Malignant mesothelioma

Summary

Malignant mesothelioma (MONDO:0006292) is a disease (an umbrella term covering 11 Mondo subtypes) with 4 cohort genes and 126 clinical trials. Molecularly, BAP1 Mutation confers sensitivity to Olaparib in Malignant Mesothelioma (CIViC Level B); 6 further subtype–drug associations are mapped below. Top therapeutic interventions include doxorubicin hydrochloride, aldesleukin, and mitomycin.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Umbrella term: 11 Mondo subtypes
• Cohort genes: 4
• ClinVar variants: 136
• Phenotypes (HPO): 17
• Clinical trials: 126
• Precision-medicine evidence (CIViC): 7 subtype–drug associations

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.22	Worldwide	Validated
Point prevalence	1-9 / 100 000	3.1	Europe	Validated
Annual incidence	1-9 / 1 000 000	0.8	France	Validated
Annual incidence	1-9 / 100 000	1.9	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0002202	Pleural effusion	Very frequent (80-99%)
HP:0000765	Abnormal thorax morphology	Frequent (30-79%)
HP:0001824	Weight loss	Frequent (30-79%)
HP:0002094	Dyspnea	Frequent (30-79%)
HP:0002098	Respiratory distress	Frequent (30-79%)
HP:0002103	Abnormality of the pleura	Frequent (30-79%)
HP:0012735	Cough	Frequent (30-79%)
HP:0025142	Constitutional symptom	Frequent (30-79%)
HP:0100749	Chest pain	Frequent (30-79%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002088	Abnormal lung morphology	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002716	Lymphadenopathy	Occasional (5-29%)
HP:0002795	Abnormal respiratory system physiology	Occasional (5-29%)
HP:0007011	Fourth cranial nerve palsy	Occasional (5-29%)
HP:0011025	Abnormality of cardiovascular system physiology	Occasional (5-29%)
HP:0031041	Obstruction of the superior vena cava	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	malignant mesothelioma
Mondo ID	MONDO:0006292
EFO	EFO:1000355
MeSH	C562839
OMIM	156240
Orphanet	50251
DOID	DOID:1790
ICD-11	369414280
NCIT	C4456
SNOMED CT	109378008
UMLS	C0345967
MedGen	91062
GARD	0007026
MedDRA	10027406
Is cancer (heuristic)	no

Also known as: advanced malignant mesothelioma · asbestos-related malignant mesothelioma · diffuse malignant mesothelioma · malignant mesothelial neoplasm · malignant mesothelial tumor · malignant mesothelial tumour · malignant mesothelioma · malignant mesothelioma (disease) · malignant neoplasm of mesothelium · malignant neoplasm of the mesothelium · malignant tumor of mesothelium · malignant tumor of the mesothelium · malignant tumour of mesothelium · malignant tumour of the mesothelium · MESOM · mesothelioma, malignant · mesothelioma, somatic

Data availability: 136 ClinVar variants · 1 HPO phenotype.

Disease family

An umbrella term covering 11 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › cancer › malignant mesothelioma

Related subtypes (32): respiratory system cancer, immune system cancer, musculoskeletal system cancer, integumentary system cancer, peritoneum cancer, cardiovascular cancer, reproductive system cancer, malignant giant cell tumor, digestive system cancer, lipomatous cancer, thoracic cancer, malignant glomus tumor, malignant mesenchymoma, carcinoma, sarcoma, blastoma, head and neck cancer, malignant mixed neoplasm, nervous system cancer, retroperitoneal cancer, malignant germ cell tumor, malignant urinary system neoplasm, childhood malignant neoplasm, anaplastic cancer, malignant spindle cell neoplasm, high grade malignant neoplasm, malignant endocrine neoplasm, malignant soft tissue neoplasm, secondary malignant neoplasm, refractory malignant neoplasm, malignant adenoma, cancer of unknown primary site

Subtypes (11): ovarian malignant mesothelioma, malignant pericardial mesothelioma, malignant pleural mesothelioma, malignant peritoneal mesothelioma, malignant epithelioid mesothelioma, malignant biphasic mesothelioma, sarcomatoid mesothelioma, localized pleural mesothelioma, diffused pleural mesothelioma, pleural mesothelioma in situ, mesothelioma of the tunica vaginalis

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

136 retrieved; paginated sample, class counts are floors:

