Undifferentiated pleomorphic sarcoma

Summary

Undifferentiated pleomorphic sarcoma (MONDO:0002142) is a cancer with 1 cohort gene (1 CIViC-evidence somatic driver; 1 ClinVar predisposition record) and 47 clinical trials. Top therapeutic interventions include pazopanib, dexrazoxane, and ifosfamide.

At a glance

• Classification: Cancer
• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 1
• Phenotypes (HPO): 9
• Clinical trials: 47

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.9	Europe	Validated
Annual incidence	1-9 / 1 000 000	0.9	United States	Validated
Point prevalence	1-9 / 100 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0002585	Abnormality of the peritoneum	Very frequent (80-99%)
HP:0002814	Abnormality of the lower limb	Very frequent (80-99%)
HP:0030448	Soft tissue sarcoma	Very frequent (80-99%)
HP:0001945	Fever	Frequent (30-79%)
HP:0003011	Abnormality of the musculature	Frequent (30-79%)
HP:0001824	Weight loss	Occasional (5-29%)
HP:0002039	Anorexia	Occasional (5-29%)
HP:0002817	Abnormality of the upper limb	Occasional (5-29%)
HP:0012378	Fatigue	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	undifferentiated pleomorphic sarcoma
Mondo ID	MONDO:0002142
EFO	EFO:1001972
MeSH	D051677
Orphanet	2023
DOID	DOID:1907
NCIT	C114541, C4247
SNOMED CT	443439001
UMLS	C0334463
MedGen	87248
GARD	0006963
MedDRA	10025552
Is cancer (heuristic)	yes

Also known as: adult malignant fibrous histiocytoma · adult unclassified pleomorphic sarcoma · adult undifferentiated pleomorphic sarcoma · fibrous histiocytoma, malignant · fibrous histiocytoma, malignant (morphologic abnormality) · fibroxanthosarcoma · fibroxanthosarcoma (morphologic abnormality) · histiocytoma, fibrous, malignant · malignant fibrohistiocytic tumors · malignant fibrohistiocytic tumours · malignant fibrous cytoma · malignant fibrous histiocytoma · malignant fibrous histiocytoma of soft tissue and bone · malignant fibrous histiocytoma of the soft tissue and bone · malignant fibroxanthoma · MFH · Storiform-pleomorphic fibrous histiocytoma · Storiform-pleomorphic malignant fibrous histiocytoma · Storiform-pleomorphic MFH · unclassified pleomorphic sarcoma (+6 more)

Data availability: 1 ClinVar variant · 66 cell lines.

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 › histiocytoma › undifferentiated pleomorphic sarcoma

Related subtypes (2): benign fibrous histiocytoma, histiocytoma, Angiomatoid fibrous

Subtypes (3): cutaneous undifferentiated pleomorphic sarcoma, malignant giant cell tumor of soft parts, undifferentiated pleomorphic sarcoma, inflammatory variant

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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
620609	NM_004260.4(RECQL4):c.1717C>T (p.Gln573Ter)	RECQL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
RECQL4	LoF	STAD

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RECQL4	Orphanet:1225	Baller-Gerold syndrome
RECQL4	Orphanet:221016	Rothmund-Thomson syndrome type 2
RECQL4	Orphanet:3021	RAPADILINO syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RECQL4	HGNC:9949	ENSG00000160957	O94761	ATP-dependent DNA helicase Q4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RECQL4	ATP-dependent DNA helicase Q4	An ATP-dependent DNA helicase which unwinds dsDNA with a 3’-overhang in a 3’-5’ direction.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RECQL4	Enzyme (other)	yes	3.6.4.12	Helicase_C-like, DNA_helicase_ATP-dep_RecQ, DEAD/DEAH_box_helicase_dom

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
lower esophagus mucosa	1
mucosa of transverse colon	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RECQL4	212	ubiquitous	yes	lower esophagus mucosa, ventricular zone, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RECQL4	6,330

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RECQL4	O94761	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
telomeric D-loop disassembly	1	1872.4×	0.003	RECQL4
telomere maintenance	1	267.5×	0.008	RECQL4
DNA replication	1	165.2×	0.008	RECQL4
double-strand break repair via homologous recombination	1	156.0×	0.008	RECQL4
DNA repair	1	63.8×	0.016	RECQL4

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Catequentinib, Ipilimumab, Nivolumab, Sintilimab, Toripalimab.

