FH

Summary

FH (fumarate hydratase, HGNC:3700) is a protein-coding gene on chromosome 1q43, encoding Fumarate hydratase, mitochondrial (P07954). Catalyzes the reversible stereospecific interconversion of fumarate to L-malate. It is a selective cancer dependency (DepMap: 15.0% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is an enzymatic component of the tricarboxylic acid (TCA) cycle, or Krebs cycle, and catalyzes the formation of L-malate from fumarate. It exists in both a cytosolic form and an N-terminal extended form, differing only in the translation start site used. The N-terminal extended form is targeted to the mitochondrion, where the removal of the extension generates the same form as in the cytoplasm. It is similar to some thermostable class II fumarases and functions as a homotetramer. Mutations in this gene can cause fumarase deficiency and lead to progressive encephalopathy.

Source: NCBI Gene 2271 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary leiomyomatosis and renal cell cancer (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 2,538 total — 280 pathogenic, 133 likely-pathogenic
• Phenotypes (HPO): 127
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 15.0% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000143

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3700
Approved symbol	FH
Name	fumarate hydratase
Location	1q43
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000091483
Ensembl biotype	protein_coding
OMIM	136850
Entrez	2271

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 14 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000366560, ENST00000493477, ENST00000497042, ENST00000682162, ENST00000682567, ENST00000683521, ENST00000684161, ENST00000684483, ENST00000865384, ENST00000865385, ENST00000865386, ENST00000865387, ENST00000865388, ENST00000865389, ENST00000865390, ENST00000932939, ENST00000958406, ENST00000958407, ENST00000958408, ENST00000958409

RefSeq mRNA: 1 — MANE Select: NM_000143 NM_000143

CCDS: CCDS1617

Canonical transcript exons

ENST00000366560 — 10 exons

Exon	Start	End
ENSE00000961688	241513603	241513713
ENSE00000961689	241511967	241512143
ENSE00000961690	241508603	241508785
ENSE00001009258	241497603	241497970
ENSE00001009262	241500437	241500590
ENSE00001069121	241504042	241504245
ENSE00001069122	241502443	241502570
ENSE00001442032	241519591	241519755
ENSE00001791261	241506003	241506168
ENSE00003687860	241517182	241517316

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 98.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 79.7489 / max 1083.6356, expressed in 1826 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
18283	79.7489	1826

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	98.35	gold quality
body of tongue	UBERON:0011876	97.98	gold quality
cardiac ventricle	UBERON:0002082	97.94	gold quality
heart left ventricle	UBERON:0002084	97.93	gold quality
apex of heart	UBERON:0002098	97.85	gold quality
right atrium auricular region	UBERON:0006631	97.74	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.69	gold quality
gastrocnemius	UBERON:0001388	97.66	gold quality
right lobe of liver	UBERON:0001114	97.62	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.62	gold quality
cardiac atrium	UBERON:0002081	97.59	gold quality
muscle of leg	UBERON:0001383	97.55	gold quality
left ventricle myocardium	UBERON:0006566	97.49	gold quality
muscle organ	UBERON:0001630	97.43	gold quality
biceps brachii	UBERON:0001507	97.36	gold quality
heart	UBERON:0000948	97.35	gold quality
liver	UBERON:0002107	97.29	gold quality
vastus lateralis	UBERON:0001379	97.25	gold quality
quadriceps femoris	UBERON:0001377	97.21	gold quality
adrenal tissue	UBERON:0018303	97.17	gold quality
mucosa of transverse colon	UBERON:0004991	97.14	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.11	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.08	gold quality
rectum	UBERON:0001052	96.99	gold quality
skeletal muscle tissue	UBERON:0001134	96.97	gold quality
right adrenal gland	UBERON:0001233	96.92	gold quality
myocardium	UBERON:0002349	96.92	gold quality
colonic mucosa	UBERON:0000317	96.88	gold quality
right adrenal gland cortex	UBERON:0035827	96.87	gold quality
deltoid	UBERON:0001476	96.84	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.12
E-MTAB-2983	no	215.46

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

21 targeting FH, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-7151-5P	99.37	67.82	613
HSA-MIR-6882-5P	99.35	71.13	1206
HSA-MIR-4528	99.18	69.77	1936
HSA-MIR-376A-3P	99.06	69.17	1128
HSA-MIR-376B-3P	99.06	69.17	1128
HSA-MIR-3194-3P	98.83	66.22	1167
HSA-MIR-6728-3P	98.63	67.63	1534
HSA-MIR-4720-3P	98.50	68.88	988
HSA-MIR-224-5P	98.33	70.12	1256
HSA-MIR-5691	98.23	67.02	1335
HSA-MIR-6805-3P	98.23	67.02	1334
HSA-MIR-4708-5P	97.77	67.82	831
HSA-MIR-376A-5P	97.70	65.61	863
HSA-MIR-1468-5P	94.18	69.04	176

