Thyroid gland papillary carcinoma

Summary

Thyroid gland papillary carcinoma (MONDO:0005075) is a cancer (an umbrella term covering 6 Mondo subtypes) with 17 cohort genes (9 GWAS associations across 1 studies; 8 CIViC-evidence somatic drivers; 4 ClinVar predisposition records) and 121 clinical trials. Molecularly, BRAF V600E confers sensitivity to Vemurafenib in Papillary Thyroid Carcinoma (CIViC Level B); 9 further subtype–drug associations are mapped below. Top therapeutic interventions include sunitinib, cabozantinib, and selpercatinib.

At a glance

• Classification: Cancer
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 17
• GWAS associations: 9
• ClinVar variants: 4
• Clinical trials: 121
• Precision-medicine evidence (CIViC): 10 subtype–drug associations

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thyroid gland papillary carcinoma
Mondo ID	MONDO:0005075
EFO	EFO:0000641
DOID	DOID:3969
NCIT	C4035
SNOMED CT	255029007
UMLS	C0238463
MedGen	66773
GARD	0024148
Anatomy (UBERON)	UBERON:0002046
Is cancer (heuristic)	yes

Also known as: papillary cancer of the thyroid · papillary cancer of the thyroid gland · papillary cancer of thyroid · papillary cancer of thyroid gland · papillary carcinoma of the thyroid · papillary carcinoma of the thyroid gland · papillary carcinoma of thyroid · papillary carcinoma of thyroid gland · papillary thyroid cancer · papillary thyroid carcinoma · papillary thyroid gland carcinoma · thyroid gland papillary cancer · thyroid gland papillary carcinoma · thyroid papillary carcinoma

Data availability: 4 ClinVar variants · 9 GWAS associations (1 study) · 1 GenCC gene-disease record · 1 HPO phenotype · 42 cell lines.

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 › carcinoma › adenocarcinoma › papillary adenocarcinoma › thyroid gland papillary carcinoma

Related subtypes (10): papillary eccrine carcinoma, breast papillary carcinoma, papillary thymic adenocarcinoma, fallopian tube papillary adenocarcinoma, ovarian serous surface papillary adenocarcinoma, gallbladder papillary neoplasm with an associated invasive carcinoma, papillary cystadenocarcinoma, papillary lung adenocarcinoma, gastric papillary adenocarcinoma, papillary renal cell carcinoma

Subtypes (6): thyroid gland diffuse sclerosing papillary carcinoma, multicentric papillary thyroid carcinoma, columnar cell variant thyroid gland papillary carcinoma, tall cell variant thyroid gland papillary carcinoma, thyroid gland papillary and follicular carcinoma, thyroid cancer, nonmedullary, 1

Genetics & variants

GWAS landscape

9 GWAS associations across 1 studies. Top hits map to 9 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs6996585	9e-12	NRG1	G	1.43
rs12990503	3e-10	DIRC3	G	1.38
rs9858271	3e-08	CFAP20DC-DT	G	1.3
rs4915076	7e-08	VAV3	T	1.34
rs4649295	9e-08	PCNX2	T	1.45
rs11175834	5e-07	LINC02454, MSRB3-AS1	T	1.36
rs72753537	5e-07	TRMO	C	1.48
rs1874564	6e-07	SOWAHB - SEPTIN11	G	1.31
rs34081947	2e-06	LINC00609	T	1.25

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST004753	Son HY	2017	410	8,279	Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer.