78 uncertain significance, 32 conflicting classifications of pathogenicity, 10 likely benign, 5 pathogenic, 4 benign/likely benign, 4 pathogenic/likely pathogenic, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2584482	NM_024426.6(WT1):c.1354+2T>C	WT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3487	NM_024426.6(WT1):c.1399C>T (p.Arg467Trp)	WT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3488	NM_024426.6(WT1):c.1316G>A (p.Arg439His)	WT1	Pathogenic	criteria provided, multiple submitters, no conflicts
3493	NM_024426.6(WT1):c.1447+5G>A	WT1	Pathogenic	criteria provided, multiple submitters, no conflicts
3494	NM_024426.6(WT1):c.1387C>T (p.Arg463Ter)	WT1	Pathogenic	criteria provided, multiple submitters, no conflicts
3497	NM_024426.6(WT1):c.1303C>T (p.Arg435Ter)	WT1	Pathogenic	criteria provided, multiple submitters, no conflicts
3500	NM_024426.6(WT1):c.1447+4C>T	WT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3599545	NM_024426.6(WT1):c.1397C>T (p.Ser466Phe)	WT1	Pathogenic	criteria provided, single submitter
419332	NM_024426.6(WT1):c.1400G>A (p.Arg467Gln)	WT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2505271	NM_024426.6(WT1):c.1498C>T (p.Arg500Trp)	WT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3599543	NM_024426.6(WT1):c.1498del (p.Arg500fs)	WT1	Likely pathogenic	criteria provided, single submitter
3599544	NM_024426.6(WT1):c.1433A>G (p.His478Arg)	WT1	Likely pathogenic	criteria provided, single submitter
1409524	NM_024426.6(WT1):c.459C>T (p.Gly153=)	LOC107982234	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1495132	NM_024426.6(WT1):c.661+15G>T	LOC107982234	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
241487	NM_024426.6(WT1):c.83G>A (p.Gly28Glu)	LOC107982234	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
406690	NM_024426.6(WT1):c.411GCC[5] (p.Pro141dup)	LOC107982234	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
476699	NM_024426.6(WT1):c.314C>G (p.Ala105Gly)	LOC107982234	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
543118	NM_024426.6(WT1):c.203G>A (p.Gly68Glu)	LOC107982234	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
652024	NM_024426.6(WT1):c.29C>T (p.Ala10Val)	LOC107982234	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
954239	NM_024426.6(WT1):c.351C>T (p.Gly117=)	LOC107982234	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1018611	NM_024426.6(WT1):c.996A>T (p.Lys332Asn)	WT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
135455	NM_024426.6(WT1):c.1154G>A (p.Arg385Gln)	WT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1426680	NM_024426.6(WT1):c.887+19C>G	WT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1568322	NM_024426.6(WT1):c.1448-13A>T	WT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1605396	NM_024426.6(WT1):c.837C>T (p.Thr279=)	WT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180586	NM_024426.6(WT1):c.764T>A (p.Met255Lys)	WT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
265295	NM_024426.6(WT1):c.151del (p.Ala51fs)	WT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2924093	NM_024426.6(WT1):c.513C>T (p.Gly171=)	WT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304419	NM_024426.6(WT1):c.1198T>C (p.Tyr400His)	WT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304429	NM_024426.6(WT1):c.162C>G (p.Ser54Arg)	WT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 20 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RNF2	Orphanet:528084	Non-specific syndromic intellectual disability
BRCA1	Orphanet:1331	Familial prostate cancer
BRCA1	Orphanet:1333	Familial pancreatic carcinoma
BRCA1	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
BRCA1	Orphanet:168829	Primary peritoneal carcinoma
BRCA1	Orphanet:227535	Hereditary breast cancer
BRCA1	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
BRCA1	Orphanet:694963	Inflammatory breast cancer
BRCA1	Orphanet:70567	Cholangiocarcinoma
BRCA1	Orphanet:84	Fanconi anemia
WT1	Orphanet:220	Denys-Drash syndrome
WT1	Orphanet:242	46,XY complete gonadal dysgenesis
WT1	Orphanet:251510	46,XY partial gonadal dysgenesis
WT1	Orphanet:3097	Meacham syndrome
WT1	Orphanet:347	Frasier syndrome
WT1	Orphanet:654	Nephroblastoma
WT1	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
WT1	Orphanet:83469	Desmoplastic small round cell tumor
WT1	Orphanet:893	WAGR syndrome
BCL10	Orphanet:52417	MALT lymphoma