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 15.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer (PMID:11865300)
• changes in the turnover number and the cocrystal structure with bound citrate due to the human missense mutation G-955-C engineered in fumarase C from Escherichia coli (PMID:12021453)
• Our findings indicate that mutations in fumarate hydratase do not play a major role in the development of sporadic leiomyosarcomas or uterine leiomyomas (PMID:12177782)
• Review. Fumarate hydratase catalyses a step in the Krebs tricarboxylic-acid cycle. Inherited heterozygous mutations in the gene encoding this enzymes causes predisposition to inherited neoplasia syndromes. (PMID:12612654)
• five new mutations affecting highly conserved residues of the FH protein in cutaneous and uterine leiomyomata (PMID:14632190)
• fumarate hydratase has a role in nonsyndromic uterine leiomyomas (PMID:15334541)
• Highly penetrant Frameshift mutations underlie multiple cuatneous anduterine leiomyomatosis. (PMID:15724016)
• 31 different germline FH mutations in 56 families with Hereditary leiomyomatosis and renal cell cancer (HLRCC) (20 missense, eight frameshifts, two nonsense, and one splice site) was indentified. (PMID:15937070)
• Fumarate hydratase inhibition, together with elevated intracellular fumarate, coincides with hypoxia-indicible factors upregulation. (PMID:16098467)
• That all missense FH mutations associating with MCUL/hereditary leiomyomatosis and renal cell cancer showed diminished FH enzymatic activity suggests that the tumor suppressor role of fumarate hydratase may relate to its enzymatic function (PMID:16237213)
• FH mutations alter significantly the gene expression profiles of uterine fibroids, most strikingly increasing the expression of genes involved in glycolysis. (PMID:16319128)
• This study shows that FH germline mutations can occur in seemingly nonsyndromic cases of ULMS (1/67, 1.5%). It appears that on the population level hereditary FH defects do play a role in pathogenesis of sporadic early onset ULMSs, albeit rarely. (PMID:16477632)
• Lymphoblastoid cell lines (n = 20) and fibroblast cell lines (n = 11) from individuals with Hereditary leiomyomatosis and renal cell cancer (HLRCC) had lower Fumarate Hydratase enzyme activity than cells from normal controls (p<0.05). (PMID:16597677)
• two patients diagnosed with ovarian mucinous cystadenoma (two out of 33, 6%) were found to be FH germline mutation carriers; results suggest that benign ovarian tumors may be associated with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID:16639410)
• study shows that some Leydig cell tumors are caused by fumarate hydratase mutations and represents one of the first reports of germline mutations in any type of adult testicular tumor (PMID:16757530)
• extramitochondrial presence of yeast fumarase is mainly caused by the poor mitochondrial targeting characteristics of its mitochondrial targeting sequence (PMID:16774737)
• In six unrelated Dutch and Spanish leiomyomatosis patients and their families, we identified six novel FH mutations, including one missense and one nonsense mutation, two deletions and two splice-site mutations. (PMID:16881969)
• a new mutation in the fumarate hydratase gene may have a role in cerebral cavernomas in a family with multiple cutaneous and uterine leiomyomas (PMID:17476294)
• Evidence for a founder effect of the germ-line FH gene mutation R58P causing hereditary leiomyomatosis and renal cell cancer is presented. (PMID:17908262)
• data demonstrate the dominant negative effect of the R190H missense mutation in the FH gene and suggest that the FH tumor-suppressing activity might be impaired in cells carrying a heterozygous mutation (PMID:17960613)
• characterization of a novel FH variant (FHv) that contains an alternative exon 1b, thus lacking the mitochondrial signal sequence (PMID:18257390)
• The cellular consequences of FH and respiratory chain (RC) deficiencies were studied, aiming to identify general responses to energy metabolism defect and those specific for FH-deficiency, suggestively connected to tumorigenesis. (PMID:18313410)
• finding, together with the two patients with whole FH gene deletion who had been detected previously, suggests that exonic or whole-gene FH deletions are not a frequent cause of HLRCC syndrome (PMID:18503824)
• Hereditary multiple cutaneous leiomyoma resulting from novel mutations in the fumarate hydratase gene are reported in two families. (PMID:18514489)
• Although the familial occurrence of these rare tumors might be coincidental, it cannot be ruled out that, beside FH, mutations in another as yet unknown gene could give rise to both leiomyosarcoma and kidney cancer (PMID:18986479)
• This study provides the first evidence that women with germline mutations in fumarate hydratase and with clinical HLRCC have an increased risk of developing uterine fibroids (PMID:19075141)
• FH-deficient fibroblasts share a common transcriptional fingerprint with FH-deficient and sporadic leiomyomas, highlighting the downregulation of serum response factor (SRF)-regulated transcripts, particularly the FOS-JUNB pathway (PMID:19151755)
• LDH-A knockdown in the background of FH knockdown results in significant reduction in tumor growth in a xenograft mouse model. (PMID:19276158)
• Data demonstrate that stable knockdown of FH in immortalized renal epithelial cells results in ROS-dependent HIF-1alpha stabilization. (PMID:19470762)
• These data suggest a novel role for fumarate metabolism in salt-induced hypertension and renal medullary oxidative stress (PMID:19546378)
• findings indicate that the severe compromise of oxidative phosphorylation and rapid glycolytic flux in UOK 262 are an essential feature of this fumarate hydratase deficient form of kidney cancer (PMID:19963135)
• Data suggest that fumarase and fumaric acid are critical elements of the DNA damage response, which underlies the tumor suppressor role of fumarase in human cells and which is most probably HIF independent. (PMID:20231875)
• first case of fumaric aciduria described in Brazil, which presented with some interesting clinical and biochemical findings such as colpocephaly, hepatic alterations, and marked metabolic acidosis since birth (PMID:20549362)
• 4 novel mutations and 1 whole-gene deletion of fumarate hydratase in families with an autosomal dominant syndrome characterized by multiple cutaneous piloleiomyomas, uterine leiomyomas and papillary type 2 renal cance (PMID:20618355)
• These experiments demonstrated that upregulation of HIF-1alpha occurs as a direct consequence of FH inactivation. (PMID:20660115)
• Novel mutations within the FH gene are associated with hereditary leiomyomatosis and renal cell cancer. (PMID:21398687)
• The crystal structure of human fumarate hydratase shows that mutations can be grouped into two distinct classes either affecting structural integrity of the core enzyme architecture, or are localized around the enzyme active site. (PMID:21445611)
• These results extend the range of clinical and biochemical variation associated with fumarase deficiency. (PMID:21560188)
• reduced FH leads to the accumulation of hypoxia inducible factor- 2alpha (HIF-2alpha) (PMID:21695080)
• Inactivation of the TCA cycle enzyme, fumarate hydratase (FH), drives a metabolic shift to aerobic glycolysis in FH-de fi cient kidney tumors (PMID:21907923)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	fh	ENSDARG00000075132
		ENSDARG00000109774
mus_musculus	Fh1	ENSMUSG00000026526
rattus_norvegicus	Fh	ENSRNOG00000003653
drosophila_melanogaster	Fum2	FBGN0029890
drosophila_melanogaster	Fum3	FBGN0036162
drosophila_melanogaster	Fum4	FBGN0051874
drosophila_melanogaster	Fum1	FBGN0286222
caenorhabditis_elegans		WBGENE00001503