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	9

MAF distribution

Bucket	Variants
common (>=0.05)	9
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	9

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs6996585	8	32543285	A>G	0.23	intron_variant	NRG1	9e-12	Tier 4: intronic/intergenic
rs12990503	2	217429494	C>A,G	0.37	intron_variant	DIRC3	3e-10	Tier 4: intronic/intergenic
rs9858271	3	59559604	G>A	0.43	intron_variant	CFAP20DC-DT	3e-08	Tier 4: intronic/intergenic
rs4915076	1	107816883	T>A,C	0.3	intron_variant	VAV3	7e-08	Tier 4: intronic/intergenic
rs4649295	1	233280792	T>A,C,G	0.18	intron_variant	PCNX2	9e-08	Tier 4: intronic/intergenic
rs11175834	12	65598856	C>T	0.15	intron_variant	LINC02454, MSRB3-AS1	5e-07	Tier 4: intronic/intergenic
rs72753537	9	97898464	T>A,C	0.07	intron_variant	TRMO	5e-07	Tier 4: intronic/intergenic
rs1874564	4	76936952	G>A	0.31	intron_variant	SOWAHB - SEPTIN11	6e-07	Tier 4: intronic/intergenic
rs34081947	14	36090325	C>T	0.41	intron_variant	LINC00609	2e-06	Tier 4: intronic/intergenic

ClinVar germline variants

4 retrieved; paginated sample, class counts are floors:

3 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
620632	NM_206937.2(LIG4):c.1673A>C (p.Gln558Pro)	LIG4	Likely pathogenic	criteria provided, single submitter
13961	NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
142147	NM_000051.4(ATM):c.8560C>T (p.Arg2854Cys)	C11orf65	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
232654	NM_024675.4(PALB2):c.2147A>G (p.Asn716Ser)	PALB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 43 · 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
BRAF	Act	BLCA,BRCA,CHOL,CLLSLL,COAD,COADREAD,CSCC,DLBCLNOS,GBM,GIST,HGGNOS,LGGNOS,LUAD,MEL,MLYM,NSCLC,OVT,PAST,PCM,PRAD,PRCC,PROSTATE,READ,SACA,SKCM,STAD,UCEC,WDTC	CIViC #5
TERT	Act	PRCC	CIViC #79
BIRC7			CIViC #14842
CD274	LoF	DLBCLNOS	CIViC #11335
NKX2-1	LoF	LGGNOS	CIViC #80
PALB2	LoF	OVT	CIViC #15013
FHIT	Act	DLBCLNOS	CIViC #1893
NRG1	Act	ESCA,PRCC,STAD	CIViC #2593

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
TINF2	Limited	Autosomal dominant	thyroid gland papillary carcinoma	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BRAF	Orphanet:1340	Cardiofaciocutaneous syndrome
BRAF	Orphanet:146	Differentiated thyroid carcinoma
BRAF	Orphanet:251615	Pilomyxoid astrocytoma
BRAF	Orphanet:389	Langerhans cell histiocytosis
BRAF	Orphanet:500	Noonan syndrome with multiple lentigines
BRAF	Orphanet:54595	Craniopharyngioma
BRAF	Orphanet:58017	Classic hairy cell leukemia
BRAF	Orphanet:626	Large/giant congenital melanocytic nevus
BRAF	Orphanet:648	Noonan syndrome
BRAF	Orphanet:840	Syringocystadenoma papilliferum
BRAF	Orphanet:96253	Cushing disease
TERT	Orphanet:146	Differentiated thyroid carcinoma
TERT	Orphanet:1501	Adrenocortical carcinoma
TERT	Orphanet:1775	Dyskeratosis congenita
TERT	Orphanet:2032	Idiopathic pulmonary fibrosis
TERT	Orphanet:2495	Meningioma
TERT	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
TERT	Orphanet:457246	Clear cell sarcoma of kidney
TERT	Orphanet:618	Familial melanoma
TERT	Orphanet:88	Idiopathic aplastic anemia
TINF2	Orphanet:1775	Dyskeratosis congenita
TINF2	Orphanet:3088	Revesz syndrome
TINF2	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
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
PALB2	Orphanet:1333	Familial pancreatic carcinoma
PALB2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
PALB2	Orphanet:178	Chordoma
PALB2	Orphanet:227535	Hereditary breast cancer
PALB2	Orphanet:84	Fanconi anemia
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
LIG4	Orphanet:235	Dubowitz syndrome
LIG4	Orphanet:39041	Omenn syndrome
LIG4	Orphanet:99812	LIG4 syndrome