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
civic_only	2
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RNF2	HGNC:10061	ENSG00000121481	Q99496	E3 ubiquitin-protein ligase RING2	civic_evidence
BRCA1	HGNC:1100	ENSG00000012048	P38398	Breast cancer type 1 susceptibility protein	civic_evidence
WT1	HGNC:12796	ENSG00000184937	P19544	Wilms tumor protein	clinvar
BCL10	HGNC:989	ENSG00000142867	O95999	B-cell lymphoma/leukemia 10	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RNF2	E3 ubiquitin-protein ligase RING2	E3 ubiquitin-protein ligase that mediates monoubiquitination of ‘Lys-119’ of histone H2A (H2AK119Ub), thereby playing a central role in histone code and gene regulation.
BRCA1	Breast cancer type 1 susceptibility protein	E3 ubiquitin-protein ligase that specifically mediates the formation of ‘Lys-6’-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage.
WT1	Wilms tumor protein	Transcription factor that plays an important role in cellular development and cell survival.
BCL10	B-cell lymphoma/leukemia 10	Plays a key role in both adaptive and innate immune signaling by bridging CARD domain-containing proteins to immune activation.

Protein-family classification

Druggable: 0 · Difficult: 3 · Unknown: 1 · 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	3	6.2×	0.013
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNF2	Transcription factor	no	2.3.2.27	Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS
BRCA1	Transcription factor	no	2.3.2.27	BRCT_dom, Znf_RING, BRCA1
WT1	Transcription factor	no		Wilms_tumour_N, Znf_C2H2_type, Znf_C2H2_sf
BCL10	Other/Unknown	no		CARD, DEATH-like_dom_sf, BCL10/E10

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
primordial germ cell in gonad	2
cortical plate	1
ganglionic eminence	1
male germ line stem cell (sensu Vertebrata) in testis	1
ventricular zone	1
germinal epithelium of ovary	1
metanephric glomerulus	1
renal glomerulus	1
esophagus squamous epithelium	1
mucosa of sigmoid colon	1
squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNF2	178	ubiquitous	marker	primordial germ cell in gonad, cortical plate, ganglionic eminence
BRCA1	208	ubiquitous	marker	ventricular zone, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
WT1	168	broad	marker	germinal epithelium of ovary, renal glomerulus, metanephric glomerulus
BCL10	280	ubiquitous	marker	esophagus squamous epithelium, mucosa of sigmoid colon, squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BRCA1	9,064
WT1	3,938
RNF2	3,814
BCL10	1,873

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BRCA1	P38398	33
WT1	P19544	28
RNF2	Q99496	15
BCL10	O95999	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 84. 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
Transcriptional Regulation by E2F6	2	146.4×	0.006	RNF2, BRCA1
SUMOylation of DNA damage response and repair proteins	2	73.2×	0.012	RNF2, BRCA1
Defective DNA double strand break response due to BRCA1 loss of function	1	1427.5×	0.015	BRCA1
Defective DNA double strand break response due to BARD1 loss of function	1	1427.5×	0.015	BRCA1
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	407.9×	0.036	BRCA1
Defective homologous recombination repair (HRR) due to PALB2 loss of function	1	237.9×	0.036	BRCA1
Nephron development	1	219.6×	0.036	WT1
Downstream signaling events of B Cell Receptor (BCR)	1	203.9×	0.036	BCL10
Protein ubiquitination	1	203.9×	0.036	BCL10
Diseases of DNA Double-Strand Break Repair	1	203.9×	0.036	BRCA1
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1	203.9×	0.036	BRCA1
Transcriptional regulation of testis differentiation	1	178.4×	0.036	WT1
SUMOylation of DNA methylation proteins	1	167.9×	0.036	RNF2
Resolution of D-Loop Structures	1	158.6×	0.036	BRCA1
Diseases of DNA repair	1	142.8×	0.036	BRCA1
TCR signaling	1	124.1×	0.036	BCL10
DNA Double Strand Break Response	1	119.0×	0.036	BRCA1
Impaired BRCA2 binding to PALB2	1	114.2×	0.036	BRCA1
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	105.7×	0.036	BRCA1
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	105.7×	0.036	BRCA1
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	105.7×	0.036	BRCA1
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	98.5×	0.036	BRCA1
Homologous DNA Pairing and Strand Exchange	1	95.2×	0.036	BRCA1
Signaling by the B Cell Receptor (BCR)	1	86.5×	0.036	BCL10
Homology Directed Repair	1	77.2×	0.036	BRCA1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	77.2×	0.036	BRCA1
Impaired BRCA2 binding to RAD51	1	77.2×	0.036	BRCA1
Metalloprotease DUBs	1	75.1×	0.036	BRCA1
Resolution of D-loop Structures through Holliday Junction Intermediates	1	75.1×	0.036	BRCA1
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	1	75.1×	0.036	RNF2

