Congenital fibrosarcoma

Summary

Congenital fibrosarcoma (MONDO:0004557) is a disease with 4 cohort genes and 3 clinical trials. Molecularly, ETV6::NTRK3 Fusion confers sensitivity to Larotrectinib in Congenital Fibrosarcoma (CIViC Level A); 5 further subtype–drug associations are mapped below. Top therapeutic interventions include larotrectinib and selpercatinib.

At a glance

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

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital fibrosarcoma
Mondo ID	MONDO:0004557
DOID	DOID:8418
NCIT	C4244
SNOMED CT	403996004
UMLS	C0334459
MedGen	87246
GARD	0024067
Is cancer (heuristic)	no

Also known as: congenital fibrosarcoma · IFS · infantile fibrosarcoma · infantile fibrosarcoma (congenital fibrosarcoma) · infantile fibrosarcoma (morphologic abnormality)

Data availability: 4 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › mesenchymal cell neoplasm › fibroblastic neoplasm › fibrosarcoma › conventional fibrosarcoma › congenital fibrosarcoma

Related subtypes (1): adult fibrosarcoma

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

4 retrieved; paginated sample, class counts are floors:

3 pathogenic, 1 other

ClinVar	Variant (HGVS)	Gene	Classification	Review
617477	LMNA-NTRK1 fusion	IQGAP3	Pathogenic	no assertion criteria provided
2413121	NM_016169.4(SUFU):c.846del (p.Glu283fs)	SUFU	Pathogenic	criteria provided, single submitter
12347	NM_000546.6(TP53):c.742C>T (p.Arg248Trp)	TP53	Pathogenic	reviewed by expert panel
978602	RBPMS-MET fusion	MET	other	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 32 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare 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
SUFU	Orphanet:2495	Meningioma
SUFU	Orphanet:251858	Medulloblastoma with extensive nodularity
SUFU	Orphanet:251863	Desmoplastic/nodular medulloblastoma
SUFU	Orphanet:263662	Familial multiple meningioma
SUFU	Orphanet:280200	Microform holoprosencephaly
SUFU	Orphanet:377	Gorlin syndrome
SUFU	Orphanet:475	Isolated Joubert syndrome
MET	Orphanet:319298	Papillary renal cell carcinoma
MET	Orphanet:33402	Pediatric hepatocellular carcinoma
MET	Orphanet:47044	Hereditary papillary renal cell carcinoma
MET	Orphanet:488265	Osteofibrous dysplasia
MET	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

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
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	clinvar
SUFU	HGNC:16466	ENSG00000107882	Q9UMX1	Suppressor of fused homolog	clinvar
IQGAP3	HGNC:20669	ENSG00000183856	Q86VI3	Ras GTPase-activating-like protein IQGAP3	clinvar
MET	HGNC:7029	ENSG00000105976	P08581	Hepatocyte growth factor receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TP53	Cellular tumor antigen p53	Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence.
SUFU	Suppressor of fused homolog	Negative regulator in the hedgehog/smoothened signaling pathway.
MET	Hepatocyte growth factor receptor	Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand.

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
Kinase	1	6.9×	0.410
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TP53	Transcription factor	no		p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn
SUFU	Other/Unknown	no		Suppressor_of_fused, Suppressor_of_fused_euk, SUFU-like_domain
IQGAP3	Other/Unknown	no		IQ_motif_EF-hand-BS, IQGAP_helical, CH_dom
MET	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Semap_dom

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ganglionic eminence	1
tendon of biceps brachii	1
ventricular zone	1
kidney epithelium	1
upper arm skin	1
vena cava	1
buccal mucosa cell	1
oocyte	1
secondary oocyte	1
cartilage tissue	1
germinal epithelium of ovary	1
pigmented layer of retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TP53	223	ubiquitous	marker	ventricular zone, ganglionic eminence, tendon of biceps brachii
SUFU	226	ubiquitous	yes	upper arm skin, kidney epithelium, vena cava
IQGAP3	180	ubiquitous	marker	buccal mucosa cell, oocyte, secondary oocyte
MET	270	ubiquitous	marker	pigmented layer of retina, germinal epithelium of ovary, cartilage tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP53	22,736
MET	5,823
IQGAP3	2,220
SUFU	2,188

