Spindle cell sarcoma

Summary

Spindle cell sarcoma (MONDO:0002927) is a cancer with 4 cohort genes (2 CIViC-evidence somatic drivers; 3 ClinVar predisposition records) and 6 clinical trials. Molecularly, KIAA1549::BRAF Fusion confers sensitivity to Sorafenib + Bevacizumab + Temsirolimus in Spindle Cell Sarcoma (CIViC Level C); 3 further subtype–drug associations are mapped below. Top therapeutic interventions include tazemetostat and elraglusib.

At a glance

• Classification: Cancer
• Cohort genes: 4
• ClinVar variants: 3
• Clinical trials: 6
• Precision-medicine evidence (CIViC): 4 subtype–drug associations

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spindle cell sarcoma
Mondo ID	MONDO:0002927
DOID	DOID:4235
NCIT	C27005
UMLS	C0205945
MedGen	64477
Is cancer (heuristic)	yes

Also known as: spindle cell sarcoma

Data availability: 3 ClinVar variants · 5 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › cancer › sarcoma › spindle cell sarcoma

Related subtypes (21): rectum sarcoma, ectomesenchymoma, colon sarcoma, sarcomatosis, dendritic cell sarcoma, orbit sarcoma, sarcoma G1, uterine corpus sarcoma, giant cell tumor of soft tissue, lymphangiosarcoma, endometrioid stromal sarcoma, myeloid sarcoma, small cell sarcoma, chondrosarcoma, osteosarcoma, reticulum cell sarcoma, Ewing sarcoma, sarcoma of cervix uteri, soft tissue sarcoma, mast cell sarcoma, bone sarcoma

Subtypes (4): spindle cell rhabdomyosarcoma, spindle cell synovial sarcoma, spindle cell liposarcoma, intimal sarcoma

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:

3 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
585331	der(15)t(5:15)(q23.2;q15.1)	MGA	Pathogenic	criteria provided, single submitter
585330	NM_000268.4(NF2):c.583_589del (p.His195fs)	NF2	Pathogenic	criteria provided, single submitter
585332	GRCh37/hg19 15q14-15.1 chr15:34638237..42057083 complex variant	RMDN3	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
MGA	LoF	CLLSLL,LUAD,PLMESO,PRAD	CIViC #9427
NF2	LoF	CCRCC,CESC,HCC,HNSC,MEL,OVT,PAAD,PLMESO,PRCC,RCC	CIViC #3870

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NF2	Orphanet:2495	Meningioma
NF2	Orphanet:634475	Mosaic NF2-related schwannomatosis
NF2	Orphanet:637	Full NF2-related schwannomatosis
NF2	Orphanet:93921	Full schwannomatosis

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MGA	HGNC:14010	ENSG00000174197	Q8IWI9	MAX gene-associated protein	clinvar
RMDN3	HGNC:25550	ENSG00000137824	Q96TC7	Regulator of microtubule dynamics protein 3	clinvar
MGAM	HGNC:7043	ENSG00000257335	O43451	Maltase-glucoamylase	clinvar
NF2	HGNC:7773	ENSG00000186575	P35240	Merlin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MGA	MAX gene-associated protein	Functions as a dual-specificity transcription factor, regulating the expression of both MAX-network and T-box family target genes.
RMDN3	Regulator of microtubule dynamics protein 3	Involved in cellular calcium homeostasis regulation.
MGAM	Maltase-glucoamylase	Alpha-(1,4) exo-glucosidase involved in breakdown of dietary starch oligosaccharides in small intestine.
NF2	Merlin	Probable regulator of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, a signaling pathway that plays a pivotal role in tumor suppression by restricting proliferation and promoting apoptosis.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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
Enzyme (other)	1	3.0×	0.605
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MGA	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, bHLH_dom
RMDN3	Other/Unknown	no		TPR-like_helical_dom_sf,
MGAM	Enzyme (other)	yes	3.2.1.20	Glyco_hydro_31_TIM, P_trefoil_dom, Gal_mutarotase_sf_dom
NF2	Other/Unknown	no		FERM_domain, Ez/rad/moesin-like, Moesin_tail_sf

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
oocyte	1
tendon	1
C1 segment of cervical spinal cord	1
cerebellar hemisphere	1
ileal mucosa	1
blood	1
bone marrow cell	1
duodenum	1
dorsal motor nucleus of vagus nerve	1
endometrium epithelium	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MGA	279	ubiquitous	marker	calcaneal tendon, oocyte, tendon
RMDN3	281	ubiquitous	marker	ileal mucosa, C1 segment of cervical spinal cord, cerebellar hemisphere
MGAM	128	tissue_specific	marker	duodenum, blood, bone marrow cell
NF2	283	ubiquitous	marker	endometrium epithelium, stromal cell of endometrium, dorsal motor nucleus of vagus nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NF2	3,208
MGAM	2,687
RMDN3	2,665
MGA	1,705

