Osteosarcoma

Summary

Osteosarcoma (MONDO:0009807) is a disease (an umbrella term covering 6 Mondo subtypes) caused by variants in RECQL4 and SQSTM1, with 15 cohort genes (15 GWAS associations across 2 studies) and 328 clinical trials. Molecularly, ERCC2 K751Q is associated with resistance to Cisplatin in Osteosarcoma (CIViC Level B); 4 further subtype–drug associations are mapped below. Top therapeutic interventions include mifamurtide acid, cabozantinib, and dexrazoxane.

At a glance

• Causal genes: RECQL4 (GenCC Strong), SQSTM1 (GenCC Strong)
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 15
• GWAS associations: 15
• Clinical trials: 328
• Precision-medicine evidence (CIViC): 5 subtype–drug associations

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	osteosarcoma
Mondo ID	MONDO:0009807
EFO	EFO:0000637
MeSH	D012516
DOID	DOID:3347
NCIT	C9145
UMLS	C0029463
MedGen	10501
Is cancer (heuristic)	no

Also known as: bone tissue neoplasm · osteogenic sarcoma · osteoid sarcoma · osteosarcoma · osteosarcoma (disease) · osteosarcoma, malignant · sarcoma of osteoid

Data availability: 15 GWAS associations (2 studies) · 5 GenCC gene-disease records · 1 HPO phenotype · 803 cell lines · 14 intOGen driver records.

Disease family

An umbrella term covering 6 Mondo subtypes.

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

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

Subtypes (6): localized osteosarcoma, extraosseous osteosarcoma, multifocal osteogenic sarcoma, pediatric osteosarcoma, bone osteosarcoma, low grade central osteosarcoma

Genetics & variants

GWAS landscape

15 GWAS associations across 2 studies. Top hits map to 12 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs1906953	8e-09	GRM4	A	1.57
rs7591996	1e-08	SILC1 - LINC01247	C	1.39
rs55933544	5e-08	GLDC	T	1.89
rs17206779	5e-07	ADAMTS6	G	1.33
rs2086452	1e-06	ADAMTS17	C	1.35
rs12146774	1e-06	HSPB8 - LINC00934	T	1.97
rs17248137	2e-06	BTC - HSPE1P23	G	2.14
rs6797464	3e-06	MECOM	A	1.8
rs6986444	3e-06	SNTB1	T	1.87
rs17465450	4e-06	LRMDA	C	2.06
rs7777171	4e-06	AGMO	T	1.55
rs4955138	6e-06	RPSAP11 - CMTM8	G	1.65
rs9332377	7e-06	COMT	T	1.78
rs2797501	8e-06	TASOR2	A	1.61
rs573666	9e-06	DLEU7, DLEU1	G	1.3

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST002056	Savage SA	2013	694	2,703	Genome-wide association study identifies two susceptibility loci for osteosarcoma.
GCST005158	Koster R	2017	0	0	Genome-wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patients.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	2
Tier 3: regulatory	0
Tier 4: intronic/intergenic	12