Cohort genes → proteins

17 cohort genes, 16 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	9
civic_only	3
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	clinvar,civic_evidence
TERT	HGNC:11730	ENSG00000164362	O14746	Telomerase reverse transcriptase	civic_evidence
TINF2	HGNC:11824	ENSG00000092330	Q9BSI4	TERF1-interacting nuclear factor 2	gencc
BIRC7	HGNC:13702	ENSG00000101197	Q96CA5	Baculoviral IAP repeat-containing protein 7	civic_evidence
CD274	HGNC:17635	ENSG00000120217	Q9NZQ7	Programmed cell death 1 ligand 1	civic_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
PALB2	HGNC:26144	ENSG00000083093	Q86YC2	Partner and localizer of BRCA2	clinvar
MSRB3	HGNC:27375	ENSG00000174099	Q8IXL7	Methionine-R-sulfoxide reductase B3	gwas
C11orf65	HGNC:28519	ENSG00000166323	Q8NCR3	Protein MFI	clinvar
FHIT	HGNC:3701	ENSG00000189283	P49789	Bis(5’-adenosyl)-triphosphatase	gwas
FOXE1	HGNC:3806	ENSG00000178919	O00358	Forkhead box protein E1	gwas
LIG4	HGNC:6601	ENSG00000174405	P49917	DNA ligase 4	clinvar
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)
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
TERT	Telomerase reverse transcriptase	Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes.
TINF2	TERF1-interacting nuclear factor 2	Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection.
BIRC7	Baculoviral IAP repeat-containing protein 7	Apoptotic regulator capable of exerting proapoptotic and anti-apoptotic activities and plays crucial roles in apoptosis, cell proliferation, and cell cycle control.
CD274	Programmed cell death 1 ligand 1	Plays a critical role in induction and maintenance of immune tolerance to self.
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.
PALB2	Partner and localizer of BRCA2	Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks.
MSRB3	Methionine-R-sulfoxide reductase B3	Catalyzes the reduction of free and protein-bound methionine sulfoxide to methionine.
C11orf65	Protein MFI	Acts as an inhibitor of mitochondrial fission.
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.
LIG4	DNA ligase 4	DNA ligase involved in DNA non-homologous end joining (NHEJ); required for double-strand break (DSB) repair and V(D)J recombination.
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: 6 · Difficult: 5 · Unknown: 6 · Druggable fraction: 0.35

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	2	3.4×	0.493
Enzyme (other)	3	2.1×	0.493
Scaffold/PPI	2	2.0×	0.510
Transcription factor	3	1.5×	0.510
Kinase	1	1.6×	0.558
Other/Unknown	6	0.6×	0.974

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
TERT	Other/Unknown	no		RT_dom, Telomerase_RT, Telomerase_RBD
TINF2	Other/Unknown	no		TINF2_N, TINF2
BIRC7	Transcription factor	no		BIR_rpt, Znf_RING, Znf_RING/FYVE/PHD
CD274	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig_V-set
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
PALB2	Scaffold/PPI	no		WD40/YVTN_repeat-like_dom_sf, PALB2_WD40, WD40_repeat_dom_sf
MSRB3	Enzyme (other)	yes	1.8.4.12	Met_Sox_Rdtase_MsrB_dom, Mss4-like_sf, Met_Sox_Rdtase_MsrB
C11orf65	Other/Unknown	no
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
LIG4	Enzyme (other)	yes	6.5.1.1	DNA_ligase_ATP-dep, BRCT_dom, DNA_ligase_ATP-dep_N
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.