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TP53	P04637	313
MET	P08581	130
SUFU	Q9UMX1	10
IQGAP3	Q86VI3	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 108. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Loss of function of TP53 in cancer due to loss of tetramerization ability	1	2855.0×	0.021	TP53
Regulation of TP53 Expression	1	1427.5×	0.021	TP53
Drug-mediated inhibition of MET activation	1	1427.5×	0.021	MET
MET activates STAT3	1	951.7×	0.021	MET
Transcriptional activation of cell cycle inhibitor p21	1	713.8×	0.021	TP53
MET activates PTPN11	1	571.0×	0.021	MET
MET interacts with TNS proteins	1	571.0×	0.021	MET
Activation of NOXA and translocation to mitochondria	1	475.8×	0.021	TP53
MET Receptor Activation	1	475.8×	0.021	MET
MET activates PI3K/AKT signaling	1	475.8×	0.021	MET
RUNX3 regulates CDKN1A transcription	1	407.9×	0.021	TP53
Sema4D mediated inhibition of cell attachment and migration	1	356.9×	0.021	MET
PI5P Regulates TP53 Acetylation	1	317.2×	0.021	TP53
Activation of PUMA and translocation to mitochondria	1	285.5×	0.021	TP53
MET receptor recycling	1	285.5×	0.021	MET
MET activates RAS signaling	1	259.6×	0.021	MET
MET activates RAP1 and RAC1	1	259.6×	0.021	MET
Listeria monocytogenes entry into host cells	1	259.6×	0.021	MET
TP53 Regulates Transcription of Caspase Activators and Caspases	1	237.9×	0.021	TP53
TP53 Regulates Transcription of Death Receptors and Ligands	1	237.9×	0.021	TP53
Urea cycle	1	219.6×	0.021	TP53
Regulation of TP53 Activity through Association with Co-factors	1	203.9×	0.021	TP53
TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain	1	190.3×	0.021	TP53
Stabilization of p53	1	190.3×	0.021	TP53
InlB-mediated entry of Listeria monocytogenes into host cell	1	190.3×	0.021	MET
TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest	1	178.4×	0.021	TP53
Formation of Senescence-Associated Heterochromatin Foci (SAHF)	1	167.9×	0.021	TP53
Sema4D in semaphorin signaling	1	167.9×	0.021	MET
Zygotic genome activation (ZGA)	1	167.9×	0.021	TP53
Regulation of NF-kappa B signaling	1	158.6×	0.021	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 4 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 helicase activity	1	4213.0×	0.006	TP53
cellular response to actinomycin D	1	4213.0×	0.006	TP53
regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1	4213.0×	0.006	TP53
negative regulation of G1 to G0 transition	1	4213.0×	0.006	TP53
positive regulation of cellular response to drug	1	4213.0×	0.006	SUFU
smoothened signaling pathway involved in ventral spinal cord interneuron specification	1	2106.5×	0.006	SUFU
smoothened signaling pathway involved in spinal cord motor neuron cell fate specification	1	2106.5×	0.006	SUFU
positive regulation of mitochondrial membrane permeability	1	2106.5×	0.006	TP53
maintenance of protein localization in organelle	1	2106.5×	0.006	SUFU
oligodendrocyte apoptotic process	1	2106.5×	0.006	TP53
negative regulation of glucose catabolic process to lactate via pyruvate	1	2106.5×	0.006	TP53
negative regulation of pentose-phosphate shunt	1	2106.5×	0.006	TP53
Ras protein signal transduction	2	102.8×	0.006	TP53, IQGAP3
obsolete homolactic fermentation	1	1404.3×	0.006	TP53
signal transduction by p53 class mediator	1	1404.3×	0.006	TP53
mitotic actomyosin contractile ring assembly actin filament organization	1	1404.3×	0.006	IQGAP3
negative regulation of miRNA processing	1	1404.3×	0.006	TP53
intrinsic apoptotic signaling pathway in response to hypoxia	1	1404.3×	0.006	TP53
regulation of fibroblast apoptotic process	1	1404.3×	0.006	TP53
T cell proliferation involved in immune response	1	1053.2×	0.007	TP53
positive regulation of programmed necrotic cell death	1	1053.2×	0.007	TP53
oxidative stress-induced premature senescence	1	1053.2×	0.007	TP53
negative regulation of hydrogen peroxide-mediated programmed cell death	1	1053.2×	0.007	MET
B cell lineage commitment	1	842.6×	0.007	TP53
T cell lineage commitment	1	842.6×	0.007	TP53
mRNA transcription	1	842.6×	0.007	TP53
positive regulation of RNA polymerase II transcription preinitiation complex assembly	1	842.6×	0.007	TP53
positive regulation of thymocyte apoptotic process	1	842.6×	0.007	TP53
cellular response to UV-C	1	842.6×	0.007	TP53
positive regulation of mammary gland epithelial cell proliferation	1	702.2×	0.007	IQGAP3

