Differentiated thyroid carcinoma

Summary

Differentiated thyroid carcinoma (MONDO:0015447) is a cancer with 10 cohort genes (32 GWAS associations across 5 studies; 3 CIViC-evidence somatic drivers) and 97 clinical trials. Top therapeutic interventions include sunitinib, cabozantinib, and lenvatinib.

At a glance

• Classification: Cancer
• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 10
• GWAS associations: 32
• Clinical trials: 97

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	5.25	Worldwide	Validated
Annual incidence	1-9 / 100 000	2	Europe	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	differentiated thyroid carcinoma
Mondo ID	MONDO:0015447
EFO	EFO:1002017
Orphanet	146
DOID	DOID:0080525
NCIT	C7153
UMLS	C1337013
MedGen	277876
GARD	0012027
Is cancer (heuristic)	yes

Also known as: differentiated thyroid cancer · differentiated thyroid carcinoma · differentiated thyroid gland cancer · differentiated thyroid gland carcinoma · papillary or follicular thyroid carcinoma · thyroid gland differentiated carcinoma · thyroid gland well differentiated carcinoma · well differentiated thyroid carcinoma · well differentiated thyroid gland carcinoma · well-differentiated thyroid cancer · well-differentiated thyroid carcinoma

Data availability: 32 GWAS associations (5 studies) · 62 cell lines · 42 intOGen driver records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › endocrine gland neoplasm › thyroid tumor › thyroid cancer › thyroid gland carcinoma › differentiated thyroid carcinoma

Related subtypes (10): thyroid gland spindle cell tumor with thymus-like differentiation, thyroid gland squamous cell carcinoma, thyroid gland undifferentiated (anaplastic) carcinoma, familial nonmedullary thyroid carcinoma, multiple endocrine neoplasia type 2, thyroid gland adenocarcinoma, intrathyroid thymic carcinoma, thyroid gland cribriform morular carcinoma, thyroid gland mixed medullary and follicular cell-derived carcinoma, thyroid gland mucinous carcinoma

Subtypes (3): thyroid gland follicular carcinoma, thyroid gland papillary carcinoma, familial papillary or follicular thyroid carcinoma

Genetics & variants

GWAS landscape

32 GWAS associations across 5 studies. Top hits map to 23 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs1588635	2e-21	PTCSC2	C	0.61
rs368187	4e-13	LINC00609	G	1.47
rs6996585	1e-10	NRG1	G	1.39
rs11693806	1e-10	DIRC3	G	0.7
rs116909374	2e-10	LINC00609 - MBIP	C	0.43
rs17767383	2e-09	MAFTRR, LINC01229	A	1.23
rs12990503	4e-09	DIRC3	G	1.34
rs11175834	4e-08	LINC02454, MSRB3-AS1	T	1.37
rs4649295	6e-08	PCNX2	T	1.43
rs4915076	8e-08	VAV3	T	1.33
rs34081947	1e-07	LINC00609	T	1.27
rs1874564	2e-07	SOWAHB - SEPTIN11	G	1.31
rs200113618	2e-07	ZNF208	C
rs2727572	2e-07	PRKAG2	T
rs1358902	2e-07	GRM1 - RAB32	G	2.02
rs28390243	2e-07	SPAG6 - PIP4K2A	A	1.89
rs9858271	7e-07	CFAP20DC-DT	G	1.26
rs7211607	7e-07	SKAP1	T	2.37
rs334729	8e-07	NFIA	G	0.7
rs10415826	9e-07	ZNF257	T	1.22
rs7726159	1e-06	TERT	A
rs3857927	1e-06	KCNQ3	T
rs17020149	3e-06	VAV3	A
rs1278519	4e-06	FAF1-AS1	C
rs16950982	4e-06	MAFTRR	G
rs9399398	5e-06	ADGRG6	A
rs12455644	6e-06	RPL17P45 - KC6	T
rs7659026	6e-06	STOX2	C
rs72753537	8e-06	TRMO	C	1.41
rs56864313	8e-06	SGCZ	G