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RECQL4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RECQL4	3.6.4.12	DNA helicase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

0 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.

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	1	RECQL4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
RECQL4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 47.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	26
PHASE1	10
Not specified	5
PHASE3	3
PHASE1/PHASE2	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06422806	PHASE3	RECRUITING	Measuring if Immunotherapy Plus Chemotherapy is Better Than Chemotherapy Alone for Patients With Aggressive Poorly Differentiated Sarcomas
NCT00346164	PHASE3	COMPLETED	Observation, Radiation Therapy, Combination Chemotherapy, and/or Surgery in Treating Young Patients With Soft Tissue Sarcoma
NCT06370871	PHASE3	WITHDRAWN	Brightline-3: A Study to Find Out Whether Brigimadlin in Combination With Ezabenlimab Helps People With Advanced Soft Tissue Sarcoma
NCT02923778	PHASE2	ACTIVE_NOT_RECRUITING	Talimogene Laherparepvec and Radiation Therapy in Treating Patients With Newly Diagnosed Soft Tissue Sarcoma That Can Be Removed by Surgery
NCT03307616	PHASE2	ACTIVE_NOT_RECRUITING	Nivolumab With and Without Ipilimumab and Radiation Therapy in Treating Patients With Recurrent or Resectable Undifferentiated Pleomorphic Sarcoma or Dedifferentiated Liposarcoma Before Surgery
NCT04332874	PHASE2	RECRUITING	A Study of Pembrolizumab Plus Local Chemotherapy Using Isolated Limb Infusion (ILI) for Patients With Sarcoma in the Arm or Leg
NCT04480502	PHASE2	ACTIVE_NOT_RECRUITING	ENVASARC: Envafolimab And Envafolimab With Ipilimumab In Patients With Undifferentiated Pleomorphic Sarcoma Or Myxofibrosarcoma
NCT05182164	PHASE2	RECRUITING	Combination of Pembrolizumab and Cabozantinib in Patients With Advanced Sarcomas
NCT05836571	PHASE2	ACTIVE_NOT_RECRUITING	Testing Ipilimumab and Nivolumab Combination With or Without Cabozantinib in People >= 18 Years Old With Advanced Soft Tissue Sarcoma
NCT05961761	PHASE2	RECRUITING	Propranolol and Pembrolizumab in Advanced Soft Tissue Sarcoma Patients
NCT06277154	PHASE2	RECRUITING	MASCT-I Combined With Doxorubicin and Ifosfamide for First-line Treatment of Advanced Soft Tissue Sarcoma
NCT07169344	PHASE2	RECRUITING	Hypofractionated, 3-week, Preoperative Proton or X-ray Radiotherapy for Patients With Localized Soft Tissue Sarcoma
NCT07173972	PHASE2	RECRUITING	Dose-escalated, Hypofractionated, Definitive Proton Radiotherapy for Patients With Inoperable Soft Tissue Sarcoma.
NCT00112463	PHASE2	COMPLETED	Depsipeptide (Romidepsin) in Treating Patients With Metastatic or Unresectable Soft Tissue Sarcoma
NCT00245102	PHASE2	COMPLETED	Sorafenib in Treating Patients With Metastatic, Locally Advanced, or Recurrent Sarcoma
NCT00400569	PHASE2	COMPLETED	Phase II Study of Sunitinib Malate for Metastatic and/or Surgically Unresectable Soft Tissue Sarcoma
NCT00503295	PHASE2	COMPLETED	Safety and Efficacy Study of REOLYSIN® in the Treatment of Bone and Soft Tissue Sarcomas Metastatic to the Lung
NCT00659360	PHASE2	COMPLETED	AZD0530 in Treating Patients With Recurrent Locally Advanced or Metastatic Soft Tissue Sarcoma