13 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)	17
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	3
oocyte	3
calcaneal tendon	2
right adrenal gland	2
right adrenal gland cortex	2
left lobe of thyroid gland	2
right lobe of thyroid gland	2
thyroid gland	2
ganglionic eminence	2
ventricular zone	2
secondary oocyte	2
colonic epithelium	1
olfactory bulb	1
stromal cell of endometrium	1
type B pancreatic cell	1
granulocyte	1
adrenal tissue	1
sural nerve	1
tibial nerve	1
cartilage tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon
TERT	105	broad	yes	stromal cell of endometrium, type B pancreatic cell, olfactory bulb
TINF2	144	ubiquitous	marker	granulocyte, right adrenal gland, right adrenal gland cortex
BIRC7	109	tissue_specific	marker	adrenal tissue, tibial nerve, sural nerve
CD274	208	ubiquitous	marker	cartilage tissue, placenta, lower lobe of lung
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
PALB2	232	ubiquitous	yes	secondary oocyte, buccal mucosa cell, oocyte
MSRB3	252	ubiquitous	marker	saphenous vein, cardiac muscle of right atrium, urethra
C11orf65	163	ubiquitous	marker	sperm, left testis, right testis
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
LIG4	275	ubiquitous	yes	endothelial cell, oocyte, secondary oocyte
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: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BRAF	7,394
TERT	5,717
PALB2	5,641
CD274	5,012
NKX2-1	2,403
LIG4	2,352
MSRB3	1,893
TINF2	1,769
FHIT	1,690
BIRC7	1,641

Intra-cohort edges

A	B	Sources
FOXE1	NKX2-1	string_interaction
FOXE1	PCNX2	string_interaction
FOXE1	TERT	intact
LIG4	NKX2-1	biogrid_interaction
PCNX2	SEPTIN11	string_interaction
TERT	TINF2	string_interaction

Structural data

PDB: 13 · AlphaFold-only: 3 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BRAF	P15056	131
CD274	Q9NZQ7	76
LIG4	P49917	31
TERT	O14746	23
BIRC7	Q96CA5	13
NRG1	Q02297	11
FHIT	P49789	9
PALB2	Q86YC2	4
TINF2	Q9BSI4	3
NKX2-1	P43699	2
MSRB3	Q8IXL7	2
VAV3	Q9UKW4	1
SEPTIN11	Q9NVA2	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C11orf65	Q8NCR3	74.69
FOXE1	O00358	62.02
PCNX2	A6NKB5	57.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 123. Enrichment computed across 17 evidence-associated genes (10 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 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Telomere Extension By Telomerase	2	91.4×	0.025	TERT, TINF2
Signaling by MRAS-complex mutants	1	285.5×	0.054	BRAF
Signalling to p38 via RIT and RIN	1	228.4×	0.054	BRAF
GRB7 events in ERBB2 signaling	1	190.3×	0.054	NRG1
Negative feedback regulation of MAPK pathway	1	190.3×	0.054	BRAF
Protein repair	1	190.3×	0.054	MSRB3
2-LTR circle formation	1	163.1×	0.054	LIG4
ARMS-mediated activation	1	163.1×	0.054	BRAF
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	163.1×	0.054	TERT
Prolonged ERK activation events	1	142.8×	0.054	BRAF
SHOC2 M1731 mutant abolishes MRAS complex function	1	142.8×	0.054	BRAF
Gain-of-function MRAS complexes activate RAF signaling	1	142.8×	0.054	BRAF
Regulation of PD-L1(CD274) translation	1	126.9×	0.054	CD274
Signaling by FGFR3	1	114.2×	0.054	BRAF
PI3K events in ERBB4 signaling	1	103.8×	0.054	NRG1
Signaling by FGFR4	1	103.8×	0.054	BRAF
STAT3 nuclear events downstream of ALK signaling	1	103.8×	0.054	CD274
Frs2-mediated activation	1	95.2×	0.054	BRAF
Downregulation of ERBB2:ERBB3 signaling	1	81.6×	0.054	NRG1
Telomere C-strand synthesis initiation	1	81.6×	0.054	TINF2
Signaling by FGFR1	1	81.6×	0.054	BRAF
ERBB2 Activates PTK6 Signaling	1	81.6×	0.054	NRG1
Processive synthesis on the C-strand of the telomere	1	76.1×	0.054	TINF2
Telomere C-strand (Lagging Strand) Synthesis	1	76.1×	0.054	TINF2
SHC1 events in ERBB4 signaling	1	71.4×	0.054	NRG1
Spry regulation of FGF signaling	1	71.4×	0.054	BRAF
ERBB2 Regulates Cell Motility	1	71.4×	0.054	NRG1
PI3K events in ERBB2 signaling	1	67.2×	0.054	NRG1
Removal of the Flap Intermediate from the C-strand	1	63.4×	0.054	TINF2
GRB2 events in ERBB2 signaling	1	63.4×	0.054	NRG1