MAF distribution

Bucket	Variants
common (>=0.05)	15
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	10
intergenic_variant	2
splice_region_variant	1
3_prime_UTR_variant	1
missense_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs1906953	6	34068669	C>T	0.05	intron_variant	GRM4	8e-09	Tier 4: intronic/intergenic
rs7591996	2	6321289	A>C,G,T	0.05	intron_variant	SILC1 - LINC01247	1e-08	Tier 4: intronic/intergenic
rs55933544	9	6534080	C>A,T	0.231	intron_variant	GLDC	5e-08	Tier 4: intronic/intergenic
rs17206779	5	65151950	C>A,G,T	0.05	splice_region_variant	ADAMTS6	5e-07	Tier 2: splice/UTR
rs2086452	15	100188458	G>A,C	0.05	intron_variant	ADAMTS17	1e-06	Tier 4: intronic/intergenic
rs12146774	12	119235698	C>T	0.05	intron_variant	HSPB8 - LINC00934	1e-06	Tier 4: intronic/intergenic
rs17248137	4	74883331	A>G	0.05	intron_variant	BTC - HSPE1P23	2e-06	Tier 4: intronic/intergenic
rs6797464	3	169495771	A>C,G	0.05	intron_variant	MECOM	3e-06	Tier 4: intronic/intergenic
rs6986444	8	120613854	T>A,C,G	0.05	intron_variant	SNTB1	3e-06	Tier 4: intronic/intergenic
rs17465450	10	76428114	A>C	0.05	intron_variant	LRMDA	4e-06	Tier 4: intronic/intergenic
rs7777171	7	15201812	C>A,T	0.05	intron_variant	AGMO	4e-06	Tier 4: intronic/intergenic
rs4955138	3	32207470	G>A,T	0.05	intergenic_variant	RPSAP11 - CMTM8	6e-06	Tier 4: intronic/intergenic
rs9332377	22	19968169	C>A,T	0.05	3_prime_UTR_variant	COMT	7e-06	Tier 2: splice/UTR
rs2797501	10	5762568	G>A,C	0.05	missense_variant	TASOR2	8e-06	Tier 1: coding
rs573666	13	50620269	C>A,G,T	0.05	intergenic_variant	DLEU7, DLEU1	9e-06	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 59 · Orphanet: 52 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RECQL4	Strong	Autosomal recessive	osteosarcoma	15
SQSTM1	Strong	Autosomal dominant	osteosarcoma	13
BLM	Moderate	Autosomal recessive	osteosarcoma	12
WRN	Moderate	Autosomal recessive	osteosarcoma	7
TNFRSF11A	Limited	Autosomal dominant	osteosarcoma	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BLM	Orphanet:125	Bloom syndrome
SQSTM1	Orphanet:275864	Behavioral variant of frontotemporal dementia
SQSTM1	Orphanet:275872	Frontotemporal dementia with motor neuron disease
SQSTM1	Orphanet:603	Distal myopathy, Welander type
SQSTM1	Orphanet:803	Amyotrophic lateral sclerosis
TNFRSF11A	Orphanet:1782	Dysosteosclerosis
TNFRSF11A	Orphanet:178389	Osteopetrosis-hypogammaglobulinemia syndrome
TNFRSF11A	Orphanet:2801	Juvenile Paget disease
TNFRSF11A	Orphanet:391490	Adult-onset myasthenia gravis
TNFRSF11A	Orphanet:85195	Familial expansile osteolysis
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
WRN	Orphanet:902	Werner syndrome
ERCC2	Orphanet:1466	COFS syndrome
ERCC2	Orphanet:220295	Xeroderma pigmentosum-Cockayne syndrome complex
ERCC2	Orphanet:33364	Trichothiodystrophy
ERCC2	Orphanet:910	Xeroderma pigmentosum
ATRX	Orphanet:100075	Neuroendocrine tumor of stomach
ATRX	Orphanet:231401	Alpha-thalassemia-myelodysplastic syndrome
ATRX	Orphanet:847	X-linked alpha-thalassemia-intellectual disability syndrome
ATRX	Orphanet:96253	Cushing disease
RB1	Orphanet:1587	Monosomy 13q14 syndrome
RB1	Orphanet:357027	Hereditary retinoblastoma
RB1	Orphanet:357034	Non-hereditary retinoblastoma
RB1	Orphanet:668	Osteosarcoma
RB1	Orphanet:70573	Small cell lung cancer
RECQL4	Orphanet:1225	Baller-Gerold syndrome
RECQL4	Orphanet:221016	Rothmund-Thomson syndrome type 2
RECQL4	Orphanet:3021	RAPADILINO syndrome
ADAMTS17	Orphanet:3449	Weill-Marchesani syndrome
ADAMTS17	Orphanet:363992	Ichthyosis-short stature-brachydactyly-microspherophakia syndrome
GLDC	Orphanet:289857	Neonatal glycine encephalopathy