Paralogs (2): ASL (ENSG00000126522), ADSL (ENSG00000239900)

Protein

Protein identifiers

Fumarate hydratase, mitochondrial — P07954 (reviewed: P07954)

All UniProt accessions (5): P07954, A0A0S2Z4C3, A0A804HI24, A0A804HKE6, A0A804HL52

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the reversible stereospecific interconversion of fumarate to L-malate. Experiments in other species have demonstrated that specific isoforms of this protein act in defined pathways and favor one direction over the other. Catalyzes the hydration of fumarate to L-malate in the tricarboxylic acid (TCA) cycle to facilitate a transition step in the production of energy in the form of NADH. Catalyzes the dehydration of L-malate to fumarate. Fumarate metabolism in the cytosol plays a role during urea cycle and arginine metabolism; fumarate being a by-product of the urea cycle and amino-acid catabolism. Also plays a role in DNA repair by promoting non-homologous end-joining (NHEJ). In response to DNA damage and phosphorylation by PRKDC, translocates to the nucleus and accumulates at DNA double-strand breaks (DSBs): acts by catalyzing formation of fumarate, an inhibitor of KDM2B histone demethylase activity, resulting in enhanced dimethylation of histone H3 ‘Lys-36’ (H3K36me2).

Subunit / interactions. Homotetramer. Interacts with H2AZ1.

Subcellular location. Mitochondrion Cytoplasm. Cytosol. Nucleus. Chromosome.

Tissue specificity. Expressed in red blood cells; underexpressed in red blood cells (cytoplasm) of patients with hereditary non-spherocytic hemolytic anemia of unknown etiology.

Post-translational modifications. Phosphorylation at Thr-236 by PRKDC in response to DNA damage promotes translocation to the nucleus and recruitment to DNA double-strand breaks (DSBs).

Disease relevance. Fumarase deficiency (FMRD) [MIM:606812] A severe autosomal recessive metabolic disorder characterized by early-onset hypotonia, profound psychomotor retardation, and brain abnormalities, such as agenesis of the corpus callosum, gyral defects, and ventriculomegaly. Many patients show neonatal distress, metabolic acidosis, and/or encephalopathy. The disease is caused by variants affecting the gene represented in this entry. Hereditary leiomyomatosis and renal cell cancer (HLRCC) [MIM:150800] A disorder characterized by predisposition to cutaneous and uterine leiomyomas, and papillary type 2 renal cancer which occurs in about 20% of patients. The disease is caused by variants affecting the gene represented in this entry. Isoform Cytoplasmic: HLRCC is probably caused by an accumulation of fumarate. Accumulation of fumarate coupled with protonation promotes the formation of non-enzymatic post-translational modification cysteine S-succination (S-(2-succinyl)cysteine) on proteins, such as SMARCC1.

Pathway. Carbohydrate metabolism; tricarboxylic acid cycle; (S)-malate from fumarate: step 1/1.

Miscellaneous. There are 2 substrate-binding sites: the catalytic A site, and the non-catalytic B site that may play a role in the transfer of substrate or product between the active site and the solvent. Alternatively, the B site may bind allosteric effectors.

Similarity. Belongs to the class-II fumarase/aspartase family. Fumarase subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P07954-1	Mitochondrial	yes
P07954-2	Cytoplasmic

RefSeq proteins (1): NP_000134* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000362	Fumarate_lyase_fam	Family
IPR005677	Fum_hydII	Family
IPR008948	L-Aspartase-like	Homologous_superfamily
IPR018951	Fumarase_C_C	Domain
IPR020557	Fumarate_lyase_CS	Conserved_site
IPR022761	Fumarate_lyase_N	Domain
IPR024083	Fumarase/histidase_N	Homologous_superfamily

Pfam: PF00206, PF10415

Enzyme classification (BRENDA):

• EC 4.2.1.2 — fumarate hydratase (BRENDA: 53 organisms, 85 substrates, 96 inhibitors, 200 Km, 90 kcat entries)

Substrate kinetics (BRENDA)