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
thyroid gland development	3	108.7×	6e-04	BRAF, NKX2-1, FOXE1
RNA-templated transcription	1	1123.5×	0.013	TERT
diadenosine triphosphate catabolic process	1	1123.5×	0.013	FHIT
DNA strand elongation	1	1123.5×	0.013	TERT
regulation of natural killer cell apoptotic process	1	1123.5×	0.013	BIRC7
establishment of integrated proviral latency	1	1123.5×	0.013	LIG4
siRNA transcription	1	1123.5×	0.013	TERT
negative regulation of tumor necrosis factor superfamily cytokine production	1	1123.5×	0.013	CD274
positive regulation of transdifferentiation	1	1123.5×	0.013	TERT
regulation of telomere maintenance via telomere lengthening	1	1123.5×	0.013	TINF2
positive regulation of activated CD8-positive, alpha-beta T cell apoptotic process	1	1123.5×	0.013	CD274
DNA biosynthetic process	2	107.0×	0.013	TERT, LIG4
negative regulation of endothelial cell apoptotic process	2	66.1×	0.013	BRAF, TERT
T cell differentiation in thymus	2	54.8×	0.013	BRAF, LIG4
negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	2	54.8×	0.013	TERT, NRG1
thymus development	2	44.9×	0.013	BRAF, FOXE1
negative regulation of neuron apoptotic process	3	22.2×	0.013	BRAF, TERT, LIG4
RNA-templated DNA biosynthetic process	1	561.7×	0.018	TERT
developmental induction	1	561.7×	0.018	NKX2-1
ERBB3 signaling pathway	1	561.7×	0.018	NRG1
positive regulation of hair cycle	1	561.7×	0.018	TERT
positive regulation of peptidyl-tyrosine autophosphorylation	1	561.7×	0.018	NRG1
positive regulation of chromosome organization	1	561.7×	0.018	LIG4
positive regulation of cell adhesion	2	36.2×	0.018	VAV3, NRG1
somatic stem cell population maintenance	2	33.0×	0.018	BRAF, LIG4
purine nucleotide metabolic process	1	374.5×	0.022	FHIT
cerebral cortex GABAergic interneuron differentiation	1	374.5×	0.022	NKX2-1
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1	374.5×	0.022	BRAF
chordate pharynx development	1	374.5×	0.022	FOXE1
animal organ morphogenesis	2	25.5×	0.022	BRAF, PALB2

Therapeutics

Drugs indicated for this disease

3 approved, 7 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Selpercatinib	Approved (phase 4)
Thyrotropin Alfa	Approved (phase 4)
Vandetanib	Approved (phase 4)
Cabozantinib	Phase 3 (in late-stage trials)
Carboplatin	Phase 3 (in late-stage trials)
Dabrafenib	Phase 3 (in late-stage trials)
Lenvatinib	Phase 3 (in late-stage trials)
Selumetinib	Phase 3 (in late-stage trials)
Sorafenib	Phase 3 (in late-stage trials)
Trametinib	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Aflibercept, Alectinib, Bortezomib, Decitabine, Durvalumab, Imatinib, Pembrolizumab, Romidepsin, Tanespimycin, Thyrotropin, Tremelimumab, Vorinostat.