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST012195	Truong T	2021	1,554	1,973	Multiethnic genome-wide association study of differentiated thyroid cancer in the EPITHYR consortium.
GCST012197	Truong T	2021	1,554	1,973	Multiethnic genome-wide association study of differentiated thyroid cancer in the EPITHYR consortium.
GCST004798	Son HY	2017	470	8,279	Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer.
GCST012196	Truong T	2021	301	0	Multiethnic genome-wide association study of differentiated thyroid cancer in the EPITHYR consortium.
GCST90308589	Zidane M	2023	283	0	Genetic factors for differentiated thyroid cancer in French Polynesia: new candidate loci.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	31

MAF distribution

Bucket	Variants
common (>=0.05)	30
low_freq (0.01-0.05)	1
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	24
non_coding_transcript_exon_variant	3
intergenic_variant	3
synonymous_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs1588635	9	97775520	A>C,T	0.45	intron_variant	PTCSC2	2e-21	Tier 4: intronic/intergenic
rs368187	14	36063370	G>A,C,T	0.37	non_coding_transcript_exon_variant	LINC00609	4e-13	Tier 4: intronic/intergenic
rs6996585	8	32543285	A>G	0.23	intron_variant	NRG1	1e-10	Tier 4: intronic/intergenic
rs11693806	2	217427435	C>A,G,T	0.34	non_coding_transcript_exon_variant	DIRC3	1e-10	Tier 4: intronic/intergenic
rs116909374	14	36269155	C>T	0.06	non_coding_transcript_exon_variant	LINC00609 - MBIP	2e-10	Tier 4: intronic/intergenic
rs17767383	16	79710504	G>A,C,T	0.32	intron_variant	MAFTRR, LINC01229	2e-09	Tier 4: intronic/intergenic
rs12990503	2	217429494	C>A,G	0.37	intron_variant	DIRC3	4e-09	Tier 4: intronic/intergenic
rs11175834	12	65598856	C>T	0.15	intron_variant	LINC02454, MSRB3-AS1	4e-08	Tier 4: intronic/intergenic
rs4649295	1	233280792	T>A,C,G	0.18	intron_variant	PCNX2	6e-08	Tier 4: intronic/intergenic
rs4915076	1	107816883	T>A,C	0.3	intron_variant	VAV3	8e-08	Tier 4: intronic/intergenic
rs34081947	14	36090325	C>T	0.41	intron_variant	LINC00609	1e-07	Tier 4: intronic/intergenic
rs1874564	4	76936952	G>A	0.31	intron_variant	SOWAHB - SEPTIN11	2e-07	Tier 4: intronic/intergenic
rs200113618	19	21974056	T>A,C,G	0.04	synonymous_variant	ZNF208	2e-07	Tier 4: intronic/intergenic
rs2727572	7	151601160	C>G,T	0.45	intron_variant	PRKAG2	2e-07	Tier 4: intronic/intergenic
rs1358902	6	146507786	A>G	0.25	intergenic_variant	GRM1 - RAB32	2e-07	Tier 4: intronic/intergenic
rs28390243	10	22503563	C>A,T	0.33	intergenic_variant	SPAG6 - PIP4K2A	2e-07	Tier 4: intronic/intergenic
rs9858271	3	59559604	G>A	0.43	intron_variant	CFAP20DC-DT	7e-07	Tier 4: intronic/intergenic
rs7211607	17	48258937	C>T	0.12	intron_variant	SKAP1	7e-07	Tier 4: intronic/intergenic
rs334729	1	61142801	C>G,T	0.05	intron_variant	NFIA	8e-07	Tier 4: intronic/intergenic
rs10415826	19	22065515	A>T	0.2	intron_variant	ZNF257	9e-07	Tier 4: intronic/intergenic
rs7726159	5	1282204	C>A	0.39	intron_variant	TERT	1e-06	Tier 4: intronic/intergenic
rs3857927	8	132454646	G>A,T	0.06	intron_variant	KCNQ3	1e-06	Tier 4: intronic/intergenic
rs17020149	1	107832667	G>A,C	0.08	intron_variant	VAV3	3e-06	Tier 4: intronic/intergenic
rs1278519	1	50431670	A>C,G	0.48	intron_variant	FAF1-AS1	4e-06	Tier 4: intronic/intergenic
rs16950982	16	79668474	A>C,G	0.37	intron_variant	MAFTRR	4e-06	Tier 4: intronic/intergenic
rs9399398	6	142306362	G>A,C	0.11	intron_variant	ADGRG6	5e-06	Tier 4: intronic/intergenic
rs12455644	18	40316632	T>G	0.1	intergenic_variant	RPL17P45 - KC6	6e-06	Tier 4: intronic/intergenic
rs7659026	4	183807529	C>G,T	0.4	intron_variant	STOX2	6e-06	Tier 4: intronic/intergenic
rs72753537	9	97898464	T>A,C	0.07	intron_variant	TRMO	8e-06	Tier 4: intronic/intergenic
rs56864313	8	15055280	A>G,T	0.15	intron_variant	SGCZ	8e-06	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 14 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 3