NCT01154452	PHASE1/PHASE2	COMPLETED	Vismodegib and Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced or Metastatic Sarcoma
NCT01532687	PHASE2	COMPLETED	Gemcitabine With or Without Pazopanib in Treating Patients With Refractory Soft Tissue Sarcoma
NCT01653028	PHASE2	COMPLETED	Alisertib in Treating Patients With Advanced or Metastatic Sarcoma
NCT02500797	PHASE2	COMPLETED	Nivolumab With or Without Ipilimumab in Treating Patients With Metastatic Sarcoma That Cannot Be Removed by Surgery
NCT02584309	PHASE2	COMPLETED	Doxorubicin With Upfront Dexrazoxane for the Treatment of Advanced or Metastatic Soft Tissue Sarcoma
NCT02601209	PHASE1/PHASE2	TERMINATED	Sapanisertib or Pazopanib Hydrochloride in Treating Patients With Locally Advanced or Metastatic Sarcoma
NCT03425279	PHASE1/PHASE2	COMPLETED	CAB-AXL-ADC Safety and Efficacy Study in Adult and Adolescent Patients With Sarcoma
NCT03651375	PHASE2	UNKNOWN	Hypofractionated Radiotherapy With Sequential Chemotherapy in Marginally Resectable Soft Tissue Sarcomas of Extremities or Trunk Wall
NCT03899805	PHASE2	COMPLETED	A Phase II Study of Eribulin and Pembrolizumab in Soft Tissue Sarcomas
NCT03946943	PHASE2	UNKNOWN	Study of Anlotinib Hydrochloride and Toripalimab in Subjects With Unresectable or Metastatic Undifferentiated Pleomorphic Sarcoma
NCT03989596	PHASE2	UNKNOWN	Hypofractionated Radiotherapy With Hyperthermia in Unresectable or Marginally Resectable Soft Tissue Sarcomas
NCT04906876	PHASE2	WITHDRAWN	A Phase 2 Study of 9-ING-41Combined With Chemotherapy in Adolescents and Adults With Advanced Sarcomas
NCT05017103	PHASE2	TERMINATED	Sintilimab for the Treatment of Locally Advanced, Metastatic, Recurrent, or Unresectable Undifferentiated Pleomorphic Sarcoma, SiARa Cancer Study
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
NCT05711615	PHASE1	RECRUITING	Testing Low-Dose Common Chemotherapy (Liposomal Doxorubicin) in Combination With an Anti-Cancer Drug, Peposertib, in Advanced Sarcoma
NCT05827614	PHASE1	ACTIVE_NOT_RECRUITING	Study of the CHK1 Inhibitor BBI-355, an ecDNA-directed Therapy (ecDTx), and the RNR Inhibitor BBI-825, in Subjects With Tumors With Oncogene Amplifications
NCT06789172	PHASE1	RECRUITING	A Phase 1, First-in-human Study of OKN4395 and Pembrolizumab in Patients With Solid Tumors
NCT02565758	PHASE1	COMPLETED	ABBV-085, an Antibody Drug Conjugate, in Subjects With Advanced Solid Tumors
NCT03009201	PHASE1	COMPLETED	Ribociclib and Doxorubicin in Treating Patients With Metastatic or Advanced Soft Tissue Sarcomas That Cannot Be Removed by Surgery
NCT03670069	PHASE1	TERMINATED	Itacitinib in Treating Patients With Refractory Metastatic/Advanced Sarcomas
NCT03752398	PHASE1	COMPLETED	A Study of XmAb®23104 in Subjects With Selected Advanced Solid Tumors (DUET-3)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PAZOPANIB	4	4
DEXRAZOXANE	4	3
IFOSFAMIDE	4	2
DACTINOMYCIN	4	1
ERIBULIN	4	1
FUTIBATINIB	4	1
RIBOCICLIB	4	1
ROMIDEPSIN	4	1
SORAFENIB	4	1
SUNITINIB MALATE	4	1
TALIMOGENE LAHERPAREPVEC	4	1
TORIPALIMAB	4	1
TRABECTEDIN	4	1
VISMODEGIB	4	1
ALISERTIB	3	1
BRIGIMADLIN	3	1
CATEQUENTINIB	3	1
ENVAFOLIMAB	3	1
EZABENLIMAB	3	1
ITACITINIB	3	1
SARACATINIB	3	1
VIMSELTINIB	3	1
ELRAGLUSIB	2	2
SAMROTAMAB VEDOTIN	2	1
SAPANISERTIB	2	1
EFROFILCON A	1	1
NEDISERTIB	1	1
CHEMBL4066465	0	1
CHEMBL3109278	0	1
CHEMBL4438584	0	1