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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
TP53	NITROFURANTOIN
MET	AFATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TP53	196	4
MET	95	4
SUFU	0	0
IQGAP3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
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
FURAZOLIDONE	4	TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53
AMITRIPTYLINE HYDROCHLORIDE	4	TP53
ETHOPROPAZINE HYDROCHLORIDE	4	TP53
MECHLORETHAMINE HYDROCHLORIDE	4	TP53
ECONAZOLE NITRATE	4	TP53
TRIFLUPROMAZINE HYDROCHLORIDE	4	TP53
PROCHLORPERAZINE EDISYLATE	4	TP53
DEQUALINIUM CHLORIDE	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
MET	2,015	Binding:2005, Functional:6, ADMET:4
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
SUFU	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MET	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TP53	869
MET	2,015

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).

Chemical tractability of cohort targets

30 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)
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
FURAZOLIDONE	4	TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53
AMITRIPTYLINE HYDROCHLORIDE	4	TP53
ETHOPROPAZINE HYDROCHLORIDE	4	TP53
MECHLORETHAMINE HYDROCHLORIDE	4	TP53
ECONAZOLE NITRATE	4	TP53
TRIFLUPROMAZINE HYDROCHLORIDE	4	TP53
PROCHLORPERAZINE EDISYLATE	4	TP53
DEQUALINIUM CHLORIDE	4	TP53

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	TP53, MET
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	SUFU, IQGAP3

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)
SUFU	1	—
IQGAP3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1
PHASE1/PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03834961	PHASE2	ACTIVE_NOT_RECRUITING	Larotrectinib in Treating Patients With Previously Untreated TRK Fusion Solid Tumors and TRK Fusion Relapsed Acute Leukemia
NCT03899792	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors
NCT05236257	Not specified	COMPLETED	A Study Called EPI VITRAKVI to Compare Treatment Results in Patients With Infantile Fibrosarcoma (IFS), a Type of Connective Soft Tissue Cancer, Who Received a Treatment Called Larotrectinib From a Study Called SCOUT With Patient Data From an External Database

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LAROTRECTINIB	4	2
SELPERCATINIB	4	1
CHEMBL5430810	0	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 6 predictive associations from 10 curated evidence items; also 5 diagnostic, 2 oncogenic.

Molecular subtype	Therapy	Effect	Level	CIViC
ETV6::NTRK3 Fusion	Larotrectinib	Sensitivity/Response	CIViC A	EID6099 +3
SQSTM1::NTRK1 Fusion	Larotrectinib	Sensitivity/Response	CIViC C	EID6103 +1
EML4::NTRK3 Fusion	Entrectinib	Sensitivity/Response	CIViC C	EID11859
ETV6::NTRK3 Fusion	Entrectinib	Sensitivity/Response	CIViC C	EID11858
LMNA::NTRK1 Fusion	Crizotinib	Sensitivity/Response	CIViC C	EID8878
RBPMS::MET Fusion	Cabozantinib	Sensitivity/Response	CIViC C	EID8892