Dual-evidence genes (GWAS + Mendelian — highest-confidence targets)

Gene	HGNC	Evidence routes
NKX2-1	NKX2-1	GWAS, Orphanet
DIRC3	DIRC3	GWAS, Orphanet
FOXE1	FOXE1	GWAS, Orphanet

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
NKX2-1	LoF	LGGNOS	CIViC #80
FHIT	Act	DLBCLNOS	CIViC #1893
NRG1	Act	ESCA,PRCC,STAD	CIViC #2593

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NKX2-1	Orphanet:1429	Benign hereditary chorea
NKX2-1	Orphanet:146	Differentiated thyroid carcinoma
NKX2-1	Orphanet:209905	Brain-lung-thyroid syndrome
NKX2-1	Orphanet:95713	Athyreosis
DIRC3	Orphanet:146	Differentiated thyroid carcinoma
DIRC3	Orphanet:422526	Hereditary clear cell renal cell carcinoma
STN1	Orphanet:2032	Idiopathic pulmonary fibrosis
STN1	Orphanet:313838	Coats plus syndrome
MSRB3	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
FHIT	Orphanet:422526	Hereditary clear cell renal cell carcinoma
FOXE1	Orphanet:1226	Bamforth-Lazarus syndrome
FOXE1	Orphanet:146	Differentiated thyroid carcinoma
FOXE1	Orphanet:319487	Familial papillary or follicular thyroid carcinoma
FOXE1	Orphanet:95713	Athyreosis

