Alveolar rhabdomyosarcoma

Summary

Alveolar rhabdomyosarcoma (MONDO:0009994) is a disease with 2 cohort genes and 7 clinical trials. Molecularly, FGFR4 Overexpression confers sensitivity to Ponatinib in Alveolar Rhabdomyosarcoma (CIViC Level D); 3 further subtype–drug associations are mapped below. Top therapeutic interventions include cyclophosphamide anhydrous, dactinomycin, and vinorelbine.

At a glance

• Prevalence: <1 / 1 000 000 (Austria) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 11
• Clinical trials: 7
• Precision-medicine evidence (CIViC): 4 subtype–drug associations

Clinical features

Epidemiology

Prevalence records

23 prevalence record(s), Orphanet, top 20 (validated / broadest geography first):

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000	0.018	Austria	Validated
Annual incidence	<1 / 1 000 000	0.054	Belgium	Validated
Annual incidence	<1 / 1 000 000	0.03	Bulgaria	Validated
Annual incidence	<1 / 1 000 000	0.017	Croatia	Validated
Annual incidence	<1 / 1 000 000	0.02	Czech Republic	Validated
Annual incidence	<1 / 1 000 000	0.009	Estonia	Validated
Annual incidence	<1 / 1 000 000	0.002	Finland	Validated
Annual incidence	<1 / 1 000 000	0.033	Germany	Validated
Annual incidence	<1 / 1 000 000	0.085	Iceland	Validated
Annual incidence	<1 / 1 000 000	0.062	Ireland	Validated
Annual incidence	<1 / 1 000 000	0.039	Italy	Validated
Annual incidence	<1 / 1 000 000	0.005	Latvia	Validated
Annual incidence	<1 / 1 000 000	0.021	Lithuania	Validated
Annual incidence	<1 / 1 000 000	0.063	Malta	Validated
Annual incidence	<1 / 1 000 000	0.035	Norway	Validated
Annual incidence	<1 / 1 000 000	0.02	Poland	Validated
Annual incidence	<1 / 1 000 000	0.02	Portugal	Validated
Annual incidence	<1 / 1 000 000	0.029	Slovakia	Validated
Annual incidence	<1 / 1 000 000	0.044	Slovenia	Validated
Annual incidence	<1 / 1 000 000	0.027	Spain	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	alveolar rhabdomyosarcoma
Mondo ID	MONDO:0009994
EFO	EFO:0000248
MeSH	D018232
OMIM	268220
Orphanet	99756
DOID	DOID:4051
ICD-11	1742058067
NCIT	C3749
SNOMED CT	404053004
UMLS	C0206655
MedGen	61651
GARD	0004701
MedDRA	10065867
Is cancer (heuristic)	no

Also known as: alveolar rhabdomyosarcoma · alveolar rhabdomyosarcoma (disease) · alveolar rhabdomyosarcoma (morphologic abnormality) · ARMS · arms · monomorphous round cell rhabdomyosarcoma · paediatric alveolar rhabdomyosarcoma · pediatric alveolar rhabdomyosarcoma · rhabdomyosarcoma 2 · rhabdomyosarcoma 2, alveolar, somatic mutation · rhabdomyosarcoma alveolar · rhabdomyosarcoma type 2 · rhabdomyosarcoma, alveolar, somatic mutation · RMS2

Data availability: 11 ClinVar variants · 1 HPO phenotype · 71 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › cancer › sarcoma › soft tissue sarcoma › rhabdomyosarcoma › alveolar rhabdomyosarcoma

Related subtypes (19): orbit rhabdomyosarcoma, spindle cell rhabdomyosarcoma, liver rhabdomyosarcoma, central nervous system rhabdomyosarcoma, mediastinum rhabdomyosarcoma, rectum rhabdomyosarcoma, gallbladder rhabdomyosarcoma, ovary rhabdomyosarcoma, breast rhabdomyosarcoma, testis rhabdomyosarcoma, rhabdomyosarcoma with mixed embryonal and alveolar features, prostate rhabdomyosarcoma, embryonal rhabdomyosarcoma, vaginal rhabdomyosarcoma, uterine corpus rhabdomyosarcoma, rhabdomyosarcoma of the cervix uteri, pleomorphic rhabdomyosarcoma, oral rhabdomyosarcoma, rhabdomyosarcoma, embryonal, 2