Cohort genes → proteins

15 cohort genes, 15 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	6
civic_only	4
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BLM	HGNC:1058	ENSG00000197299	P54132	RecQ-like DNA helicase BLM	gencc
SQSTM1	HGNC:11280	ENSG00000161011	Q13501	Sequestosome-1	gencc
TNFRSF11A	HGNC:11908	ENSG00000141655	Q9Y6Q6	Tumor necrosis factor receptor superfamily member 11A	gencc
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	civic_evidence
WRN	HGNC:12791	ENSG00000165392	Q14191	Bifunctional 3’-5’ exonuclease/ATP-dependent helicase WRN	gencc
ERCC2	HGNC:3434	ENSG00000104884	P18074	General transcription and DNA repair factor IIH helicase subunit XPD	civic_evidence
ATRX	HGNC:886	ENSG00000085224	P46100	Transcriptional regulator ATRX	civic_evidence
RB1	HGNC:9884	ENSG00000139687	P06400	Retinoblastoma-associated protein	civic_evidence
RECQL4	HGNC:9949	ENSG00000160957	O94761	ATP-dependent DNA helicase Q4	gencc
ADAMTS17	HGNC:17109	ENSG00000140470	Q8TE56	A disintegrin and metalloproteinase with thrombospondin motifs 17	gwas
ADAMTS6	HGNC:222	ENSG00000049192	Q9UKP5	A disintegrin and metalloproteinase with thrombospondin motifs 6	gwas
TASOR2	HGNC:23484	ENSG00000108021	Q5VWN6	Protein TASOR 2	gwas
GDI2	HGNC:4227	ENSG00000057608	P50395	Rab GDP dissociation inhibitor beta	gwas
GLDC	HGNC:4313	ENSG00000178445	P23378	Glycine dehydrogenase (decarboxylating), mitochondrial	gwas
GRM4	HGNC:4596	ENSG00000124493	Q14833	Metabotropic glutamate receptor 4	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BLM	RecQ-like DNA helicase BLM	ATP-dependent DNA helicase that unwinds double-stranded (ds)DNA in a 3’-5’ direction.
SQSTM1	Sequestosome-1	Molecular adapter required for selective macroautophagy (aggrephagy) by acting as a bridge between polyubiquitinated proteins and autophagosomes.
TNFRSF11A	Tumor necrosis factor receptor superfamily member 11A	Receptor for TNFSF11/RANKL/TRANCE/OPGL; essential for RANKL-mediated osteoclastogenesis.
TP53	Cellular tumor antigen p53	Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence.
WRN	Bifunctional 3’-5’ exonuclease/ATP-dependent helicase WRN	Multifunctional enzyme that has magnesium and ATP-dependent 3’-5’ DNA-helicase activity on partially duplex substrates.
ERCC2	General transcription and DNA repair factor IIH helicase subunit XPD	ATP-dependent 5’-3’ DNA helicase.
ATRX	Transcriptional regulator ATRX	Involved in transcriptional regulation and chromatin remodeling.
RB1	Retinoblastoma-associated protein	Tumor suppressor that is a key regulator of the G1/S transition of the cell cycle.
RECQL4	ATP-dependent DNA helicase Q4	An ATP-dependent DNA helicase which unwinds dsDNA with a 3’-overhang in a 3’-5’ direction.
TASOR2	Protein TASOR 2	Core component of the HUSH2 complex, a multiprotein complex that mediates epigenetic repression of interferon-stimulated genes.
GDI2	Rab GDP dissociation inhibitor beta	GDP-dissociation inhibitor preventing the GDP to GTP exchange of most Rab proteins.
GLDC	Glycine dehydrogenase (decarboxylating), mitochondrial	The glycine cleavage system catalyzes the degradation of glycine.
GRM4	Metabotropic glutamate receptor 4	G-protein coupled receptor for glutamate.

Protein-family classification

Druggable: 8 · Difficult: 3 · Unknown: 4 · Druggable fraction: 0.53

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)	5	4.0×	0.030
Protease	2	4.9×	0.155
Transcription factor	3	1.6×	0.450
GPCR	1	1.6×	0.591
Other/Unknown	4	0.5×	0.995

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BLM	Enzyme (other)	yes	3.6.4.12	Helicase_C-like, HRDC_dom, DNA/RNA_helicase_DEAH_CS
SQSTM1	Transcription factor	no		PB1_dom, Znf_ZZ, UBA-like_sf
TNFRSF11A	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_11, TNFR_11A
TP53	Transcription factor	no		p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn
WRN	Enzyme (other)	yes	3.6.4.12	Helicase_C-like, HRDC_dom, 3’-5’_exonuclease_dom
ERCC2	Enzyme (other)	yes	3.6.4.12	RAD3/XPD, DNA/RNA_helicase_DEAH_CS, Helicase-like_DEXD_c2
ATRX	Transcription factor	no		SNF2_N, Helicase_C-like, Znf_FYVE_PHD
RB1	Other/Unknown	no		RB_B, RB_A, Cyclin-like_dom
RECQL4	Enzyme (other)	yes	3.6.4.12	Helicase_C-like, DNA_helicase_ATP-dep_RecQ, DEAD/DEAH_box_helicase_dom
ADAMTS17	Protease	yes		TSP1_rpt, Peptidase_M12B, Peptidase_M12B_N
ADAMTS6	Protease	yes		TSP1_rpt, Peptidase_M12B, Peptidase_M12B_N
TASOR2	Other/Unknown	no		GARIL-like_Rab2B-bd, TASOR_DUF3715, TASOR
GDI2	Other/Unknown	no		RabGDI, GDP_dissociation_inhibitor, FAD/NAD-bd_sf
GLDC	Enzyme (other)	yes	1.4.1.27	ArAA_b-elim_lyase/Thr_aldolase, GcvP, PyrdxlP-dep_Trfase_major
GRM4	GPCR	yes		GPCR_3_mtglu_rcpt, GPCR_3, GPCR_3_mGluR4

Expression context

Cohort genes with no expression data: 0.