Cohort genes → proteins

10 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NKX2-1	HGNC:11825	ENSG00000136352	P43699	Homeobox protein Nkx-2.1	gwas
VAV3	HGNC:12659	ENSG00000134215	Q9UKW4	Guanine nucleotide exchange factor VAV3	gwas
DIRC3	HGNC:17805	ENSG00000231672		disrupted in renal carcinoma 3	gwas
SEPTIN11	HGNC:25589	ENSG00000138758	Q9NVA2	Septin-11	gwas
STN1	HGNC:26200	ENSG00000107960	Q9H668	CST complex subunit STN1	gwas
MSRB3	HGNC:27375	ENSG00000174099	Q8IXL7	Methionine-R-sulfoxide reductase B3	gwas
FHIT	HGNC:3701	ENSG00000189283	P49789	Bis(5’-adenosyl)-triphosphatase	gwas
FOXE1	HGNC:3806	ENSG00000178919	O00358	Forkhead box protein E1	gwas
NRG1	HGNC:7997	ENSG00000157168	Q02297	Pro-neuregulin-1, membrane-bound isoform	gwas
PCNX2	HGNC:8736	ENSG00000135749	A6NKB5	Pecanex-like protein 2	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NKX2-1	Homeobox protein Nkx-2.1	Transcription factor that binds and activates the promoter of thyroid specific genes such as thyroglobulin, thyroperoxidase, and thyrotropin receptor.
VAV3	Guanine nucleotide exchange factor VAV3	Exchange factor for GTP-binding proteins RhoA, RhoG and, to a lesser extent, Rac1.
SEPTIN11	Septin-11	Filament-forming cytoskeletal GTPase.
STN1	CST complex subunit STN1	Component of the CST complex proposed to act as a specialized replication factor promoting DNA replication under conditions of replication stress or natural replication barriers such as the telomere duplex.
MSRB3	Methionine-R-sulfoxide reductase B3	Catalyzes the reduction of free and protein-bound methionine sulfoxide to methionine.
FHIT	Bis(5’-adenosyl)-triphosphatase	Possesses dinucleoside triphosphate hydrolase activity.
FOXE1	Forkhead box protein E1	Transcription factor that binds consensus sites on a variety of gene promoters and activate their transcription.
NRG1	Pro-neuregulin-1, membrane-bound isoform	Direct ligand for ERBB3 and ERBB4 tyrosine kinase receptors.
PCNX2	Pecanex-like protein 2	May play a role in tumorigenesis of colorectal carcinomas with high microsatellite instability (MSI-H).

Protein-family classification

Druggable: 3 · Difficult: 3 · Unknown: 4 · Druggable fraction: 0.3

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
Antibody/Immunoglobulin	1	2.9×	0.561
Enzyme (other)	2	2.4×	0.561
Scaffold/PPI	1	1.7×	0.561
Transcription factor	2	1.6×	0.561
Other/Unknown	4	0.7×	0.907

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NKX2-1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
VAV3	Scaffold/PPI	no		DH_dom, SH2, GDS_CDC24_CS
DIRC3	Other/Unknown	no
SEPTIN11	Other/Unknown	no		Septin, P-loop_NTPase, G_SEPTIN_dom
STN1	Other/Unknown	no		NA-bd_OB_tRNA, NA-bd_OB-fold, Stn1
MSRB3	Enzyme (other)	yes	1.8.4.12	Met_Sox_Rdtase_MsrB_dom, Mss4-like_sf, Met_Sox_Rdtase_MsrB
FHIT	Enzyme (other)	yes	3.6.1.29	HIT-like, Histidine_triad_CS, HIT-like_sf
FOXE1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
NRG1	Antibody/Immunoglobulin	yes		EGF, Neuregulin_C, Ig_sub2
PCNX2	Other/Unknown	no		Pecanex_C, Pecanex

Expression context

Cohort genes with no expression data: 0.

9 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)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left lobe of thyroid gland	2
right lobe of thyroid gland	2
thyroid gland	2
ganglionic eminence	2
ventricular zone	2
esophagus squamous epithelium	1
renal medulla	1
tongue squamous epithelium	1
layer of synovial tissue	1
male germ line stem cell (sensu Vertebrata) in testis	1
synovial joint	1
calcaneal tendon	1
esophagus mucosa	1
lower esophagus mucosa	1
oral cavity	1
cardiac muscle of right atrium	1
saphenous vein	1
urethra	1
left adrenal gland cortex	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NKX2-1	101	broad	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
VAV3	258	ubiquitous	marker	tongue squamous epithelium, renal medulla, esophagus squamous epithelium
DIRC3	161	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, layer of synovial tissue, synovial joint
SEPTIN11	299	ubiquitous	marker	ventricular zone, ganglionic eminence, calcaneal tendon
STN1	284	ubiquitous	marker	lower esophagus mucosa, oral cavity, esophagus mucosa
MSRB3	252	ubiquitous	marker	saphenous vein, cardiac muscle of right atrium, urethra
FHIT	188	ubiquitous	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland cortex
FOXE1	94	tissue_specific	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
NRG1	209	ubiquitous	marker	ventricular zone, ganglionic eminence, oocyte
PCNX2	266	ubiquitous	marker	buccal mucosa cell, middle temporal gyrus, cerebellar vermis

