TF_DNA-bd_sf
RNF213	Transcription factor	no		Znf_RING, AAA+_ATPase, Znf_RING/FYVE/PHD
PALB2	Scaffold/PPI	no		WD40/YVTN_repeat-like_dom_sf, PALB2_WD40, WD40_repeat_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
epithelium of bronchus	1
mucosa of paranasal sinus	1
olfactory segment of nasal mucosa	1
granulocyte	1
metanephros cortex	1
pancreatic ductal cell	1
buccal mucosa cell	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RUNX1	253	ubiquitous	marker	olfactory segment of nasal mucosa, epithelium of bronchus, mucosa of paranasal sinus
RNF213	252	ubiquitous	marker	granulocyte, metanephros cortex, pancreatic ductal cell
PALB2	232	ubiquitous	yes	secondary oocyte, buccal mucosa cell, oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PALB2	5,641
RUNX1	4,994
RNF213	2,368

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RUNX1	Q01196	5
RNF213	Q63HN8	4
PALB2	Q86YC2	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 64. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RUNX3 regulates RUNX1-mediated transcription	1	1268.9×	0.012	RUNX1
RUNX1 regulates expression of components of tight junctions	1	761.3×	0.012	RUNX1
RUNX1 regulates transcription of genes involved in interleukin signaling	1	761.3×	0.012	RUNX1
RUNX2 regulates genes involved in differentiation of myeloid cells	1	761.3×	0.012	RUNX1
RUNX1 regulates estrogen receptor mediated transcription	1	634.4×	0.012	RUNX1
RUNX1 regulates transcription of genes involved in BCR signaling	1	634.4×	0.012	RUNX1
RUNX1 regulates transcription of genes involved in WNT signaling	1	634.4×	0.012	RUNX1
Suppression of apoptosis	1	543.8×	0.012	RNF213
RUNX1 regulates transcription of genes involved in differentiation of myeloid cells	1	475.8×	0.012	RUNX1
Response of Mtb to phagocytosis	1	475.8×	0.012	RNF213
RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)	1	380.7×	0.012	RUNX1
RUNX1 regulates transcription of genes involved in differentiation of keratinocytes	1	380.7×	0.012	RUNX1
RUNX3 regulates p14-ARF	1	380.7×	0.012	RUNX1
Infection with Mycobacterium tuberculosis	1	380.7×	0.012	RNF213
Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)	1	292.8×	0.015	RUNX1
SLC-mediated transport of organic cations	1	253.8×	0.015	RUNX1
R-HSA-549132	1	253.8×	0.015	RUNX1
Regulation of RUNX1 Expression and Activity	1	223.9×	0.016	RUNX1
Infectious disease	2	16.6×	0.016	RUNX1, RNF213
Impaired BRCA2 binding to PALB2	1	152.3×	0.020	PALB2
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	141.0×	0.020	PALB2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	141.0×	0.020	PALB2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	141.0×	0.020	PALB2
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	131.3×	0.020	PALB2
Homologous DNA Pairing and Strand Exchange	1	126.9×	0.020	PALB2
Pre-NOTCH Expression and Processing	1	122.8×	0.020	RUNX1
Bacterial Infection Pathways	1	112.0×	0.021	RNF213
Resolution of D-loop Structures through Holliday Junction Intermediates	1	100.2×	0.022	PALB2
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	1	100.2×	0.022	RUNX1
Transcriptional regulation by RUNX3	1	90.6×	0.022	RUNX1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lipid ubiquitination	1	5617.3×	0.004	RNF213
regulation of connective tissue replacement	1	5617.3×	0.004	RUNX1
myeloid leukocyte differentiation	1	1872.4×	0.004	RUNX1
regulation of plasminogen activation	1	1872.4×	0.004	RUNX1
negative regulation of CD4-positive, alpha-beta T cell differentiation	1	1404.3×	0.004	RUNX1
cardiac muscle tissue regeneration	1	1404.3×	0.004	RUNX1
positive regulation of extracellular matrix organization	1	1404.3×	0.004	RUNX1
positive regulation of CD8-positive, alpha-beta T cell differentiation	1	1123.5×	0.004	RUNX1
regulation of cardiac muscle cell proliferation	1	1123.5×	0.004	RUNX1
negative regulation of non-canonical Wnt signaling pathway	1	1123.5×	0.004	RNF213
positive regulation of granulocyte differentiation	1	936.2×	0.005	RUNX1
xenophagy	1	802.5×	0.005	RNF213
negative regulation of granulocyte differentiation	1	702.2×	0.005	RUNX1
peripheral nervous system neuron development	1	510.7×	0.007	RUNX1
inner cell mass cell proliferation	1	330.4×	0.009	PALB2
lipid droplet formation	1	330.4×	0.009	RNF213
post-anal tail morphogenesis	1	244.2×	0.011	PALB2
myeloid cell differentiation	1	216.1×	0.011	RUNX1
positive regulation of collagen biosynthetic process	1	216.1×	0.011	RUNX1
hematopoietic stem cell proliferation	1	216.1×	0.011	RUNX1
mesoderm development	1	175.5×	0.013	PALB2
sprouting angiogenesis	1	160.5×	0.013	RNF213
embryonic organ development	1	160.5×	0.013	PALB2
positive regulation of interleukin-2 production	1	156.0×	0.013	RUNX1
regulation of lipid metabolic process	1	144.0×	0.013	RNF213
regulation of cell differentiation	1	144.0×	0.013	RUNX1
immune system process	1	130.6×	0.014	RNF213
somitogenesis	1	124.8×	0.014	PALB2
chondrocyte differentiation	1	100.3×	0.016	RUNX1
hemopoiesis	1	89.2×	0.017	RUNX1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
RUNX1	APOMORPHINE HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RUNX1	2	4
RNF213	0	0
PALB2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
APOMORPHINE HYDROCHLORIDE	4	RUNX1
MOLIBRESIB	2	RUNX1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
RUNX1	20	Binding:17, Functional:3
RNF213	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
APOMORPHINE HYDROCHLORIDE	4	RUNX1
MOLIBRESIB	2	RUNX1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RUNX1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	RNF213, PALB2