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 4 · Phased (≥1): 6 · Undrugged: 11

Druggability breadth: 7 of 17 evidence-associated genes (41%) 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
BRAF	VEMURAFENIB
TERT	BERBERINE
CD274	MOCLOBEMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BRAF	48	4
TERT	10	4
CD274	4	4
BIRC7	3	2
MSRB3	1	2
FHIT	1	3
TINF2	0	0
NKX2-1	0	0
VAV3	0	0
DIRC3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	BRAF
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF
SORAFENIB	4	BRAF
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF
DASATINIB	4	BRAF
ERLOTINIB	4	BRAF
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
MOCLOBEMIDE	4	CD274
PYRVINIUM	4	CD274
RIFABUTIN	4	CD274
MASITINIB	3	BRAF
AVUTOMETINIB	3	BRAF
NAPORAFENIB	3	BRAF
QUERCETIN	3	BRAF
MOTESANIB	3	BRAF

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
CD274	525	Binding:520, Functional:5
TERT	391	Binding:389, Functional:2
FHIT	21	Binding:19, ADMET:2
BIRC7	14	Binding:13, Functional:1
MSRB3	7	Binding:6, ADMET:1
LIG4	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
MSRB3	1.8.4.12, 1.8.4.B3	peptide-methionine (R)-S-oxide reductase,
FHIT	3.6.1.29	bis(5’-adenosyl)-triphosphatase
LIG4	6.5.1.1	DNA ligase (ATP)

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BRAF	1,442
TERT	391
CD274	525

Pharmacogenomics

Cohort genes with a PharmGKB record: 17; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

26 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)
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF
DASATINIB	4	BRAF
ERLOTINIB	4	BRAF
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
MOCLOBEMIDE	4	CD274
PYRVINIUM	4	CD274
RIFABUTIN	4	CD274
MASITINIB	3	BRAF
AVUTOMETINIB	3	BRAF
NAPORAFENIB	3	BRAF
QUERCETIN	3	BRAF
MOTESANIB	3	BRAF