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NKX2-1	2,403
MSRB3	1,893
STN1	1,863
FHIT	1,690
FOXE1	1,606
VAV3	1,575
SEPTIN11	1,226
PCNX2	351
NRG1	197
DIRC3	0

Intra-cohort edges

A	B	Sources
FOXE1	NKX2-1	string_interaction
FOXE1	PCNX2	string_interaction
PCNX2	SEPTIN11	string_interaction
PCNX2	STN1	string_interaction

Structural data

PDB: 7 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NRG1	Q02297	11
FHIT	P49789	9
STN1	Q9H668	8
NKX2-1	P43699	2
MSRB3	Q8IXL7	2
VAV3	Q9UKW4	1
SEPTIN11	Q9NVA2	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FOXE1	O00358	62.02
PCNX2	A6NKB5	57.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 46. Enrichment computed across 10 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
GRB7 events in ERBB2 signaling	1	475.8×	0.020	NRG1
Protein repair	1	475.8×	0.020	MSRB3
PI3K events in ERBB4 signaling	1	259.6×	0.020	NRG1
Downregulation of ERBB2:ERBB3 signaling	1	203.9×	0.020	NRG1
Telomere C-strand synthesis initiation	1	203.9×	0.020	STN1
ERBB2 Activates PTK6 Signaling	1	203.9×	0.020	NRG1
Telomere C-strand (Lagging Strand) Synthesis	1	190.3×	0.020	STN1
SHC1 events in ERBB4 signaling	1	178.4×	0.020	NRG1
ERBB2 Regulates Cell Motility	1	178.4×	0.020	NRG1
PI3K events in ERBB2 signaling	1	167.9×	0.020	NRG1
GRB2 events in ERBB2 signaling	1	158.6×	0.020	NRG1
Extension of Telomeres	1	150.3×	0.020	STN1
Azathioprine ADME	1	124.1×	0.020	VAV3
SHC1 events in ERBB2 signaling	1	119.0×	0.020	NRG1
Long-term potentiation	1	119.0×	0.020	NRG1
Signaling by ERBB2 TMD/JMD mutants	1	119.0×	0.020	NRG1
Polymerase switching on the C-strand of the telomere	1	105.7×	0.020	STN1
Signaling by ERBB2 KD Mutants	1	105.7×	0.020	NRG1
VEGFR2 mediated vascular permeability	1	102.0×	0.020	VAV3
Downregulation of ERBB2 signaling	1	95.2×	0.020	NRG1
Telomere Maintenance	1	92.1×	0.020	STN1
DAP12 signaling	1	92.1×	0.020	VAV3
FCERI mediated Ca+2 mobilization	1	89.2×	0.020	VAV3
Signaling by ERBB2	1	86.5×	0.020	NRG1
Nuclear signaling by ERBB4	1	86.5×	0.020	NRG1
FCERI mediated MAPK activation	1	86.5×	0.020	VAV3
GPVI-mediated activation cascade	1	77.2×	0.022	VAV3
Signaling by ERBB4	1	68.0×	0.024	NRG1
EPH-ephrin mediated repulsion of cells	1	54.9×	0.029	VAV3
Chromosome Maintenance	1	52.9×	0.029	STN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
thyroid gland development	2	135.9×	0.010	NKX2-1, FOXE1
diadenosine triphosphate catabolic process	1	2106.5×	0.015	FHIT
developmental induction	1	1053.2×	0.015	NKX2-1
ERBB3 signaling pathway	1	1053.2×	0.015	NRG1
positive regulation of peptidyl-tyrosine autophosphorylation	1	1053.2×	0.015	NRG1
purine nucleotide metabolic process	1	702.2×	0.015	FHIT
cerebral cortex GABAergic interneuron differentiation	1	702.2×	0.015	NKX2-1
chordate pharynx development	1	702.2×	0.015	FOXE1
embryonic organ morphogenesis	1	526.6×	0.015	FOXE1
globus pallidus development	1	421.3×	0.015	NKX2-1
forebrain neuron fate commitment	1	421.3×	0.015	NKX2-1
ERBB signaling pathway	1	421.3×	0.015	NRG1
negative regulation of secretion	1	421.3×	0.015	NRG1
soft palate development	1	421.3×	0.015	FOXE1
club cell differentiation	1	421.3×	0.015	NKX2-1
protein repair	1	351.1×	0.015	MSRB3
ERBB4 signaling pathway	1	351.1×	0.015	NRG1
ERBB2-ERBB4 signaling pathway	1	351.1×	0.015	NRG1
positive regulation of striated muscle cell differentiation	1	351.1×	0.015	NRG1
endocardial cell differentiation	1	351.1×	0.015	NRG1
ERBB4-ERBB4 signaling pathway	1	300.9×	0.015	NRG1
ventricular cardiac muscle cell differentiation	1	300.9×	0.015	NRG1
forebrain dorsal/ventral pattern formation	1	263.3×	0.015	NKX2-1
lung saccule development	1	263.3×	0.015	NKX2-1
type II pneumocyte differentiation	1	263.3×	0.015	NKX2-1
immune response-regulating cell surface receptor signaling pathway	1	234.1×	0.015	VAV3
telomere maintenance via telomere lengthening	1	234.1×	0.015	STN1
activation of protein kinase B activity	1	234.1×	0.015	NRG1
ERBB2 signaling pathway	1	234.1×	0.015	NRG1
anatomical structure formation involved in morphogenesis	1	234.1×	0.015	NKX2-1

