Pleomorphic xanthoastrocytoma

Summary

Pleomorphic xanthoastrocytoma (MONDO:0016690) is a disease with 3 cohort genes and 9 clinical trials. Molecularly, BRAF V600E confers sensitivity to Dabrafenib + Trametinib in Pleomorphic Xanthoastrocytoma (CIViC Level A); 1 further subtype–drug associations are mapped below. Top therapeutic interventions include dabrafenib, trametinib, and mebendazole.

At a glance

• Prevalence: <1 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 2
• Clinical trials: 9
• Precision-medicine evidence (CIViC): 2 subtype–drug associations

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000	0.01	Europe	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	pleomorphic xanthoastrocytoma
Mondo ID	MONDO:0016690
Orphanet	251607
DOID	DOID:4852
NCIT	C4323
UMLS	C0334586
MedGen	137786
GARD	0010631
Is cancer (heuristic)	no

Also known as: pleomorphic Xantho-astrocytoma · PXA

Data availability: 2 ClinVar variants.

Disease family

Classification path: disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › nervous system neoplasm › neuroepithelial neoplasm › glioma › astrocytic tumor › astrocytoma (excluding glioblastoma) › low-grade astrocytoma › pleomorphic xanthoastrocytoma

Related subtypes (4): pituicytoma, diffuse astrocytoma, pilocytic astrocytoma, subependymal giant cell astrocytoma

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

2 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
402244	TMEM106B-BRAF fusion	POT1	Pathogenic	no assertion criteria provided
12364	NM_000546.6(TP53):c.844C>T (p.Arg282Trp)	TP53	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 35 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BRAF	Orphanet:1340	Cardiofaciocutaneous syndrome
BRAF	Orphanet:146	Differentiated thyroid carcinoma
BRAF	Orphanet:251615	Pilomyxoid astrocytoma
BRAF	Orphanet:389	Langerhans cell histiocytosis
BRAF	Orphanet:500	Noonan syndrome with multiple lentigines
BRAF	Orphanet:54595	Craniopharyngioma
BRAF	Orphanet:58017	Classic hairy cell leukemia
BRAF	Orphanet:626	Large/giant congenital melanocytic nevus
BRAF	Orphanet:648	Noonan syndrome
BRAF	Orphanet:840	Syringocystadenoma papilliferum
BRAF	Orphanet:96253	Cushing disease
TP53	Orphanet:1333	Familial pancreatic carcinoma
TP53	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
TP53	Orphanet:1501	Adrenocortical carcinoma
TP53	Orphanet:210159	Adult hepatocellular carcinoma
TP53	Orphanet:251576	Gliosarcoma
TP53	Orphanet:251579	Giant cell glioblastoma
TP53	Orphanet:251899	Choroid plexus carcinoma
TP53	Orphanet:2807	Papilloma of choroid plexus
TP53	Orphanet:293199	Pleomorphic rhabdomyosarcoma
TP53	Orphanet:3318	Essential thrombocythemia
TP53	Orphanet:524	Li-Fraumeni syndrome
TP53	Orphanet:52688	Myelodysplastic syndrome
TP53	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
TP53	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
TP53	Orphanet:668	Osteosarcoma
TP53	Orphanet:67038	B-cell chronic lymphocytic leukemia
TP53	Orphanet:70573	Small cell lung cancer
TP53	Orphanet:96253	Cushing disease
TP53	Orphanet:99756	Alveolar rhabdomyosarcoma
TP53	Orphanet:99757	Embryonal rhabdomyosarcoma
POT1	Orphanet:251627	Oligodendroglioma
POT1	Orphanet:251630	Anaplastic oligodendroglioma
POT1	Orphanet:618	Familial melanoma
POT1	Orphanet:67038	B-cell chronic lymphocytic leukemia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
civic_only	1
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	civic_evidence
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	clinvar
POT1	HGNC:17284	ENSG00000128513	Q9NUX5	Protection of telomeres protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
TP53	Cellular tumor antigen p53	Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence.
POT1	Protection of telomeres protein 1	Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Kinase	1	9.2×	0.313
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
TP53	Transcription factor	no		p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn
POT1	Other/Unknown	no		Telomer_end-bd_POT1/Cdc13, NA-bd_OB-fold, POT1

Expression context

Cohort genes with no expression data: 0.