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

11 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 2 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
279964	NM_181458.4(PAX3):c.812G>A (p.Arg271His)	PAX3	Pathogenic	criteria provided, multiple submitters, no conflicts
3382706	NM_181458.4(PAX3):c.452-1G>A	PAX3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
689508	NM_001135254.2(PAX7):c.220C>T (p.Arg74Ter)	PAX7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3764710	NM_181458.4(PAX3):c.178G>T (p.Val60Leu)	PAX3	Likely pathogenic	criteria provided, single submitter
504786	NM_181458.4(PAX3):c.580G>A (p.Glu194Lys)	PAX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
504788	NM_181458.4(PAX3):c.540C>G (p.Ser180Arg)	PAX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1306788	NM_181458.4(PAX3):c.1036T>C (p.Ser346Pro)	LOC126806529	Uncertain significance	criteria provided, multiple submitters, no conflicts
1387929	NM_181458.4(PAX3):c.998C>T (p.Pro333Leu)	LOC126806529	Uncertain significance	criteria provided, multiple submitters, no conflicts
3382692	NM_181458.4(PAX3):c.709G>C (p.Ala237Pro)	PAX3	Uncertain significance	criteria provided, single submitter
3891909	NM_001135254.2(PAX7):c.304G>A (p.Gly102Ser)	PAX7	Uncertain significance	criteria provided, single submitter
998310	NM_001135254.2(PAX7):c.335C>T (p.Pro112Leu)	PAX7	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PAX3	Orphanet:1529	Craniofacial-deafness-hand syndrome
PAX3	Orphanet:894	Waardenburg syndrome type 1
PAX3	Orphanet:896	Waardenburg syndrome type 3
PAX3	Orphanet:99756	Alveolar rhabdomyosarcoma
PAX7	Orphanet:99756	Alveolar rhabdomyosarcoma

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PAX3	HGNC:8617	ENSG00000135903	P23760	Paired box protein Pax-3	clinvar
PAX7	HGNC:8621	ENSG00000009709	P23759	Paired box protein Pax-7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PAX3	Paired box protein Pax-3	Transcription factor that may regulate cell proliferation, migration and apoptosis.
PAX7	Paired box protein Pax-7	Transcription factor that is involved in the regulation of muscle stem cells proliferation, playing a role in myogenesis and muscle regeneration.

Protein-family classification

Druggable: 0 · Difficult: 2 · 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	8.3×	0.015

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PAX3	Transcription factor	no		HD, Paired_dom, Homeodomain-like_sf
PAX7	Transcription factor	no		HD, Paired_dom, OAR_dom

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
nasal cavity mucosa	2
olfactory segment of nasal mucosa	2
male germ line stem cell (sensu Vertebrata) in testis	1
nasal cavity epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PAX3	116	broad	marker	olfactory segment of nasal mucosa, male germ line stem cell (sensu Vertebrata) in testis, nasal cavity mucosa
PAX7	61	tissue_specific	marker	olfactory segment of nasal mucosa, nasal cavity epithelium, nasal cavity mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PAX3	2,960
PAX7	2,847