15 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
FUMARATE	0.0039–8.8	64
(S)-MALATE	0.0256–32	50
L-MALATE	0.0025–57	39
MESACONATE	0.03–3.2	10
(S)-CITRAMALATE	0.52–1.08	8
S-MALATE	0.005–12.6	6
(2S,3S)-TARTRATE	0.8–6.2	4
(S,S)-TARTRATE	0.8–6.2	4
D-TARTRATE	0.51–0.8	3
ACETYLENE DICARBOXYLATE	0.145–0.9	2
FLUOROFUMARATE	0.027–1.7	2
BROMOFUMARATE	0.11	1
CHLOROFUMARATE	0.11	1
IODOFUMARATE	0.12	1
L-TARTRATE	1.3	1

Catalyzed reactions (Rhea), 1 shown:

• (S)-malate = fumarate + H2O (RHEA:12460)

UniProt features (92 total): modified residue 24, helix 24, sequence variant 12, strand 8, binding site 6, turn 6, mutagenesis site 5, active site 2, transit peptide 1, chain 1, site 1, splice variant 1, initiator methionine 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
5UPP	X-RAY DIFFRACTION	1.8
6VBE	X-RAY DIFFRACTION	1.9
3E04	X-RAY DIFFRACTION	1.95
5D6B	X-RAY DIFFRACTION	2.1
7LUB	X-RAY DIFFRACTION	2.15
6EBT	X-RAY DIFFRACTION	2.3
6V8F	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07954-F1	92.92	0.89

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 378 (important for catalytic activity); 235 (proton donor/acceptor); 365

Ligand- & substrate-binding residues (6): 145–147; 176–179 (in site b); 186–188; 234; 366; 371–373

Post-translational modifications (24): 61, 61, 66, 66, 80, 80, 85, 90, 94, 115, 115, 122, 122, 213, 223, 223, 236, 256, 292, 292 …

Mutagenesis-validated functional residues (5):

Position	Phenotype
46	does not affect phosphorylation by prkdc.
147	does not affect phosphorylation by prkdc.
187	does not affect phosphorylation by prkdc.
236	abolished interaction with h2az1 and localization to chromatin in response to dna damage.
236	phosphomimetic mutant; promotes interaction with h2az1, leading to increased localization to chromatin in response to dn

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-71403	Citric acid cycle (TCA cycle)
R-HSA-9837999	Mitochondrial protein degradation

MSigDB gene sets: 560 (showing top): GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, MORF_DNMT1, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, MORF_RRM1, TGACCTY_ERR1_Q2, MORF_HDAC2, GOBP_REGULATION_OF_DNA_REPAIR, GNF2_RRM1, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, OUELLET_OVARIAN_CANCER_INVASIVE_VS_LMP_UP, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, OSWALD_HEMATOPOIETIC_STEM_CELL_IN_COLLAGEN_GEL_UP, HOSHIDA_LIVER_CANCER_SUBCLASS_S3

GO Biological Process (11): urea cycle (GO:0000050), obsolete regulation of arginine metabolic process (GO:0000821), tricarboxylic acid cycle (GO:0006099), fumarate metabolic process (GO:0006106), malate metabolic process (GO:0006108), DNA repair (GO:0006281), arginine metabolic process (GO:0006525), DNA damage response (GO:0006974), homeostasis of number of cells within a tissue (GO:0048873), positive regulation of cold-induced thermogenesis (GO:0120162), positive regulation of double-strand break repair via nonhomologous end joining (GO:2001034)

GO Molecular Function (5): fumarate hydratase activity (GO:0004333), histone binding (GO:0042393), catalytic activity (GO:0003824), protein binding (GO:0005515), lyase activity (GO:0016829)

GO Cellular Component (8): nucleus (GO:0005634), chromosome (GO:0005694), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), site of double-strand break (GO:0035861), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
dicarboxylic acid metabolic process	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
cytoplasm	2
biosynthetic process	1
urea metabolic process	1
aerobic respiration	1
primary metabolic process	1
DNA metabolic process	1
DNA damage response	1
amino acid metabolic process	1
carboxylic acid metabolic process	1
cellular response to stress	1
tissue homeostasis	1
homeostasis of number of cells	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
double-strand break repair via nonhomologous end joining	1
positive regulation of double-strand break repair	1
regulation of double-strand break repair via nonhomologous end joining	1
hydro-lyase activity	1
protein binding	1
molecular_function	1
binding	1
catalytic activity	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
mitochondrion	1
intracellular organelle lumen	1
site of DNA damage	1
extracellular vesicle	1

Protein interactions and networks

STRING

3366 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FH	CS	O75390	945
FH	IDH1	O75874	939
FH	IDH2	P48735	907
FH	ACO2	Q99798	903
FH	SDHB	P21912	893
FH	ACO1	P21399	892
FH	MDH2	P40926	810
FH	EPAS1	Q99814	800
FH	SDHD	O14521	776
FH	SDHA	P31040	769
FH	OGDH	Q02218	747
FH	PC	P11498	744
FH	EIF5B	O60841	742
FH	HIF1A	Q16665	731
FH	ACLY	P53396	725