Therapeutics

Drugs indicated for this disease

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

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Cisplatin, Lithium Carbonate.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 8

Druggability breadth: 2 of 10 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MSRB3	1	2
FHIT	1	3
NKX2-1	0	0
VAV3	0	0
DIRC3	0	0
SEPTIN11	0	0
STN1	0	0
FOXE1	0	0
NRG1	0	0
PCNX2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SURAMIN	3	FHIT
MOLIBRESIB	2	MSRB3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
FHIT	21	Binding:19, ADMET:2
MSRB3	7	Binding:6, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MSRB3	1.8.4.12, 1.8.4.B3	peptide-methionine (R)-S-oxide reductase,
FHIT	3.6.1.29	bis(5’-adenosyl)-triphosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

2 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Compound	Max phase	Cohort target (bioactivity)
SURAMIN	3	FHIT
MOLIBRESIB	2	MSRB3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	2	MSRB3, FHIT
C	Druggable family + PDB, no drug	1	NRG1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	7	NKX2-1, VAV3, DIRC3, SEPTIN11, STN1, FOXE1, PCNX2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NKX2-1	0	—
VAV3	0	—
DIRC3	0	—
SEPTIN11	0	—
STN1	0	—
FOXE1	0	—
NRG1	0	—
PCNX2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 97.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	45
PHASE2	29
PHASE3	11
PHASE1/PHASE2	6
PHASE1	5
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03690388	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Cabozantinib Compared With Placebo in Subjects With Radioiodine-refractory Differentiated Thyroid Cancer Who Have Progressed After Prior Vascular Endothelial Growth Factor Receptor (VEGFR) -Targeted Therapy
NCT04940052	PHASE3	ACTIVE_NOT_RECRUITING	Study of Efficacy and Safety of Dabrafenib in Combination With Trametinib in Previously Treated Patients With Metastatic, Radio-active Iodine Refractory BRAF V600E Mutation Positive Differentiated Thyroid Cancer
NCT06475989	PHASE3	RECRUITING	Study of Targeted Therapy vs. Chemotherapy in Patients With Thyroid Cancer
NCT00295763	PHASE3	COMPLETED	A New Study to Follow-up Thyroid Cancer Patients Who Participated in a Previous Study, Which Compared the Success of Destruction of the Thyroid Remnant Using Standard Treatment or Thyrogen.
NCT01843062	PHASE3	TERMINATED	Comparing Complete Remission After Treatment With Selumetinib/Placebo in Patient With Differentiated Thyroid Cancer