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 gene expression via chromosomal CpG island methylation	2	526.6×	6e-04	BRCA1, WT1
germ cell development	2	227.7×	0.002	RNF2, WT1
negative regulation of metanephric glomerular mesangial cell proliferation	1	4213.0×	0.006	WT1
regulation of animal organ formation	1	2106.5×	0.006	WT1
adrenal cortex formation	1	2106.5×	0.006	WT1
visceral serous pericardium development	1	2106.5×	0.006	WT1
posterior mesonephric tubule development	1	2106.5×	0.006	WT1
positive regulation of metanephric ureteric bud development	1	2106.5×	0.006	WT1
negative regulation of cell growth	2	72.0×	0.006	BRCA1, WT1
positive regulation of DNA-templated transcription	3	21.0×	0.006	BRCA1, WT1, BCL10
positive regulation of lymphotoxin A production	1	1404.3×	0.007	BCL10
negative regulation of mature B cell apoptotic process	1	1053.2×	0.007	BCL10
positive regulation of heart growth	1	1053.2×	0.007	WT1
metanephric S-shaped body morphogenesis	1	1053.2×	0.007	WT1
negative regulation of female gonad development	1	1053.2×	0.007	WT1
thorax and anterior abdomen determination	1	842.6×	0.007	WT1
positive regulation of mast cell cytokine production	1	842.6×	0.007	BCL10
cardiac muscle cell fate commitment	1	842.6×	0.007	WT1
cellular response to indole-3-methanol	1	842.6×	0.007	BRCA1
metanephric epithelium development	1	842.6×	0.007	WT1
chromatin remodeling	2	36.5×	0.007	RNF2, BRCA1
chordate embryonic development	1	702.2×	0.008	BRCA1
cellular response to gonadotropin stimulus	1	702.2×	0.008	WT1
negative regulation of centriole replication	1	601.9×	0.008	BRCA1
metanephric mesenchyme development	1	601.9×	0.008	WT1
positive regulation of apoptotic process	2	28.4×	0.009	WT1, BCL10
DNA strand resection involved in replication fork processing	1	526.6×	0.009	BRCA1
tissue development	1	468.1×	0.009	WT1
diaphragm development	1	468.1×	0.009	WT1
DNA damage tolerance	1	421.3×	0.009	BRCA1

Therapeutics

Drugs indicated for this disease

1 approved. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Ipilimumab	Approved (phase 4)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Brentuximab Vedotin, Carboplatin, Cisplatin, Nivolumab, Pemetrexed, Ramucirumab.

Drug target analysis

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

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
BRCA1	RIBOFLAVIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BRCA1	12	4
RNF2	0	0
WT1	0	0
BCL10	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
RIBOFLAVIN	4	BRCA1
DAUNORUBICIN HYDROCHLORIDE	4	BRCA1
TOPOTECAN HYDROCHLORIDE	4	BRCA1
DAUNORUBICIN	4	BRCA1
DOXORUBICIN HYDROCHLORIDE	4	BRCA1
MESALAMINE	4	BRCA1
DIPYRIDAMOLE	4	BRCA1
CURCUMIN	3	BRCA1
SURAMIN	3	BRCA1
SURAMIN HEXASODIUM	3	BRCA1
SODIUM TANSHINONE IIA SULFONATE	2	BRCA1
HOMIDIUM BROMIDE	2	BRCA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
RNF2	16	Binding:16
BRCA1	13	Binding:9, Functional:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RNF2	2.3.2.27	RING-type E3 ubiquitin transferase
BRCA1	2.3.2.27	RING-type E3 ubiquitin transferase

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

11 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)
RIBOFLAVIN	4	BRCA1
DAUNORUBICIN HYDROCHLORIDE	4	BRCA1
TOPOTECAN HYDROCHLORIDE	4	BRCA1
DAUNORUBICIN	4	BRCA1
MESALAMINE	4	BRCA1
DIPYRIDAMOLE	4	BRCA1
CURCUMIN	3	BRCA1
SURAMIN	3	BRCA1
SURAMIN HEXASODIUM	3	BRCA1
SODIUM TANSHINONE IIA SULFONATE	2	BRCA1
HOMIDIUM BROMIDE	2	BRCA1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	BRCA1
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	RNF2, WT1, BCL10