IntAct

107 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
FH	EXOSC5	psi-mi:“MI:0915”(physical association)	0.660
FH	H2AZ1	psi-mi:“MI:0914”(association)	0.620
FH	H2AZ1	psi-mi:“MI:0915”(physical association)	0.620
PIM1	FH	psi-mi:“MI:0915”(physical association)	0.560
FH	PIM1	psi-mi:“MI:0915”(physical association)	0.560
FH	MRP8	psi-mi:“MI:0915”(physical association)	0.560
MRP8	FH	psi-mi:“MI:0915”(physical association)	0.560
TNPO2	FH	psi-mi:“MI:0915”(physical association)	0.560
FH	CCDC57	psi-mi:“MI:0915”(physical association)	0.560
FH	DGCR6	psi-mi:“MI:0915”(physical association)	0.560
FH	CCDC102B	psi-mi:“MI:0915”(physical association)	0.560
FH	LMNB2	psi-mi:“MI:0915”(physical association)	0.560
FH	SAT1	psi-mi:“MI:0915”(physical association)	0.560
FH	CSTPP1	psi-mi:“MI:0915”(physical association)	0.560
FH	TTC19	psi-mi:“MI:0915”(physical association)	0.560
FH	KLHL6	psi-mi:“MI:0915”(physical association)	0.560
POLR1C	FH	psi-mi:“MI:0915”(physical association)	0.560
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
	FH	psi-mi:“MI:0945”(oxidoreductase activity electron transfer reaction)	0.440
SAE1	FH	psi-mi:“MI:0915”(physical association)	0.400
FH	DBT	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (236): PIM1 (Two-hybrid), ANXA11 (Co-fractionation), ASS1 (Co-fractionation), C11orf54 (Co-fractionation), C9orf64 (Co-fractionation), CAB39 (Co-fractionation), CBR1 (Co-fractionation), CRIP1 (Co-fractionation), ENO1 (Co-fractionation), FAHD2A (Co-fractionation), FH (Co-fractionation), FH (Co-fractionation), FH (Co-fractionation), FH (Co-fractionation), FH (Co-fractionation)

ESM2 similar proteins: O17214, O69294, O94552, P05042, P07343, P07954, P08417, P10173, P14408, P55250, P71384, P93033, P97807, Q49YP8, Q54VA2, Q60HF9, Q6G884, Q6GFK5, Q71XE0, Q7N4H8, Q7SX99, Q7W0A2, Q7W4N9, Q7WG65, Q81SA0, Q822D5, Q83CL8, Q83ML8, Q89XM2, Q8FHA7, Q8FQP8, Q8FX90, Q8KTE1, Q8NRN8, Q8NVV1, Q8TS07, Q8UEY7, Q8X769, Q8Y551, Q8YB50

Diamond homologs: A0A3Q0KQY7, O17214, O25883, O66271, O69294, O84863, O94552, P05042, P07343, P07954, P08417, P10173, P14408, P28894, P55250, P64172, P64173, P71384, P93033, P95331, P97807, P9WN92, P9WN93, Q1RHL6, Q49YP8, Q4L7F5, Q4UMT4, Q51404, Q54VA2, Q55674, Q5HES4, Q5HN85, Q60022, Q60HF9, Q68W74, Q6G884, Q6GFK5, Q71XE0, Q72VY3, Q7N4H8

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
FH	“down-regulates quantity”	fumarate(2-)	“chemical modification”
FH	“up-regulates quantity”	(S)-malate(2-)	“chemical modification”
PAK4	“down-regulates quantity”	FH	phosphorylation
p38	“up-regulates activity”	FH	phosphorylation
AMPK	“up-regulates activity”	FH	phosphorylation
FH	“up-regulates activity”	ATF2	binding
PRKDC	“up-regulates activity”	FH	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 77 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
epidermal growth factor receptor signaling pathway	5	19.4×	5e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

2538 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	280
Likely pathogenic	133
Uncertain significance	984
Likely benign	545
Benign	47

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1010275	NM_000143.4(FH):c.1497del (p.Glu499fs)	Pathogenic
1011241	NM_000143.4(FH):c.1176_1181del (p.Ala393_Val394del)	Pathogenic
1060809	NM_000143.4(FH):c.1177G>C (p.Ala393Pro)	Pathogenic
1067347	NM_000143.4(FH):c.827G>A (p.Gly276Asp)	Pathogenic
1069140	NM_000143.4(FH):c.102del (p.Ser35fs)	Pathogenic
1070254	NM_000143.4(FH):c.735_736delinsTT (p.Gln246Ter)	Pathogenic
1070679	NM_000143.4(FH):c.109del (p.Trp37fs)	Pathogenic
1070792	NM_000143.4(FH):c.1280del (p.Ala426_Ser427insTer)	Pathogenic
1072328	NM_000143.4(FH):c.267+1G>T	Pathogenic
1072523	NM_000143.4(FH):c.102_120del (p.Ser35fs)	Pathogenic
1072934	NM_000143.4(FH):c.688A>C (p.Lys230Gln)	Pathogenic
1072957	NM_000143.3(FH):c.1392delG	Pathogenic
1073160	NM_000143.4(FH):c.1259_1262dup (p.Arg421fs)	Pathogenic
1073357	NM_000143.4(FH):c.936del (p.Phe312fs)	Pathogenic
1073831	NC_000001.10:g.(?241682881)(241683022_?)del	Pathogenic
1073832	NC_000001.10:g.(?241661128)(241661280_?)del	Pathogenic
1074128	NM_000143.4(FH):c.1457C>A (p.Ala486Asp)	Pathogenic
1074129	NM_000143.4(FH):c.950C>T (p.Ala317Val)	Pathogenic
1074197	NM_000143.4(FH):c.823G>T (p.Gly275Ter)	Pathogenic
1076097	NM_000143.4(FH):c.1457del (p.Ala486fs)	Pathogenic
1076451	NM_000143.4(FH):c.32_69del (p.Ser11fs)	Pathogenic
1076604	NM_000143.4(FH):c.734_735del (p.Gly245fs)	Pathogenic
1076641	NM_000143.4(FH):c.1499G>A (p.Trp500Ter)	Pathogenic
1298467	NM_000143.4(FH):c.634del (p.Gln212fs)	Pathogenic
1322912	NM_000143.4(FH):c.1237-2A>G	Pathogenic
1324397	NM_000143.4(FH):c.922G>A (p.Ala308Thr)	Pathogenic
1373577	NM_000143.4(FH):c.674_675del (p.Phe225fs)	Pathogenic
1384577	NM_000143.4(FH):c.822dup (p.Gly275fs)	Pathogenic
1387287	NM_000143.4(FH):c.887_888del (p.Lys296fs)	Pathogenic
1391292	NM_000143.4(FH):c.667A>T (p.Lys223Ter)	Pathogenic