14 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)	15
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	3
parotid gland	2
primordial germ cell in gonad	2
secondary oocyte	2
left adrenal gland	2
right adrenal gland	2
jejunal mucosa	2
mucosa of sigmoid colon	2
ventricular zone	2
right lobe of liver	2
right adrenal gland cortex	1
ganglionic eminence	1
tendon of biceps brachii	1
male germ cell	1
sperm	1
stromal cell of endometrium	1
colonic epithelium	1
endothelial cell	1
choroid plexus epithelium	1
epithelium of nasopharynx	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BLM	199	ubiquitous	marker	parotid gland, primordial germ cell in gonad, secondary oocyte
SQSTM1	241	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland
TNFRSF11A	221	broad	marker	parotid gland, mucosa of sigmoid colon, jejunal mucosa
TP53	223	ubiquitous	marker	ventricular zone, ganglionic eminence, tendon of biceps brachii
WRN	252	ubiquitous	marker	calcaneal tendon, sperm, male germ cell
ERCC2	184	ubiquitous	marker	stromal cell of endometrium, right adrenal gland, left adrenal gland
ATRX	294	ubiquitous	marker	endothelial cell, calcaneal tendon, colonic epithelium
RB1	287	ubiquitous	marker	epithelium of nasopharynx, choroid plexus epithelium, visceral pleura
RECQL4	212	ubiquitous	yes	lower esophagus mucosa, ventricular zone, mucosa of transverse colon
ADAMTS17	177	broad	marker	thymus, primordial germ cell in gonad, right lobe of liver
ADAMTS6	185	ubiquitous	marker	tibia, calcaneal tendon, mucosa of stomach
TASOR2	283	ubiquitous	marker	secondary oocyte, oocyte, sural nerve
GDI2	295	ubiquitous	marker	jejunal mucosa, ileal mucosa, mucosa of sigmoid colon
GLDC	216	broad	marker	right lobe of liver, liver, nephron tubule
GRM4	145	broad	marker	paraflocculus, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP53	22,736
SQSTM1	7,269
RECQL4	6,330
ATRX	5,796
RB1	4,374
WRN	3,258
BLM	3,010
GDI2	2,933
ERCC2	2,746
GLDC	2,559

Intra-cohort edges

A	B	Sources
ATRX	TP53	string_interaction
RB1	TP53	string_interaction
SQSTM1	TNFRSF11A	string_interaction