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	BRAF, TERT, CD274
B	Phased (≥1) drug, not yet approved	3	BIRC7, MSRB3, FHIT
C	Druggable family + PDB, no drug	2	LIG4, NRG1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	9	TINF2, NKX2-1, VAV3, DIRC3, SEPTIN11, PALB2, C11orf65, FOXE1, PCNX2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TINF2	0	—
NKX2-1	0	—
VAV3	0	—
DIRC3	0	—
SEPTIN11	0	—
PALB2	0	—
C11orf65	0	—
FOXE1	0	—
LIG4	2	—
NRG1	0	—
PCNX2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 121.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	77
PHASE2	29
PHASE1	8
PHASE1/PHASE2	4
PHASE4	1
PHASE3	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07354698	PHASE4	NOT_YET_RECRUITING	Application of Mitoxantrone Hydrochloride Injection in Transoral Robotic Thyroid Cancer Surgery
NCT06791005	PHASE3	RECRUITING	A Clinical Study on the Benefits of Carbon Nanoparticles Injection Time in Patients With Thyroid Cancer.
NCT02152995	PHASE2	ACTIVE_NOT_RECRUITING	Trametinib in Increasing Tumoral Iodine Incorporation in Patients With Recurrent or Metastatic Thyroid Cancer
NCT02568267	PHASE2	ACTIVE_NOT_RECRUITING	Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangements (Fusions)
NCT03899792	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors
NCT03914300	PHASE2	ACTIVE_NOT_RECRUITING	Testing the Combination of Cabozantinib, Nivolumab, and Ipilimumab (CaboNivoIpi) for Advanced Differentiated Thyroid Cancer
NCT04544111	PHASE2	ACTIVE_NOT_RECRUITING	PDR001 Combination Therapy for Radioiodine-Refractory Thyroid Cancer
NCT04759911	PHASE2	ACTIVE_NOT_RECRUITING	Selpercatinib Before Surgery for the Treatment of RET-Altered Thyroid Cancer
NCT05668962	PHASE2	RECRUITING	Restor. I-131 Upt. + Selpercatinib in RET F-P RAI-R TC
NCT06440850	PHASE2	RECRUITING	Vemurafenib and Cobimetinib for the Treatment of Patients With High Risk Differentiated Thyroid Carcinoma With BRAFV600E Mutation
NCT06959641	PHASE2	RECRUITING	XL092 for the Treatment of Locally Advanced or Metastatic Radioiodine Refractory Differentiated Thyroid Cancer
NCT07521670	PHASE2	NOT_YET_RECRUITING	Sacituzumab Tirumotecan in Recurrent/Metastatic Adenoid Cystic Carcinoma and Papillary Thyroid Carcinoma (STRAP)
NCT00085293	PHASE2	COMPLETED	Decitabine in Treating Patients With Metastatic Papillary Thyroid Cancer or Follicular Thyroid Cancer Unresponsive to Iodine I 131
NCT00095693	PHASE2	TERMINATED	Sorafenib Tosylate in Treating Patients With Locally Advanced, Metastatic, or Locally Recurrent Thyroid Cancer
NCT00098813	PHASE2	COMPLETED	Romidepsin in Treating Patients With Recurrent and/or Metastatic Thyroid Cancer That Has Not Responded to Radioactive Iodine
NCT00104871	PHASE2	COMPLETED	Bortezomib in Treating Patients With Metastatic Thyroid Cancer That Did Not Respond to Radioactive Iodine Therapy
NCT00118248	PHASE2	COMPLETED	Tanespimycin in Treating Patients With Inoperable Locoregionally Advanced or Metastatic Thyroid Cancer
NCT00134043	PHASE2	COMPLETED	Suberoylanilide Hydroxamic Acid in Treating Patients With Metastatic and/or Locally Advanced or Locally Recurrent 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
NCT00519896	PHASE2	COMPLETED	Sunitinib Malate in Treating Patients With Iodine-Refractory Recurrent or Metastatic Thyroid Cancer
NCT00559949	PHASE2	COMPLETED	Selumetinib in Treating Patients With Papillary Thyroid Cancer That Did Not Respond to Radioactive Iodine
NCT00668811	PHASE2	COMPLETED	Sutent Adjunctive Treatment of Differentiated Thyroid Cancer
NCT00729157	PHASE2	COMPLETED	Aflibercept in Treating Patients With Recurrent and/or Metastatic Thyroid Cancer That Did Not Respond to Radioactive Iodine Therapy
NCT01208051	PHASE1/PHASE2	COMPLETED	Cediranib Maleate With or Without Lenalidomide for the Treatment of Thyroid Cancer
NCT01502410	PHASE2	COMPLETED	Sorafenib Tosylate in Treating Younger Patients With Relapsed or Refractory Rhabdomyosarcoma, Wilms Tumor, Liver Cancer, or Thyroid Cancer
NCT01723202	PHASE2	COMPLETED	Dabrafenib With or Without Trametinib in Treating Patients With Advanced Differentiated Thyroid Cancer
NCT01811212	PHASE2	COMPLETED	Cabozantinib-S-Malate in Treating Patients With Refractory Thyroid Cancer
NCT02138214	PHASE2	COMPLETED	Central Neck Dissection in Patients With Clinical Node Negative Thyroid Cancer
NCT02393690	PHASE2	COMPLETED	Iodine I-131 With or Without Selumetinib in Treating Patients With Recurrent or Metastatic Thyroid Cancer
NCT02973997	PHASE2	COMPLETED	Lenvatinib and Pembrolizumab in Differentiated Thyroid Cancers (DTC)
NCT03506048	PHASE2	TERMINATED	Lenvatinib and Iodine Therapy in Treating Patients With Radioactive Iodine-Sensitive Differentiated Thyroid Cancer
NCT03630120	PHASE2	TERMINATED	Adaptive Tyrosine Kinase Inhibitor (TKI) Therapy In Patients With Thyroid Cancer
NCT03753919	PHASE2	TERMINATED	Durvalumab Plus Tremelimumab for the Treatment of Patients With Progressive, Refractory Advanced Thyroid Carcinoma -The DUTHY Trial
NCT04731467	PHASE1/PHASE2	COMPLETED	A Study of CM24 in Combination with Nivolumab in Adults with Advanced Solid Tumors
NCT05500508	PHASE1/PHASE2	TERMINATED	Oral AMXT 1501 Dicaprate in Combination With IV DFMO
NCT00004074	PHASE1	COMPLETED	Interleukin-12 and Trastuzumab in Treating Patients With Cancer That Has High Levels of HER2/Neu
NCT00451880	PHASE1	COMPLETED	Study of XL281 in Adults With Solid Tumors
NCT00470496	PHASE1	COMPLETED	Photodynamic Therapy Using HPPH in Treating Patients Undergoing Surgery for Primary or Recurrent Head and Neck Cancer
NCT01100619	PHASE1	COMPLETED	A Drug-Drug Interaction Study of the Effects of XL184 (Cabozantinib) on Rosiglitazone in Subjects With Solid Tumors
NCT01413113	PHASE1	COMPLETED	Iodine I 131 and Pazopanib Hydrochloride in Treating Patients With Recurrent and/or Metastatic Thyroid Cancer Previously Treated With Iodine I 131 That Cannot Be Removed By Surgery