SpliceAI

1746 predictions. Top by Δscore:

Variant	Effect	Δscore
1:241497969:CC:C	acceptor_gain	1.0000
1:241497970:CC:C	acceptor_gain	1.0000
1:241497971:C:T	acceptor_gain	1.0000
1:241500432:CTTA:C	donor_loss	1.0000
1:241500433:TTA:T	donor_loss	1.0000
1:241500435:A:AC	donor_gain	1.0000
1:241500435:ACCTA:A	donor_loss	1.0000
1:241500436:C:A	donor_loss	1.0000
1:241500436:C:CT	donor_gain	1.0000
1:241500436:CCT:C	donor_gain	1.0000
1:241500436:CCTA:C	donor_gain	1.0000
1:241500436:CCTAT:C	donor_gain	1.0000
1:241500589:ATC:A	acceptor_loss	1.0000
1:241500591:C:CC	acceptor_gain	1.0000
1:241500591:CTTTG:C	acceptor_loss	1.0000
1:241500592:T:C	acceptor_gain	1.0000
1:241500593:T:C	acceptor_gain	1.0000
1:241500593:T:TC	acceptor_gain	1.0000
1:241500597:G:C	acceptor_gain	1.0000
1:241500597:G:GC	acceptor_gain	1.0000
1:241500601:G:C	acceptor_gain	1.0000
1:241500601:G:GC	acceptor_gain	1.0000
1:241502436:AGCTT:A	donor_loss	1.0000
1:241502437:GCTTA:G	donor_loss	1.0000
1:241502438:CTTA:C	donor_loss	1.0000
1:241502439:TTACC:T	donor_loss	1.0000
1:241502440:TA:T	donor_loss	1.0000
1:241502441:A:AC	donor_gain	1.0000
1:241502442:C:CC	donor_gain	1.0000
1:241502442:CCAT:C	donor_gain	1.0000

AlphaMissense

3341 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:241502560:G:C	N373K	1.000
1:241502560:G:T	N373K	1.000
1:241504047:A:G	M368T	1.000
1:241504052:A:C	S366R	1.000
1:241504052:A:T	S366R	1.000
1:241504054:T:G	S366R	1.000
1:241504055:G:C	S365R	1.000
1:241504055:G:T	S365R	1.000
1:241504057:T:G	S365R	1.000
1:241508629:C:G	D238H	1.000
1:241508777:A:C	N188K	1.000
1:241508777:A:T	N188K	1.000
1:241508783:G:C	S186R	1.000
1:241508783:G:T	S186R	1.000
1:241508785:T:G	S186R	1.000
1:241512066:A:C	N152K	1.000
1:241512066:A:T	N152K	1.000
1:241512069:C:A	M151I	1.000
1:241512069:C:G	M151I	1.000
1:241512069:C:T	M151I	1.000
1:241512085:C:T	G146E	1.000
1:241512091:C:T	G144E	1.000
1:241512101:A:G	W141R	1.000
1:241512101:A:T	W141R	1.000
1:241517212:A:C	F79L	1.000
1:241517212:A:T	F79L	1.000
1:241517214:A:G	F79L	1.000
1:241517227:T:A	R74S	1.000
1:241517227:T:G	R74S	1.000
1:241517228:C:G	R74T	1.000

dbSNP variants (sampled 300 via entrez): RS1000205644 (1:241497295 T>C), RS1000382827 (1:241500212 C>T), RS1000426999 (1:241503916 T>G), RS1000435396 (1:241499934 T>C), RS1000589147 (1:241508394 T>C), RS1000655833 (1:241506801 A>C), RS1000657431 (1:241497401 T>C), RS1000697960 (1:241501781 G>T), RS1000857946 (1:241516676 C>A,T), RS1000918122 (1:241508802 A>C,G), RS1001118630 (1:241516455 A>G), RS1001147432 (1:241502828 A>C,G), RS1001334367 (1:241509486 A>G), RS1001387952 (1:241509142 A>G), RS1001643704 (1:241512880 G>C)

Disease associations

OMIM: gene MIM:136850 | disease phenotypes: MIM:606812, MIM:150800, MIM:167000, MIM:617769, MIM:150699, MIM:114550, MIM:115310