Structural data

PDB: 11 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TP53	P04637	313
WRN	Q14191	51
ERCC2	P18074	51
SQSTM1	Q13501	26
RB1	P06400	19
BLM	P54132	15
ATRX	P46100	12
GRM4	Q14833	8
GLDC	P23378	3
RECQL4	O94761	2
TNFRSF11A	Q9Y6Q6	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GDI2	P50395	93.71
ADAMTS6	Q9UKP5	77.45
ADAMTS17	Q8TE56	70.06
TASOR2	Q5VWN6	40.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 182. Enrichment computed across 15 evidence-associated genes (13 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 13 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Processive synthesis on the C-strand of the telomere	2	117.1×	0.007	BLM, WRN
Formation of Senescence-Associated Heterochromatin Foci (SAHF)	2	103.3×	0.007	TP53, RB1
G2/M DNA damage checkpoint	3	27.7×	0.007	BLM, TP53, WRN
Regulation of TP53 Activity through Phosphorylation	3	27.2×	0.007	BLM, TP53, WRN
Alternative Lengthening of Telomeres (ALT)	1	878.5×	0.009	ATRX
Defective translocation of RB1 mutants to the nucleus	1	878.5×	0.009	RB1
Defective Inhibition of DNA Recombination at Telomere	1	878.5×	0.009	ATRX
Diseases of Telomere Maintenance	1	878.5×	0.009	ATRX
Loss of function of TP53 in cancer due to loss of tetramerization ability	1	878.5×	0.009	TP53
Impaired BRCA2 binding to PALB2	2	70.3×	0.009	BLM, WRN
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	2	65.1×	0.009	BLM, WRN
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	2	65.1×	0.009	BLM, WRN
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	2	65.1×	0.009	BLM, WRN
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	2	60.6×	0.009	BLM, WRN
Homologous DNA Pairing and Strand Exchange	2	58.6×	0.009	BLM, WRN
Telomere Maintenance	2	56.7×	0.009	BLM, ATRX
Oncogene Induced Senescence	2	51.7×	0.009	TP53, RB1
Defective B3GALTL causes PpS	2	47.5×	0.009	ADAMTS17, ADAMTS6
Impaired BRCA2 binding to RAD51	2	47.5×	0.009	BLM, WRN
O-glycosylation of TSR domain-containing proteins	2	46.2×	0.009	ADAMTS17, ADAMTS6
Resolution of D-loop Structures through Holliday Junction Intermediates	2	46.2×	0.009	BLM, WRN
HDR through Single Strand Annealing (SSA)	2	45.0×	0.009	BLM, WRN
Presynaptic phase of homologous DNA pairing and strand exchange	2	41.8×	0.009	BLM, WRN
Diseases associated with O-glycosylation of proteins	2	33.1×	0.012	ADAMTS17, ADAMTS6
Chromosome Maintenance	2	32.5×	0.012	BLM, ATRX
Regulation of TP53 Expression	1	439.2×	0.013	TP53
Defective Inhibition of DNA Recombination at Telomere Due to DAXX Mutations	1	439.2×	0.013	ATRX
Defective Inhibition of DNA Recombination at Telomere Due to ATRX Mutations	1	439.2×	0.013	ATRX
HDR through Homologous Recombination (HRR)	2	29.3×	0.013	BLM, WRN
TP53 Regulates Transcription of DNA Repair Genes	2	27.9×	0.013	TP53, ERCC2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 15 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	3	374.5×	1e-05	BLM, WRN, RECQL4
determination of adult lifespan	3	86.4×	6e-04	TP53, WRN, ERCC2
replication fork processing	3	84.3×	6e-04	BLM, WRN, ATRX
telomere maintenance via semi-conservative replication	2	374.5×	8e-04	BLM, WRN
DNA geometric change	2	280.9×	0.001	BLM, WRN
telomere maintenance	3	53.5×	0.001	BLM, WRN, RECQL4
negative regulation of glial cell proliferation	2	224.7×	0.001	TP53, RB1
cellular response to hydroxyurea	2	187.2×	0.001	BLM, ATRX
t-circle formation	2	187.2×	0.001	BLM, WRN
transcription by RNA polymerase II	4	18.8×	0.001	SQSTM1, ERCC2, ATRX, RB1
replicative senescence	2	132.2×	0.003	TP53, WRN
DNA replication	3	33.0×	0.003	BLM, WRN, RECQL4
response to X-ray	2	118.3×	0.003	BLM, TP53
glial cell proliferation	2	118.3×	0.003	TP53, RB1
double-strand break repair via homologous recombination	3	31.2×	0.003	BLM, WRN, RECQL4
hematopoietic stem cell differentiation	2	102.1×	0.003	TP53, ERCC2
multicellular organism growth	3	27.4×	0.003	TP53, ERCC2, ATRX
extracellular matrix organization	3	24.4×	0.004	ADAMTS17, ADAMTS6, ERCC2
cellular response to gamma radiation	2	80.2×	0.004	TP53, WRN
chromosome organization	2	77.5×	0.004	TP53, RB1
intrinsic apoptotic signaling pathway by p53 class mediator	2	77.5×	0.004	TP53, ERCC2
embryonic organ development	2	64.2×	0.006	TP53, ERCC2
cellular response to ionizing radiation	2	54.8×	0.008	BLM, TP53
response to methylamine	1	1123.5×	0.009	GLDC
negative regulation of helicase activity	1	1123.5×	0.009	TP53
positive regulation of hydrolase activity	1	1123.5×	0.009	WRN
cellular response to actinomycin D	1	1123.5×	0.009	TP53
positive regulation of strand invasion	1	1123.5×	0.009	WRN
regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1	1123.5×	0.009	TP53
negative regulation of G1 to G0 transition	1	1123.5×	0.009	TP53

Therapeutics

Drugs indicated for this disease

1 approved, 8 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Levoleucovorin	Approved (phase 4)
Cisplatin	Phase 3 (in late-stage trials)
Doxorubicin	Phase 3 (in late-stage trials)
Etoposide	Phase 3 (in late-stage trials)
Ifosfamide	Phase 3 (in late-stage trials)
Methotrexate	Phase 3 (in late-stage trials)
PEGINTERFERON ALFA-2B	Phase 3 (in late-stage trials)
Ridaforolimus	Phase 3 (in late-stage trials)
Socazolimab	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Atezolizumab, Avelumab, Bevacizumab, Cabozantinib, Camrelizumab, Carboplatin, Ceralasertib, Denosumab, Dinutuximab, Dinutuximab Beta, Endostatin, N-Terminal-Mggshhhhh, Everolimus, Filgrastim, Gemcitabine, Glucarpidase, Interferon Alfa, Lenvatinib, Nivolumab, Olaparib, Palbociclib, Pazopanib, Pembrolizumab, Pemetrexed, Regorafenib, Rivoceranib, Saracatinib, Sargramostim, Sirolimus, Sorafenib, Surufatinib, Temsirolimus, Thiotepa, Trastuzumab, Trastuzumab Deruxtecan, Trilaciclib, Tucidinostat.