3 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
calcaneal tendon	2
buccal mucosa cell	1
colonic epithelium	1
ganglionic eminence	1
tendon of biceps brachii	1
ventricular zone	1
germinal epithelium of ovary	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon
TP53	223	ubiquitous	marker	ventricular zone, ganglionic eminence, tendon of biceps brachii
POT1	279	ubiquitous	marker	secondary oocyte, germinal epithelium of ovary, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP53	22,736
BRAF	7,394
POT1	1,842

Intra-cohort edges

A	B	Sources
BRAF	TP53	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TP53	P04637	313
BRAF	P15056	131
POT1	Q9NUX5	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 98. 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
DNA Damage/Telomere Stress Induced Senescence	2	108.8×	0.011	TP53, POT1
Loss of function of TP53 in cancer due to loss of tetramerization ability	1	3806.7×	0.013	TP53
Regulation of TP53 Expression	1	1903.3×	0.014	TP53
Transcriptional activation of cell cycle inhibitor p21	1	951.7×	0.014	TP53
Signaling by MRAS-complex mutants	1	951.7×	0.014	BRAF
Signalling to p38 via RIT and RIN	1	761.3×	0.014	BRAF
Activation of NOXA and translocation to mitochondria	1	634.4×	0.014	TP53
Negative feedback regulation of MAPK pathway	1	634.4×	0.014	BRAF
ARMS-mediated activation	1	543.8×	0.014	BRAF
RUNX3 regulates CDKN1A transcription	1	543.8×	0.014	TP53
Prolonged ERK activation events	1	475.8×	0.014	BRAF
SHOC2 M1731 mutant abolishes MRAS complex function	1	475.8×	0.014	BRAF
Gain-of-function MRAS complexes activate RAF signaling	1	475.8×	0.014	BRAF
PI5P Regulates TP53 Acetylation	1	423.0×	0.014	TP53
Activation of PUMA and translocation to mitochondria	1	380.7×	0.014	TP53
Signaling by FGFR3	1	380.7×	0.014	BRAF
Signaling by FGFR4	1	346.1×	0.014	BRAF
Frs2-mediated activation	1	317.2×	0.014	BRAF
TP53 Regulates Transcription of Caspase Activators and Caspases	1	317.2×	0.014	TP53
TP53 Regulates Transcription of Death Receptors and Ligands	1	317.2×	0.014	TP53
Urea cycle	1	292.8×	0.014	TP53
Telomere C-strand synthesis initiation	1	271.9×	0.014	POT1
Signaling by FGFR1	1	271.9×	0.014	BRAF
Regulation of TP53 Activity through Association with Co-factors	1	271.9×	0.014	TP53
Processive synthesis on the C-strand of the telomere	1	253.8×	0.014	POT1
Telomere C-strand (Lagging Strand) Synthesis	1	253.8×	0.014	POT1
TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain	1	253.8×	0.014	TP53
Stabilization of p53	1	253.8×	0.014	TP53
Spry regulation of FGF signaling	1	237.9×	0.014	BRAF
TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest	1	237.9×	0.014	TP53