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary leiomyomatosis and renal cell cancer	Definitive	Autosomal dominant
fumaric aciduria	Definitive	Autosomal recessive
pheochromocytoma-paraganglioma	Strong	Autosomal dominant
leiomyosarcoma	Moderate	Autosomal dominant
hereditary pheochromocytoma-paraganglioma	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hereditary leiomyomatosis and renal cell cancer	Definitive	AD

Mondo (15): fumaric aciduria (MONDO:0011730), hereditary neoplastic syndrome (MONDO:0015356), hereditary leiomyomatosis and renal cell cancer (MONDO:0007888), ovarian cancer (MONDO:0008170), spinocerebellar ataxia 45 (MONDO:0033480), leiomyoma cutis (MONDO:0003291), uterine corpus leiomyoma (MONDO:0007886), hepatocellular carcinoma (MONDO:0007256), pheochromocytoma/paraganglioma syndrome 4 (MONDO:0007273), hepatoblastoma (MONDO:0018666), microcephaly (MONDO:0001149), breast cancer (MONDO:0007254), pheochromocytoma-paraganglioma (MONDO:0035540), leiomyosarcoma (MONDO:0005058), hereditary pheochromocytoma-paraganglioma (MONDO:0017366)

Orphanet (8): Inherited cancer-predisposing syndrome (Orphanet:140162), Fumaric aciduria (Orphanet:24), Hereditary leiomyomatosis and renal cell cancer (Orphanet:523), Rare ovarian cancer (Orphanet:213500), Spinocerebellar ataxia type 45 (Orphanet:589527), Hepatocellular carcinoma (Orphanet:88673), Hereditary pheochromocytoma-paraganglioma (Orphanet:29072), Hepatoblastoma (Orphanet:449)

HPO phenotypes

127 total (30 of 127 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000096	Glomerular sclerosis
HP:0000131	Uterine leiomyoma
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000316	Hypertelorism
HP:0000405	Conductive hearing impairment
HP:0000463	Anteverted nares
HP:0000505	Visual impairment
HP:0000518	Cataract
HP:0000526	Aniridia
HP:0000648	Optic atrophy
HP:0000740	Episodic paroxysmal anxiety
HP:0000790	Hematuria
HP:0000817	Reduced eye contact
HP:0000980	Pallor
HP:0000989	Pruritus
HP:0001069	Episodic hyperhidrosis
HP:0001095	Hypertensive retinopathy
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001273	Abnormal corpus callosum morphology
HP:0001274	Agenesis of corpus callosum
HP:0001290	Generalized hypotonia
HP:0001293	Cranial nerve compression

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003518_79	Daytime sleep phenotypes	4.000000e-06
GCST006041_42	Major depressive disorder	3.000000e-06
GCST009391_1703	Metabolite levels	2.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement
EFO:0010340	cholesteryl ester 14:0 measurement

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D006528	Carcinoma, Hepatocellular	C04.557.470.200.025.255; C04.588.274.623.160; C06.301.623.160; C06.552.697.160
D018197	Hepatoblastoma	C04.557.435.380
D007890	Leiomyosarcoma	C04.557.450.590.455; C04.557.450.795.455
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
C538191	Fumaric aciduria (supp.)
C535516	Hereditary leiomyomatosis and renal cell cancer (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066495 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

80 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
bisphenol A	decreases expression, increases expression	4
sodium arsenite	affects response to substance, affects expression, decreases expression, decreases reaction, affects reaction (+2 more)	4
bisphenol F	increases expression, affects cotreatment, decreases expression	3
trichostatin A	affects cotreatment, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
bisphenol S	increases expression	2
Cyclosporine	decreases expression	2
ML-265	decreases expression, decreases reaction	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
lasiocarpine	decreases expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases expression, decreases reaction	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	decreases expression	1
2,6-dichloro-4-nitrophenol	decreases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
cobaltous chloride	decreases expression	1
pinosylvin	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
macrosphelide A	affects binding, decreases activity	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
erastin	decreases response to substance	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
olaparib	increases response to substance	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651427	Binding	Binding affinity to human FH incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_1D72	UOK262	Cancer cell line	Female
CVCL_1D73	UOK268	Cancer cell line	Female
CVCL_E7RC	UOK271	Cancer cell line	Female
CVCL_E7RD	UOK348	Cancer cell line	Female
CVCL_E7RE	UOK350	Cancer cell line	Male
CVCL_RN43	UOK262-WT	Cancer cell line	Female

Clinical trials (associated diseases)