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RNF213	1	—
PALB2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 15.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	7
PHASE2	5
PHASE1/PHASE2	2
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01096368	PHASE3	COMPLETED	Maintenance Chemotherapy or Observation Following Induction Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Ependymoma
NCT05278208	PHASE1/PHASE2	RECRUITING	Lutathera for Treatment of Recurrent or Progressive High-Grade CNS Tumors
NCT00243490	PHASE2	WITHDRAWN	Photodynamic Therapy in the Treatment of Malignant Intracranial Tumors
NCT01095094	PHASE2	TERMINATED	Ritonavir and Lopinavir in Treating Patients With Progressive or Recurrent High-Grade Glioma
NCT01295944	PHASE2	COMPLETED	Carboplatin and Bevacizumab for Recurrent Ependymoma
NCT01721577	PHASE1/PHASE2	TERMINATED	Phase I/II Trial of AXL1717 in the Treatment of Recurrent Malignant Astrocytomas
NCT01836549	PHASE2	TERMINATED	Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors
NCT03727841	PHASE2	TERMINATED	Marizomib for Recurrent Low-Grade and Anaplastic Supratentorial, Infratentorial, and Spinal Cord Ependymoma
NCT03750513	PHASE1	RECRUITING	LET Optimized IMPT in Treating Pediatric Patients With Ependymoma
NCT04978727	PHASE1	ACTIVE_NOT_RECRUITING	A Pilot Study of SurVaxM in Children Progressive or Relapsed Medulloblastoma, High Grade Glioma, Ependymoma and Newly Diagnosed Diffuse Intrinsic Pontine Glioma
NCT01082926	PHASE1	COMPLETED	Phase I Study of Cellular Immunotherapy for Recurrent/Refractory Malignant Glioma Using Intratumoral Infusions of GRm13Z40-2, An Allogeneic CD8+ Cytolitic T-Cell Line Genetically Modified to Express the IL 13-Zetakine and HyTK and to be Resistant to Glucocorticoids, in Combination With Interleukin-2
NCT02101905	PHASE1	COMPLETED	Lapatinib Ditosylate Before Surgery in Treating Patients With Recurrent High-Grade Glioma
NCT02722512	PHASE1	TERMINATED	Trial of Heat Shock Protein Peptide Complex-96 (HSPPC-96) Vaccine
NCT03434262	PHASE1	COMPLETED	SJDAWN: St. Jude Children’s Research Hospital Phase 1 Study Evaluating Molecularly-Driven Doublet Therapies for Children and Young Adults With Recurrent Brain Tumors
NCT04521946	PHASE1	WITHDRAWN	Chemotherapy and Donor Stem Transplant for the Treatment of Patients With High Grade Brain Cancer

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
2-MERCAPTOETHANESULFONIC ACID	4	2
IMETELSTAT SODIUM	4	1
SONIDEGIB	4	1
VINCRISTINE	4	1
MARIZOMIB	3	1
AXL-1717	2	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 1 predictive associations from 1 curated evidence items.

Molecular subtype	Therapy	Effect	Level	CIViC
KANK1::NTRK2 Fusion	Larotrectinib	Sensitivity/Response	CIViC C	EID10360