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)
RNF2	16	—
WT1	0	—
BCL10	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 126.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	55
PHASE1	29
Not specified	22
PHASE1/PHASE2	12
PHASE3	7
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00003034	PHASE3	UNKNOWN	ONCONASE Plus Doxorubicin Versus Doxorubicin Alone For Patients With Malignant Pleural or Peritoneal Mesothelioma Who Have Had No More Than One Prior Chemotherapy Regimen
NCT00004920	PHASE3	COMPLETED	Cisplatin With or Without Raltitrexed in Treating Patients With Malignant Mesothelioma of the Pleura
NCT00005636	PHASE3	COMPLETED	Cisplatin With or Without Pemetrexed Disodium in Treating Patients With Malignant Mesothelioma of the Pleura That Cannot be Removed by Surgery
NCT00006231	PHASE3	COMPLETED	Radiation Therapy in Preventing Metastatic Cancer in Patients Who Have Diagnostic Procedures to Identify Malignant Mesothelioma
NCT00075699	PHASE3	COMPLETED	Active Symptom Control With or Without Chemotherapy in Treating Patients With Malignant Pleural Mesothelioma
NCT00821860	PHASE3	COMPLETED	Video-Assisted Surgery or Talc Pleurodesis in Treating Patients With Malignant Mesothelioma
NCT02349412	PHASE3	COMPLETED	Early Palliative Care With Standard Care or Standard Care Alone in Improving Quality of Life of Patients With Incurable Lung or Non-colorectal Gastrointestinal Cancer and Their Family Caregivers
NCT01064648	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Pemetrexed Disodium and Cisplatin With or Without Cediranib Maleate in Treating Patients With Malignant Pleural Mesothelioma
NCT03007030	PHASE2	RECRUITING	Brentuximab Vedotin in Treating Patients With CD30+ Malignant Mesothelioma That Cannot Be Removed by Surgery
NCT03907852	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Phase 1/2 Trial of Gavo-cel (TC-210) in Patients With Advanced Mesothelin-Expressing Cancer
NCT04104776	PHASE1/PHASE2	RECRUITING	A Study of Tulmimetostat DZR123 (CPI-0209) in Patients With Advanced Solid Tumors and Lymphomas
NCT05188859	PHASE2	RECRUITING	First Line Sintilimab Combined With Anlotinib and Platinum Doublet Chemotherapy in Malignant Pleural Mesothelioma
NCT05451849	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Phase 1/2 Trial of TC-510 In Patients With Advanced Mesothelin-Expressing Cancer
NCT05944237	PHASE1/PHASE2	RECRUITING	HTL0039732 in Participants With Advanced Solid Tumours
NCT06051695	PHASE1/PHASE2	RECRUITING	A Study to Evaluate the Safety and Efficacy of Mesothelin-Targeting Logic-gated CAR T, in Participants With Solid Tumors That Express MSLN and Have Lost HLA-A*02 Expression
NCT06057935	PHASE2	RECRUITING	A Study of Additional Chemotherapy After Surgery for People With Malignant Peritoneal Mesothelioma
NCT07131345	PHASE1/PHASE2	NOT_YET_RECRUITING	Study of Iparomlimab and Tuvonralimab Plus Chemotherapy in Malignant Mesothelioma
NCT07282873	PHASE1/PHASE2	NOT_YET_RECRUITING	Study of TYK-01054 Capsules in Patients With Advanced Solid Tumors
NCT00002465	PHASE1/PHASE2	UNKNOWN	High-Dose Megestrol in Treating Patients With Metastatic Breast Cancer, Endometrial Cancer, or Mesothelioma
NCT00002475	PHASE2	COMPLETED	Cyclophosphamide Plus Vaccine Therapy in Treating Patients With Advanced Cancer
NCT00002608	PHASE2	COMPLETED	Combination Chemotherapy and Tamoxifen in Treating Patients With Solid Tumors