402 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00727961	PHASE4	COMPLETED	A Study to Evaluate Efficacy and Tolerance of Caelyx in Patients With Epithelial Ovarian Cancer. (Study P04072)(COMPLETED)
NCT00740116	PHASE4	COMPLETED	Tranexamic Acid in Surgery of Advanced Ovarian Cancer
NCT00817479	PHASE4	COMPLETED	Tumor Gene Expression in Women With Ovarian Cancer
NCT01432015	PHASE4	COMPLETED	Fosaprepitant Versus Aprepitant in the Prevention of Chemotherapy Induced Nausea and Vomiting
NCT01706120	PHASE4	UNKNOWN	Study of Clinical and Biological Prognostic Factors in Patients With Ovarian Cancer Receiving Carboplatin +Paclitaxel With Bevacizumab
NCT01932125	PHASE4	COMPLETED	An Interventional Study of Avastin (Bevacizumab) in Patients With Advanced/Metastatic Epithelial Ovarian Cancer, Fallopian Tube Cancer or Primary Peritoneal Cancer
NCT01953107	PHASE4	COMPLETED	Oral Iron vs. Placebo in Newly Diagnosed Gynecologic Oncology Patients Who Are Surgical Candidates.
NCT02035345	PHASE4	TERMINATED	Slowed Carboplatin Infusion for Ovarian Cancer Patients Receiving Carboplatin Re-Treatment
NCT02243059	PHASE4	WITHDRAWN	Magnetic Resonance Imaging for Lymph Node Staging in Ovarian Cancer
NCT03164980	PHASE4	TERMINATED	QoL-Comparison Between Trabectedin/PLD and Pt-based Therapy in Patients With Pt-sensitive Recurrent Ovarian Cancer
NCT03384511	PHASE4	COMPLETED	The Use of 18F-ALF-NOTA-PRGD2 PET/CT Scan to Predict the Efficacy and Adverse Events of Apatinib in Malignancies.
NCT03543462	PHASE4	COMPLETED	Diaphragmatic Resection And Gynecological Ovarian Neoplasm
NCT03752216	PHASE4	COMPLETED	NIraparib and Quality of LifE is a Longitudinal Study Evaluating in Real Life the Tolerability of Niraparib.
NCT03858166	PHASE4	TERMINATED	Efficacy and Safety of PEG-rhG-CSF Secondary Prophylaxis vs. Therapeutic Administration in Patients With Ovarian Cancer
NCT04024254	PHASE4	COMPLETED	A Study of Serum Folate Levels in Patients Treated With Olaparib
NCT04330040	PHASE4	COMPLETED	Prospective Multicentre Phase-IV Clinical Trial of Olaparib in Indian Patients With Ovarian and Metastatic Breast Cancer
NCT04352439	PHASE4	COMPLETED	Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving Neoadjuvant Chemotherapy
NCT05187208	PHASE4	UNKNOWN	PARP Inhibitor Oral Maintenance in Low-Risk Ovarian Cancer
NCT05606692	PHASE4	RECRUITING	Influences of Propofol and Sevoflurane Anesthesia in Ovarian Cancer (Anesthetics)
NCT05926336	PHASE4	RECRUITING	The Effects of Using Different Anesthetics on the Prognosis of Primary Tumors and Its Mechanism of Action
NCT06412120	PHASE4	RECRUITING	Study Evaluating Safety, Tolerability, and Metabolism of Niraparib
NCT06871787	PHASE4	NOT_YET_RECRUITING	Near-Infrared Fluorescence Imaging With Indocyanine Green to Evaluate Bowel Anastomoses in Gynecologic Oncology Surgery
NCT06887933	PHASE4	NOT_YET_RECRUITING	A Trial to Evaluate the Safety of Niraparib Tablets in Adult Female Participants With Advanced or Relapsed Epithelial Ovarian Cancer
NCT07469202	PHASE4	NOT_YET_RECRUITING	CYTALUX Dose Extension Study
NCT01343277	PHASE3	COMPLETED	A Study of Trabectedin or Dacarbazine for the Treatment of Patients With Advanced Liposarcoma or Leiomyosarcoma
NCT01692678	PHASE3	COMPLETED	A Study of Trabectedin (YONDELIS) in Patients With Locally Advanced or Metastatic Liposarcoma or Leiomyosarcoma
NCT03016819	PHASE3	RECRUITING	Phase III Trial of Anlotinib, Catequentinib in Advanced Alveolar Soft Part Sarcoma, Leiomyosarcoma, Synovial Sarcoma (APROMISS)
NCT03773510	PHASE3	WITHDRAWN	Study on Leiomyosarcoma, Liposarcomas and Synovial Sarcoma With Trabectedin
NCT04031677	PHASE3	RECRUITING	Surgery With or Without Neoadjuvant Chemotherapy in High Risk RetroPeritoneal Sarcoma
NCT06088290	PHASE3	ACTIVE_NOT_RECRUITING	Study of Lurbinectedin in Combination With Doxorubicin Versus Doxorubicin Alone as First-line Treatment in Participants With Metastatic Leiomyosarcoma (SaLuDo)
NCT00001806	PHASE3	COMPLETED	Methods in Education for Breast Cancer Genetics
NCT00002477	PHASE3	UNKNOWN	Adjuvant Chemotherapy Compared With Observation in Treating Patients With Resected Early Stage Ovarian Epithelial Cancer
NCT00002568	PHASE3	COMPLETED	Combination Chemotherapy With or Without Surgery in Treating Patients With Stage III Ovarian Epithelial Cancer
NCT00002641	PHASE3	COMPLETED	Surgery With or Without Chemotherapy in Treating Patients With Soft Tissue Sarcoma
NCT00002717	PHASE3	COMPLETED	Paclitaxel and Cisplatin in Treating Patients With Stage III or Stage IV Ovarian Cancer or Primary Peritoneal Cancer
NCT00002764	PHASE3	COMPLETED	Surgery With or Without Combination Chemotherapy in Treating Patients With Lung Metastases From Soft Tissue Sarcoma
NCT00002819	PHASE3	TERMINATED	Chemotherapy With or Without Peripheral Stem Cell Transplantation in Treating Patients With Persistent Ovarian Epithelial Cancer
NCT00002894	PHASE3	COMPLETED	Platinum-based Chemotherapy With or Without Paclitaxel in Treating Patients With Relapsed Ovarian Cancer