NCT01876784	PHASE3	COMPLETED	Evaluation of Efficacy, Safety of Vandetanib in Patients With Differentiated Thyroid Cancer
NCT02586337	PHASE2/PHASE3	UNKNOWN	Study of Anlotinib in Patients With Differentiated Thyroid Cancer(ALTER01032)
NCT02966093	PHASE3	COMPLETED	A Trial of Lenvatinib (E7080) in Radioiodine (131 I)-Refractory Differentiated Thyroid Cancer in China
NCT03048877	PHASE3	UNKNOWN	Efficacy of Apatinib in Radioactive Iodine-refractory Differentiated Thyroid Cancer
NCT03602495	PHASE3	TERMINATED	A Phase 3 Study of Donafenib in Patients With Radioiodine-refractory Differentiated Thyroid Cancer
NCT04964284	PHASE3	UNKNOWN	Efficacy and Safety Study of rhTSH for Adjuvant Radioiodine Ablation Therapy in Patients With Differentiated Thyroid Cancer
NCT04971473	PHASE3	COMPLETED	Comparison of the Efficacy and Safety of rhTSH as An Adjunctive Diagnostic Tool in Differentiated Thyroid Cancer Patients Who Had Been Thyroidectomized Vs. Patients Who After Thyroid Hormone Withdrawal
NCT03914300	PHASE2	ACTIVE_NOT_RECRUITING	Testing the Combination of Cabozantinib, Nivolumab, and Ipilimumab (CaboNivoIpi) for Advanced Differentiated Thyroid Cancer
NCT04061980	PHASE2	ACTIVE_NOT_RECRUITING	Encorafenib and Binimetinib With or Without Nivolumab in Treating Patients With Metastatic Radioiodine Refractory BRAF V600 Mutant Thyroid Cancer
NCT04321954	PHASE2	ACTIVE_NOT_RECRUITING	Lenvatinib in Locally Advanced Invasive Thyroid Cancer
NCT05783323	PHASE2	RECRUITING	Larotrectinib to Enhance RAI Avidity in Differentiated Thyroid Cancer
NCT05852223	PHASE2	RECRUITING	Pembrolizumab in High-risk Thyroid Cancer
NCT05989425	PHASE2	RECRUITING	Surufatinib as Neoadjuvant Treatment for Locally Advanced or Metastatic Differentiated Thyroid Cancer
NCT06235216	PHASE2	RECRUITING	Sacituzumab govitEcan in THYroid Cancers
NCT06359847	PHASE2	RECRUITING	Study of ST-1898 in Locally Advanced or Metastatic Radioiodine-Refractory Differentiated Thyroid Cancer
NCT06458036	PHASE2	RECRUITING	Selpercatinib Pre-RAI in Patients With RET Fusion Thyroid Cancer (RAISE)
NCT06790589	PHASE2	NOT_YET_RECRUITING	COACH - Comparing Two Different Methods to Suppress Thyrotropin in Patients With Advanced Thyroid Cancer
NCT06848920	PHASE2	NOT_YET_RECRUITING	Study of Sinibolimab Combined with Lenvatinib As Neoadjuvant Therapy for Locally Advanced Unresectable Differentiated Thyroid Carcinoma
NCT06959641	PHASE2	RECRUITING	XL092 for the Treatment of Locally Advanced or Metastatic Radioiodine Refractory Differentiated Thyroid Cancer