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PAX3	P23760	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PAX7	P23759	63.21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Specification of the neural plate border	2	634.4×	7e-06	PAX3, PAX7
Transcriptional and post-translational regulation of MITF-M expression and activity	1	89.2×	0.017	PAX3
HATs acetylate histones	1	39.6×	0.025	PAX3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
skeletal muscle satellite cell commitment	1	8426.0×	0.003	PAX7
regulation of cell fate commitment	1	2808.7×	0.004	PAX7
nervous system development	2	45.9×	0.004	PAX3, PAX7
muscle tissue morphogenesis	1	1203.7×	0.005	PAX7
skeletal muscle satellite cell differentiation	1	1053.2×	0.005	PAX7
regulation of chromatin organization	1	766.0×	0.005	PAX7
positive regulation of myoblast proliferation	1	702.2×	0.005	PAX7
spinal cord association neuron differentiation	1	648.1×	0.005	PAX7
skeletal muscle tissue regeneration	1	443.5×	0.005	PAX7
dorsal/ventral neural tube patterning	1	401.2×	0.005	PAX7
neuron fate commitment	1	401.2×	0.005	PAX7
positive regulation of transcription by RNA polymerase II	2	14.9×	0.009	PAX3, PAX7
embryonic skeletal system development	1	195.9×	0.009	PAX7
regulation of transcription by RNA polymerase II	2	11.7×	0.013	PAX3, PAX7
cartilage development	1	125.8×	0.013	PAX7
animal organ morphogenesis	1	95.8×	0.016	PAX3
muscle organ development	1	83.4×	0.017	PAX3
anatomical structure morphogenesis	1	69.6×	0.019	PAX7
sensory perception of sound	1	50.5×	0.025	PAX3
chromatin remodeling	1	36.5×	0.032	PAX7
transcription by RNA polymerase II	1	35.3×	0.032	PAX7
negative regulation of apoptotic process	1	17.4×	0.062	PAX7
apoptotic process	1	14.3×	0.070	PAX3
positive regulation of DNA-templated transcription	1	14.0×	0.070	PAX3

Therapeutics

Drugs indicated or in trials for this disease

4 approved drugs — disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Status
Dactinomycin	Approved (phase 3)
Temsirolimus	Approved (phase 3)
Vincristine	Approved (phase 3)
Vinorelbine	Approved (phase 3)

4 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Bevacizumab	Phase 2
Etoposide	Phase 2
Ifosfamide	Phase 2
Temozolomide	Phase 2

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PAX3	0	0
PAX7	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PAX3	17	Binding:17

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	PAX3, PAX7

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)
PAX3	17	—
PAX7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	3
PHASE1/PHASE2	2
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02567435	PHASE3	ACTIVE_NOT_RECRUITING	Combination Chemotherapy With or Without Temsirolimus in Treating Patients With Intermediate Risk Rhabdomyosarcoma
NCT04994132	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Compare Early Use of Vinorelbine and Maintenance Therapy for Patients With High Risk Rhabdomyosarcoma
NCT06669013	PHASE3	RECRUITING	Chemo-immunotherapy in Patients Under 18 Years of Age With Bone and Soft Tissue Sarcomas
NCT05071209	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Elimusertib for the Treatment of Relapsed or Refractory Solid Tumors
NCT00923351	PHASE1/PHASE2	COMPLETED	Therapy to Treat Ewing’s Sarcoma, Rhabdomyosarcoma or Neuroblastoma
NCT03296371	Not specified	ACTIVE_NOT_RECRUITING	Genetic Mutational Analysis of Saliva or Buccal Mucosa Samples From Patients With Embryonal or Alveolar Rhabdomyosarcoma
NCT01923701	Not specified	COMPLETED	Cognitive Behavioral Therapy for the Prevention of Paranoia in Adolescents at High Risk

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CYCLOPHOSPHAMIDE ANHYDROUS	4	2
DACTINOMYCIN	4	2
VINORELBINE	4	2
DINUTUXIMAB BETA	4	1
IRINOTECAN HYDROCHLORIDE	4	1
TEMSIROLIMUS	4	1
ELIMUSERTIB	1	1
CHEMBL4748391	0	2
CHEMBL541887	0	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 4 predictive associations from 4 curated evidence items; also 6 diagnostic, 2 prognostic.

Molecular subtype	Therapy	Effect	Level	CIViC
FGFR4 Overexpression	Ponatinib	Sensitivity/Response	CIViC D	EID7137
MET Overexpression AND ALK Overexpression	Crizotinib	Sensitivity/Response	CIViC D	EID7136
PAX3::FOXO1 Fusion	BET Inhibitor	Sensitivity/Response	CIViC D	EID7011
CDK4 Overexpression	Ribociclib + Palbociclib	Resistance	CIViC D	EID7138