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 5 · Phased (≥1): 6 · Undrugged: 9

Druggability breadth: 8 of 15 evidence-associated genes (53%) 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
BLM	AMIFOSTINE
TP53	NITROFURANTOIN
WRN	INDIGOTINDISULFONATE
ERCC2	SUNITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BLM	284	4
TP53	196	4
ERCC2	16	4
GRM4	3	3
WRN	2	4
RB1	1	2
SQSTM1	0	0
TNFRSF11A	0	0
ATRX	0	0
RECQL4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMIFOSTINE	4	BLM
BEXAROTENE	4	BLM
DICLOFENAC SODIUM	4	BLM
CLOTRIMAZOLE	4	BLM, TP53
FLUORESCEIN	4	BLM
OXCARBAZEPINE	4	BLM
BUMETANIDE	4	BLM
GLIPIZIDE	4	BLM
SALMETEROL XINAFOATE	4	BLM, TP53
AMIODARONE HYDROCHLORIDE	4	BLM, TP53
INDIGOTINDISULFONATE	4	BLM, WRN
TRIHEXYPHENIDYL HYDROCHLORIDE	4	BLM
RALOXIFENE HYDROCHLORIDE	4	BLM, TP53
IDARUBICIN	4	BLM
EDROPHONIUM CHLORIDE	4	BLM
PINACIDIL ANHYDROUS	4	BLM
DITHIAZANINE	4	BLM
TRIMETREXATE	4	BLM
NICARDIPINE HYDROCHLORIDE	4	BLM, TP53
PILOCARPINE HYDROCHLORIDE	4	BLM
PHENYLEPHRINE HYDROCHLORIDE	4	BLM
APRACLONIDINE HYDROCHLORIDE	4	BLM
DOXYLAMINE SUCCINATE	4	BLM
ROPINIROLE HYDROCHLORIDE	4	BLM
TETRAHYDROZOLINE HYDROCHLORIDE	4	BLM
MOLINDONE HYDROCHLORIDE	4	BLM
PARGYLINE HYDROCHLORIDE	4	BLM
GUANFACINE HYDROCHLORIDE	4	BLM
BROMOCRIPTINE MESYLATE	4	BLM
DIHYDROERGOTAMINE MESYLATE	4	BLM

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

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

Symbol	Assays	Type breakdown
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
GRM4	252	Functional:161, Binding:91
BLM	82	Binding:78, Functional:4
RB1	59	Binding:59
WRN	32	Binding:30, Functional:2
SQSTM1	20	Binding:20
ERCC2	3	Binding:3
GDI2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BLM	3.6.4.12	DNA helicase
WRN	3.6.4.12	DNA helicase
ERCC2	3.6.4.12	DNA helicase
RECQL4	3.6.4.12	DNA helicase
GLDC	1.4.1.27, 1.4.4.2	glycine cleavage system, glycine dehydrogenase (aminomethyl-transferring)

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TP53	869
GRM4	252

Pharmacogenomics

Cohort genes with a PharmGKB record: 15; 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)
AMIFOSTINE	4	BLM
BEXAROTENE	4	BLM
DICLOFENAC SODIUM	4	BLM
CLOTRIMAZOLE	4	BLM, TP53
FLUORESCEIN	4	BLM
OXCARBAZEPINE	4	BLM
BUMETANIDE	4	BLM
GLIPIZIDE	4	BLM
SALMETEROL XINAFOATE	4	BLM, TP53
AMIODARONE HYDROCHLORIDE	4	BLM, TP53
INDIGOTINDISULFONATE	4	BLM, WRN
TRIHEXYPHENIDYL HYDROCHLORIDE	4	BLM
RALOXIFENE HYDROCHLORIDE	4	BLM, TP53
IDARUBICIN	4	BLM
EDROPHONIUM CHLORIDE	4	BLM
PINACIDIL ANHYDROUS	4	BLM
DITHIAZANINE	4	BLM
TRIMETREXATE	4	BLM
NICARDIPINE HYDROCHLORIDE	4	BLM, TP53
PILOCARPINE HYDROCHLORIDE	4	BLM
PHENYLEPHRINE HYDROCHLORIDE	4	BLM
APRACLONIDINE HYDROCHLORIDE	4	BLM
DOXYLAMINE SUCCINATE	4	BLM
ROPINIROLE HYDROCHLORIDE	4	BLM
TETRAHYDROZOLINE HYDROCHLORIDE	4	BLM
MOLINDONE HYDROCHLORIDE	4	BLM
PARGYLINE HYDROCHLORIDE	4	BLM
GUANFACINE HYDROCHLORIDE	4	BLM
BROMOCRIPTINE MESYLATE	4	BLM
DIHYDROERGOTAMINE MESYLATE	4	BLM