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MGAM	O43451	12
NF2	P35240	6
RMDN3	Q96TC7	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MGA	Q8IWI9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 4 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
Digestion of dietary carbohydrate	1	317.2×	0.019	MGAM
Digestion and absorption	1	253.8×	0.019	MGAM
Digestion	1	190.3×	0.019	MGAM
RHO GTPases activate PAKs	1	181.3×	0.019	NF2
Innate Immune System	2	17.0×	0.019	MGAM, NF2
Transcriptional Regulation by E2F6	1	97.6×	0.026	MGA
Fcgamma receptor (FCGR) dependent phagocytosis	1	92.8×	0.026	NF2
Regulation of actin dynamics for phagocytic cup formation	1	61.4×	0.032	NF2
Immune System	2	8.6×	0.032	MGAM, NF2
RHO GTPase Effectors	1	22.7×	0.074	NF2
Signaling by Rho GTPases	1	11.4×	0.123	NF2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	11.2×	0.123	NF2
Neutrophil degranulation	1	7.7×	0.155	MGAM
RNA Polymerase II Transcription	1	7.5×	0.155	MGA
Gene expression (Transcription)	1	6.0×	0.180	MGA
Generic Transcription Pathway	1	5.0×	0.197	MGA
Signal Transduction	1	3.4×	0.267	NF2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
maltose catabolic process	1	2106.5×	0.006	MGAM
starch catabolic process	1	2106.5×	0.006	MGAM
dextrin catabolic process	1	2106.5×	0.006	MGAM
Schwann cell proliferation	1	1404.3×	0.006	NF2
regulation of gliogenesis	1	1404.3×	0.006	NF2
negative regulation of cell growth involved in contact inhibition	1	842.6×	0.007	NF2
regulation of organelle assembly	1	842.6×	0.007	NF2
negative regulation of Schwann cell proliferation	1	601.9×	0.008	NF2
regulation of hippo signaling	1	601.9×	0.008	NF2
regulation of protein localization to nucleus	1	526.6×	0.008	NF2
positive regulation of early endosome to late endosome transport	1	468.1×	0.008	NF2
positive regulation of protein localization to early endosome	1	421.3×	0.008	NF2
regulation of neural precursor cell proliferation	1	421.3×	0.008	NF2
negative regulation of osteoblast proliferation	1	383.0×	0.008	NF2
osteoblast proliferation	1	351.1×	0.008	NF2
regulation of stem cell proliferation	1	351.1×	0.008	NF2
ectoderm development	1	300.9×	0.008	NF2
lens fiber cell differentiation	1	263.3×	0.009	NF2
negative regulation of cell-cell adhesion	1	247.8×	0.009	NF2
negative regulation of cell-matrix adhesion	1	221.7×	0.009	NF2
negative regulation of receptor signaling pathway via JAK-STAT	1	221.7×	0.009	NF2
hippo signaling	1	183.2×	0.011	NF2
cell-cell junction organization	1	156.0×	0.012	NF2
cell fate specification	1	131.7×	0.014	MGA
mesoderm formation	1	123.9×	0.014	NF2
positive regulation of stress fiber assembly	1	78.0×	0.020	NF2
odontogenesis of dentin-containing tooth	1	75.2×	0.020	NF2
negative regulation of MAPK cascade	1	75.2×	0.020	NF2
positive regulation of cell differentiation	1	66.9×	0.022	NF2
hippocampus development	1	57.7×	0.025	NF2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) 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
MGAM	MIGLUSTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MGAM	10	4
MGA	0	0
RMDN3	0	0
NF2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MIGLUSTAT	4	MGAM
MIGALASTAT	4	MGAM
MIGLITOL	4	MGAM
ACARBOSE	4	MGAM
VOGLIBOSE	4	MGAM
LUCERASTAT	3	MGAM
QUERCETIN	3	MGAM
THIAZOLIDINEDIONE	3	MGAM
DUVOGLUSTAT	2	MGAM
GENISTEIN	2	MGAM

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MGAM	253	Binding:253

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MGAM	3.2.1.20, 3.2.1.3	alpha-glucosidase, glucan 1,4-alpha-glucosidase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MGAM	253

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

10 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Compound	Max phase	Cohort target (bioactivity)
MIGLUSTAT	4	MGAM
MIGALASTAT	4	MGAM
MIGLITOL	4	MGAM
ACARBOSE	4	MGAM
VOGLIBOSE	4	MGAM
LUCERASTAT	3	MGAM
QUERCETIN	3	MGAM
THIAZOLIDINEDIONE	3	MGAM
DUVOGLUSTAT	2	MGAM
GENISTEIN	2	MGAM

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MGAM
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	3	MGA, RMDN3, NF2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MGA	0	—
RMDN3	0	—
NF2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE2	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04906876	PHASE2	WITHDRAWN	A Phase 2 Study of 9-ING-41Combined With Chemotherapy in Adolescents and Adults With Advanced Sarcomas
NCT05116800	PHASE2	WITHDRAWN	Phase 2 Study of 9-ING-41 With Chemotherapy in Sarcoma
NCT04420975	PHASE1	ACTIVE_NOT_RECRUITING	Nivolumab and BO-112 Before Surgery for the Treatment of Resectable Soft Tissue Sarcoma
NCT05974410	Not specified	AVAILABLE	Expanded Access to Immunomodulatory AVM0703 for Solid Tumor and Blood Cancer Patients
NCT06526897	Not specified	NOT_YET_RECRUITING	Evaluation of Chest CT Versus Chest X-Ray for Lung Surveillance After Curative-Intent Resection of High-Risk Truncal-Extremity Soft Tissue Sarcoma
NCT03874455	Not specified	NO_LONGER_AVAILABLE	Tazemetostat Expanded Access Program for Adults With Solid Tumors

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TAZEMETOSTAT	4	1
ELRAGLUSIB	2	2
CHEMBL1510899	0	2
CHEMBL5398431	0	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 4 predictive associations from 5 curated evidence items.

Molecular subtype	Therapy	Effect	Level	CIViC
KIAA1549::BRAF Fusion	Sorafenib + Bevacizumab + Temsirolimus	Sensitivity/Response	CIViC C	EID1664 +1
LMNA::NTRK1 Fusion	TRK Inhibitor	Sensitivity/Response	CIViC C	EID8902
QKI::RAF1 Fusion	Trametinib	Sensitivity/Response	CIViC C	EID10326
TPM3::NTRK1 Fusion	Larotrectinib	Sensitivity/Response	CIViC C	EID7419