NCT07453225	PHASE1/PHASE2	NOT_YET_RECRUITING	Empirical Radioactive Iodine Therapy in DTC
NCT00251316	PHASE2	COMPLETED	Effect of Lithium Carbonate on Low-Dose Radioiodine Therapy in Early Thyroid Cancer
NCT00381641	PHASE2	COMPLETED	Sunitinib Malate in Treating Patients With Thyroid Cancer That Did Not Respond to Iodine I 131 and Cannot Be Removed by Surgery
NCT00625846	PHASE2	COMPLETED	Pazopanib Hydrochloride in Treating Patients With Advanced Thyroid Cancer
NCT00654238	PHASE2	COMPLETED	Phase II Trial of Sorafenib (Nexavar) in Patients With Advanced Thyroid Cancer
NCT00668811	PHASE2	COMPLETED	Sutent Adjunctive Treatment of Differentiated Thyroid Cancer
NCT01208051	PHASE1/PHASE2	COMPLETED	Cediranib Maleate With or Without Lenalidomide for the Treatment of Thyroid Cancer
NCT01263951	PHASE2	UNKNOWN	Study of Everolimus and Sorafenib in Patients With Advanced Thyroid Cancer Who Progressed on Sorafenib Alone
NCT01788982	PHASE2	COMPLETED	Nintedanib(BIBF1120) in Thyroid Cancer
NCT02041260	PHASE2	UNKNOWN	A Phase II Trial of Cabozantinib for the Treatment of Radioiodine (RAI)-Refractory Differentiated Thyroid Carcinoma (DTC) in the First-line Setting
NCT02244463	PHASE1/PHASE2	COMPLETED	A Phase I/II Study of MLN0128 in Metastatic Anaplastic Thyroid Cancer and Incurably Poorly Differentiated or Radioidodine Refractory Differentiated Thyroid Cancer
NCT02432274	PHASE1/PHASE2	COMPLETED	Study of Lenvatinib in Children and Adolescents With Refractory or Relapsed Solid Malignancies and Young Adults With Osteosarcoma
NCT02870569	PHASE2	COMPLETED	Phase 2 Trial of Donafenib in 131I-Refractory Differentiated Thyroid Cancer
NCT02973997	PHASE2	COMPLETED	Lenvatinib and Pembrolizumab in Differentiated Thyroid Cancers (DTC)
NCT03002623	PHASE2	TERMINATED	CUDC-907 Treatment in People With Metastatic and Locally Advanced Thyroid Cancer
NCT03167385	PHASE2	UNKNOWN	Phase 2 Trial of Apatinib Mesylate in Locally Advanced/Metastatic Differentiated Thyroid Carcinoma

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SUNITINIB	4	7
CABOZANTINIB	4	6
LENVATINIB	4	4
DABRAFENIB	4	2
SORAFENIB	4	2
TRAMETINIB	4	2
VANDETANIB	4	2
ATEZOLIZUMAB	4	1
BINIMETINIB	4	1
ENCORAFENIB	4	1
LAROTRECTINIB	4	1
LEVOTHYROXINE SODIUM	4	1
LIOTHYRONINE SODIUM	4	1
LITHIUM CARBONATE	4	1
NINTEDANIB	4	1
PAZOPANIB HYDROCHLORIDE	4	1
SACITUZUMAB GOVITECAN	4	1
SELPERCATINIB	4	1
SELUMETINIB	4	1
CEDIRANIB	3	3
RIVOCERANIB	3	2
CATEQUENTINIB	3	1
IODINE	3	1
SURUFATINIB	3	1
ZANZALINTINIB	3	1
FIMEPINOSTAT	2	1
SAPANISERTIB	2	1
CLATURAFENIB	1	1
CHEMBL4215501	0	4
CHEMBL4849721	0	4