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	BLM, TP53, WRN, ERCC2
B	Phased (≥1) drug, not yet approved	2	RB1, GRM4
C	Druggable family + PDB, no drug	2	RECQL4, GLDC
D	Druggable family + AlphaFold only, no drug	2	ADAMTS17, ADAMTS6
E	Difficult family or no structure, no drug	5	SQSTM1, TNFRSF11A, ATRX, TASOR2, GDI2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SQSTM1	20	—
TNFRSF11A	0	—
ATRX	0	—
RECQL4	0	—
ADAMTS17	0	—
ADAMTS6	0	—
TASOR2	0	—
GDI2	1	—
GLDC	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 328.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	112
Not specified	89
PHASE1	67
PHASE1/PHASE2	38
PHASE3	9
EARLY_PHASE1	6
PHASE2/PHASE3	5
PHASE4	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01669369	PHASE4	UNKNOWN	Clinical Trial of Lithium Carbonate Combined With Neo-adjuvant Chemotherapy to Treat Osteosarcoma
NCT04854018	PHASE4	COMPLETED	Indo-cyanine Green (ICG) in Paediatric Oncology MIS
NCT05235165	PHASE3	RECRUITING	Thoracotomy Versus Thoracoscopic Management of Pulmonary Metastases in Patients With Osteosarcoma
NCT05328258	PHASE3	RECRUITING	Use of GnRHa During Chemotherapy for Fertility Protection
NCT05691478	PHASE2/PHASE3	RECRUITING	A Study to Test the Addition of the Drug Cabozantinib to Chemotherapy in Patients With Newly Diagnosed Osteosarcoma
NCT06935409	PHASE3	ACTIVE_NOT_RECRUITING	Study of HS-20093 Versus Gemcitabine in Combination With Docetaxel in Treatment of Osteosarcoma After Previous Second-line Treatment Failure
NCT00001217	PHASE3	COMPLETED	Osteosarcoma Study #2: A Randomized Trial of Pre-Surgical Chemotherapy vs. Immediate Surgery and Adjuvant Chemotherapy in the Treatment of Non-Metastatic Osteosarcoma. A Pediatric Oncology Group Phase III Study
NCT00134030	PHASE3	COMPLETED	Combination Chemotherapy, PEG-Interferon Alfa-2b, and Surgery in Treating Patients With Osteosarcoma
NCT00180908	PHASE3	COMPLETED	Comparison of High-Dose Methotrexate (HDM) Plus Doxorubicin to HDM Plus Etoposide-Ifosfamide in Osteosarcoma Children
NCT00691236	PHASE2/PHASE3	UNKNOWN	Evaluation of Zoledronic Acid as a Single Agent or as an Adjuvant to Chemotherapy in High Grade Osteosarcoma
NCT01176981	PHASE3	COMPLETED	Outpatient Administration of High Dose Methotrexate (HD MTX) in Patients With Osteosarcoma
NCT01987596	PHASE3	TERMINATED	Study of Fixed vs. Flexible Filgrastim to Accelerate Bone Marrow Recovery After Chemotherapy in Children With Cancer
NCT02711007	PHASE2/PHASE3	COMPLETED	Apatinib for Advanced Osteosarcoma After Failure of Standard Multimodal Therapy
NCT02856048	PHASE2/PHASE3	UNKNOWN	Co-treatment With GnRH Analogs on the Ovarian Reserve in Young Women Treated With Alkylating Agents for Cancer
NCT05024253	PHASE3	COMPLETED	Perioperative Use of Tranexamic (TXA) in Bone Tumor Surgery Will Change in Blood Loss and Transfusion Requirements.
NCT05057130	PHASE2/PHASE3	UNKNOWN	Neoadjuvant Combination of Doxorubicin, Cisplatin and Methotrexate in Patients Aged 24-40 Years With Primary Bone Tumors
NCT00840047	PHASE2	ACTIVE_NOT_RECRUITING	Methionine PET/CT Studies In Patients With Cancer
NCT02243605	PHASE2	ACTIVE_NOT_RECRUITING	Cabozantinib S-malate in Treating Patients With Relapsed Osteosarcoma or Ewing Sarcoma
NCT02389244	PHASE2	ACTIVE_NOT_RECRUITING	A Phase II Study Evaluating Efficacy and Safety of Regorafenib in Patients With Metastatic Bone Sarcomas
NCT02502786	PHASE2	ACTIVE_NOT_RECRUITING	Humanized Monoclonal Antibody 3F8 (Hu3F8) With Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) in the Treatment of Recurrent Osteosarcoma
NCT02867592	PHASE2	ACTIVE_NOT_RECRUITING	Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumors
NCT03155620	PHASE2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
NCT03213652	PHASE2	ACTIVE_NOT_RECRUITING	Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)
NCT03213704	PHASE2	ACTIVE_NOT_RECRUITING	Larotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial)
NCT03373097	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Anti-GD2 CAR T Cells in Pediatric Patients Affected by High Risk and/or Relapsed/Refractory Neuroblastoma or Other GD2-positive Solid Tumors
NCT03449108	PHASE2	ACTIVE_NOT_RECRUITING	LN-145 or LN-145-S1 in Treating Patients With Relapsed or Refractory Ovarian Cancer, Triple Negative Breast Cancer (TNBC), Anaplastic Thyroid Cancer, Osteosarcoma, or Other Bone and Soft Tissue Sarcomas
NCT03598595	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Gemcitabine, Docetaxel, and Hydroxychloroquine in Treating Participants With Recurrent or Refractory Osteosarcoma
NCT03643133	PHASE2	ACTIVE_NOT_RECRUITING	Mifamurtide Combined With Post-operative Chemotherapy for Newly Diagnosed High Risk Osteosarcoma Patients
NCT03698994	PHASE2	ACTIVE_NOT_RECRUITING	Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)
NCT04040205	PHASE2	RECRUITING	Abemaciclib for Bone and Soft Tissue Sarcoma With Cyclin-Dependent Kinase (CDK) Pathway Alteration
NCT04195555	PHASE2	ACTIVE_NOT_RECRUITING	Ivosidenib in Treating Patients With Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With IDH1 Mutations (A Pediatric MATCH Treatment Trial)
NCT04284774	PHASE2	ACTIVE_NOT_RECRUITING	Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial
NCT04320888	PHASE2	ACTIVE_NOT_RECRUITING	Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediatric MATCH Treatment Trial
NCT04417062	PHASE2	ACTIVE_NOT_RECRUITING	Olaparib With Ceralasertib in Recurrent Osteosarcoma
NCT04668300	PHASE2	ACTIVE_NOT_RECRUITING	Oleclumab and Durvalumab for the Treatment of Recurrent, Refractory, or Metastatic Sarcoma
NCT04698785	PHASE2	RECRUITING	Efficacy of Regorafenib Combined With Best Supportive Care as Maintenance Treatment in High Grade Bone Sarcomas Patients
NCT04758000	PHASE2	RECRUITING	Metformin as Maintenance Therapy in Patients With Bone Sarcoma and High Risk of Relapse
NCT04803877	PHASE2	ACTIVE_NOT_RECRUITING	SARC038: Phase 2 Study of Regorafenib and Nivolumab in Osteosarcoma
NCT04851119	PHASE1/PHASE2	RECRUITING	Tegavivint for the Treatment of Recurrent or Refractory Solid Tumors, Including Lymphomas and Desmoid Tumors
NCT04901702	PHASE1/PHASE2	RECRUITING	Study of Onivyde With Talazoparib or Temozolomide in Children With Recurrent Solid Tumors and Ewing Sarcoma