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
negative regulation of telomere maintenance via telomerase	2	488.5×	9e-04	TP53, POT1
T cell differentiation in thymus	2	274.0×	0.001	BRAF, TP53
cellular response to xenobiotic stimulus	2	160.5×	0.003	BRAF, TP53
negative regulation of helicase activity	1	5617.3×	0.003	TP53
positive regulation of DNA strand elongation	1	5617.3×	0.003	POT1
cellular response to actinomycin D	1	5617.3×	0.003	TP53
regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1	5617.3×	0.003	TP53
negative regulation of G1 to G0 transition	1	5617.3×	0.003	TP53
positive regulation of telomeric D-loop disassembly	1	5617.3×	0.003	POT1
positive regulation of mitochondrial membrane permeability	1	2808.7×	0.005	TP53
oligodendrocyte apoptotic process	1	2808.7×	0.005	TP53
negative regulation of glucose catabolic process to lactate via pyruvate	1	2808.7×	0.005	TP53
negative regulation of pentose-phosphate shunt	1	2808.7×	0.005	TP53
obsolete homolactic fermentation	1	1872.4×	0.005	TP53
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1	1872.4×	0.005	BRAF
signal transduction by p53 class mediator	1	1872.4×	0.005	TP53
negative regulation of miRNA processing	1	1872.4×	0.005	TP53
intrinsic apoptotic signaling pathway in response to hypoxia	1	1872.4×	0.005	TP53
regulation of fibroblast apoptotic process	1	1872.4×	0.005	TP53
T cell proliferation involved in immune response	1	1404.3×	0.005	TP53
telomere assembly	1	1404.3×	0.005	POT1
positive regulation of programmed necrotic cell death	1	1404.3×	0.005	TP53
oxidative stress-induced premature senescence	1	1404.3×	0.005	TP53
B cell lineage commitment	1	1123.5×	0.005	TP53
T cell lineage commitment	1	1123.5×	0.005	TP53
mRNA transcription	1	1123.5×	0.005	TP53
positive regulation of RNA polymerase II transcription preinitiation complex assembly	1	1123.5×	0.005	TP53
positive regulation of axon regeneration	1	1123.5×	0.005	BRAF
positive regulation of thymocyte apoptotic process	1	1123.5×	0.005	TP53
cellular response to UV-C	1	1123.5×	0.005	TP53

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 evidence-associated genes (100%) 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
BRAF	VEMURAFENIB
TP53	NITROFURANTOIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TP53	196	4
BRAF	48	4
POT1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	BRAF
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF
SORAFENIB	4	BRAF
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF
DASATINIB	4	BRAF
ERLOTINIB	4	BRAF
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
POT1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
BRAF	1,442
TP53	869

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

29 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)
VEMURAFENIB	4	BRAF
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF
SORAFENIB	4	BRAF
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF
DASATINIB	4	BRAF
ERLOTINIB	4	BRAF
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	BRAF, TP53
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	1	POT1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
POT1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 9.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE2	2
PHASE4	1
PHASE1/PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03975829	PHASE4	RECRUITING	Pediatric Long-Term Follow-up and Rollover Study
NCT05180825	PHASE2	RECRUITING	Pediatric Low Grade Glioma - MEKinhibitor TRIal vs Chemotherapy
NCT01837862	PHASE1/PHASE2	COMPLETED	A Phase I Study of Mebendazole for the Treatment of Pediatric Gliomas
NCT02684058	PHASE2	COMPLETED	Study of Efficacy and Safety of Dabrafenib in Combination With Trametinib in Pediatric Patients With BRAF V600 Mutation Positive LGG or Relapsed or Refractory HGG Tumors
NCT04541082	PHASE1	RECRUITING	Phase I Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms
NCT04065776	Not specified	RECRUITING	Evaluation of Hippocampal-Avoidance Using Proton Therapy in Low-Grade Glioma
NCT07448480	Not specified	ACTIVE_NOT_RECRUITING	Comprehensive Analysis of Chemotherapy and Targeted Therapy Outcomes in Recurrent Malignant Gliomas
NCT03593993	Not specified	TERMINATED	A Biospecimen Collection Study in BRAF-V600E Mutated Recurrent Gliomas
NCT03900689	Not specified	COMPLETED	Social Determinants of Health in Glioblastoma Population

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DABRAFENIB	4	2
TRAMETINIB	4	2
MEBENDAZOLE	4	1
VINBLASTINE	4	1
ONC-206	1	1
CHEMBL5433950	0	3
CHEMBL4788494	0	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 2 predictive associations from 3 curated evidence items.

Molecular subtype	Therapy	Effect	Level	CIViC
BRAF V600E	Dabrafenib + Trametinib	Sensitivity/Response	CIViC A	EID11312 +1
BRAF V600E	Vemurafenib	Sensitivity/Response	CIViC C	EID3786