NCT00003508	PHASE2	TERMINATED	Antineoplaston Therapy in Treating Patients With Advanced Mesothelioma
NCT00003723	PHASE2	COMPLETED	S9810: Gemcitabine Plus Cisplatin in Treating Patients With Malignant Mesothelioma of the Pleura That Cannot Be Removed by Surgery
NCT00004033	PHASE2	COMPLETED	Liposomal-Cisplatin Analogue (L-NDDP) in Treating Patients With Malignant Pleural Mesothelioma
NCT00004183	PHASE2	COMPLETED	Capecitabine in Treating Patients With Malignant Mesothelioma
NCT00004254	PHASE2	COMPLETED	Raltitrexed in Treating Patients With Malignant Mesothelioma That Cannot Be Surgically Removed
NCT00006014	PHASE2	COMPLETED	SU5416 in Treating Patients With Malignant Mesothelioma
NCT00017186	PHASE2	COMPLETED	Gemcitabine and Epirubicin in Treating Patients With Malignant Mesothelioma
NCT00024076	PHASE2	COMPLETED	Radiofrequency Ablation in Treating Patients With Refractory or Advanced Lung Cancer
NCT00024271	PHASE2	UNKNOWN	Surgery, Chemotherapy, and Radiation Therapy in Treating Patients With Peritoneal Cancer
NCT00025207	PHASE2	COMPLETED	Gefitinib in Treating Patients With Malignant Mesothelioma
NCT00027508	PHASE2	TERMINATED	Ecteinascidin 743 in Treating Patients With Malignant Mesothelioma
NCT00027703	PHASE2	COMPLETED	Combination Chemotherapy With or Without Bevacizumab in Treating Patients With Malignant Mesothelioma
NCT00030459	PHASE2	UNKNOWN	Palliative Therapy With or Without Chemotherapy in Treating Patients With Malignant Mesothelioma
NCT00030745	PHASE2	COMPLETED	Combination Chemotherapy Before Surgery in Treating Patients With Mesothelioma of the Lung
NCT00039182	PHASE2	COMPLETED	Erlotinib in Treating Patients With Malignant Mesothelioma of the Lung
NCT00053885	PHASE2	COMPLETED	PTK787/ZK 222584 in Treating Patients With Unresectable Malignant Mesothelioma
NCT00054002	PHASE2	COMPLETED	Surgery and Photodynamic Therapy in Treating Patients With Malignant Mesothelioma
NCT00062283	PHASE2	COMPLETED	Alanosine in Treating Patients With Cancer
NCT00107432	PHASE2	COMPLETED	Sorafenib Tosylate in Treating Patients With Malignant Mesothelioma.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DOXORUBICIN HYDROCHLORIDE	4	5
ALDESLEUKIN	4	3
MITOMYCIN	4	3
PORFIMER SODIUM	4	3
TALC ANHYDROUS	4	3
VINORELBINE TARTRATE	4	3
DASATINIB ANHYDROUS	4	2
RALTITREXED	4	2
TREMELIMUMAB	4	2
ABEMACICLIB	4	1
AVELUMAB	4	1
BELINOSTAT	4	1
BRENTUXIMAB VEDOTIN	4	1
CEDAZURIDINE	4	1
CYANOCOBALAMIN	4	1
DOSTARLIMAB	4	1
EPIRUBICIN HYDROCHLORIDE	4	1
ERLOTINIB HYDROCHLORIDE	4	1
EVEROLIMUS	4	1
GANCICLOVIR	4	1
GEFITINIB	4	1
MEGESTROL ACETATE	4	1
NIRAPARIB	4	1
PAZOPANIB HYDROCHLORIDE	4	1
PEMETREXED DISODIUM	4	1
RAMUCIRUMAB	4	1
RUCAPARIB	4	1
SARGRAMOSTIM	4	1
SODIUM THIOSULFATE	4	1
SORAFENIB TOSYLATE	4	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 7 predictive associations from 8 curated evidence items.

Molecular subtype	Therapy	Effect	Level	CIViC
BAP1 Mutation	Olaparib	Sensitivity/Response	CIViC B	EID11740 +1
BAP1 Mutation OR NF2 Mutation OR SETD2 Mutation	Samotolisib	Sensitivity/Response	CIViC B	EID11742
BRCA1 Loss-of-function OR BAP1 Loss-of-function	Rucaparib	Sensitivity/Response	CIViC B	EID11739
TMB Low	Nivolumab	Sensitivity/Response	CIViC B	EID12918
BAP1 ALTERNATIVE TRANSCRIPT (ATI)	Olaparib + Apitolisib	Sensitivity/Response	CIViC D	EID5929
BRCA1 Expression	Vinorelbine	Sensitivity/Response	CIViC D	EID933
BAP1 Loss	Mocetinostat + Vorinostat	Sensitivity/Response	CIViC E	EID1235