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MIFAMURTIDE ACID	4	13
CABOZANTINIB	4	9
DEXRAZOXANE	4	6
GLUCARPIDASE	4	4
LAROTRECTINIB	4	4
EFLORNITHINE	4	3
AZACITIDINE	4	2
DINUTUXIMAB	4	2
DOXORUBICIN	4	2
ENSARTINIB	4	2
IFOSFAMIDE	4	2
INDOCYANINE GREEN ACID FORM	4	2
IVOSIDENIB	4	2
REGORAFENIB	4	2
SELPERCATINIB	4	2
TAZEMETOSTAT	4	2
TRILACICLIB	4	2
VEMURAFENIB	4	2
ABEMACICLIB	4	1
AFAMITRESGENE AUTOLEUCEL	4	1
AVELUMAB	4	1
CALCIUM CARBONATE	4	1
COPANLISIB	4	1
DISULFIRAM	4	1
DOSTARLIMAB	4	1
ERDAFITINIB	4	1
ERIBULIN MESYLATE	4	1
FERUMOXYTOL	4	1
IMATINIB MESYLATE	4	1
IMETELSTAT SODIUM	4	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 5 predictive associations from 5 curated evidence items; also 3 oncogenic, 2 diagnostic, 1 prognostic.

Molecular subtype	Therapy	Effect	Level	CIViC
ERCC2 K751Q	Cisplatin	Resistance	CIViC B	EID676
ATRX Underexpression	VE-821 + AZ20	Sensitivity/Response	CIViC D	EID5832
RB1 Loss-of-function	Olaparib + Niraparib + Talazoparib	Sensitivity/Response	CIViC D	EID12032
ZNF217 Overexpression	Triciribine	Sensitivity/Response	CIViC D	EID12210
TP53 R273H	Doxorubicin + Methotrexate	Resistance	CIViC D	EID7430