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SUNITINIB	4	9
CABOZANTINIB	4	7
SELPERCATINIB	4	4
SORAFENIB	4	4
FLUDEOXYGLUCOSE F 18	4	3
DABRAFENIB	4	2
LENVATINIB	4	2
SELUMETINIB	4	2
TRAMETINIB	4	2
COBIMETINIB	4	1
DECITABINE	4	1
EFLORNITHINE	4	1
ENTRECTINIB	4	1
FAMOTIDINE	4	1
FERUMOXYTOL	4	1
MITOXANTRONE	4	1
PAZOPANIB HYDROCHLORIDE	4	1
ROMIDEPSIN	4	1
VANDETANIB	4	1
VEMURAFENIB	4	1
VORINOSTAT	4	1
IODINE	3	4
CEDIRANIB	3	3
THYROID	3	2
SACITUZUMAB TIRUMOTECAN	3	1
SPARTALIZUMAB	3	1
TANESPIMYCIN	3	1
ZANZALINTINIB	3	1
EDODEKIN ALFA	2	1
HPPH	2	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 10 predictive associations from 14 curated evidence items; also 12 prognostic, 2 diagnostic.

Molecular subtype	Therapy	Effect	Level	CIViC
BRAF V600E	Vemurafenib	Sensitivity/Response	CIViC B	EID1591 +4
BRAF V600E	Dabrafenib	Sensitivity/Response	CIViC B	EID7761
BRAF V600E	Trametinib + Dabrafenib	Sensitivity/Response	CIViC B	EID7762
RET Fusion	Selpercatinib	Sensitivity/Response	CIViC B	EID7069
EML4::NTRK3 Fusion	Entrectinib	Sensitivity/Response	CIViC C	EID10635
ETV6::NTRK2 Fusion AND TERT c.-124C.T	Larotrectinib	Sensitivity/Response	CIViC C	EID11278
SQSTM1::NTRK1 Fusion	Larotrectinib	Sensitivity/Response	CIViC C	EID11575
TPM3::NTRK1 Fusion	Larotrectinib	Sensitivity/Response	CIViC C	EID8042
TPR::NTRK1 Fusion	Larotrectinib	Sensitivity/Response	CIViC C	EID11747
BRAF V600E	Dasatinib	Sensitivity/Response	CIViC D	EID3775