Thyroid gland carcinoma

Summary

Thyroid gland carcinoma (MONDO:0015075) is a cancer (an umbrella term covering 11 Mondo subtypes) with 31 cohort genes (225 GWAS associations across 34 studies; 15 CIViC-evidence somatic drivers; 1 ClinVar predisposition record) and 504 clinical trials. The dominant Reactome pathway is Signaling by ERBB2 KD Mutants (5 cohort genes). Molecularly, RET Fusion confers sensitivity to Pralsetinib in Thyroid Cancer (CIViC Level A); 22 further subtype–drug associations are mapped below. Top therapeutic interventions include cabozantinib, dabrafenib, and sunitinib.

At a glance

• Classification: Cancer
• Prevalence: 1-5 / 10 000 (Worldwide) [Orphanet-validated]
• Umbrella term: 11 Mondo subtypes
• Cohort genes: 31
• GWAS associations: 225
• ClinVar variants: 1
• Clinical trials: 504
• Precision-medicine evidence (CIViC): 23 subtype–drug associations

Clinical features

Epidemiology

Prevalence records

27 prevalence record(s), Orphanet, top 20 (validated / broadest geography first):

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	3.1	Worldwide	Validated
Point prevalence	1-5 / 10 000	12.7	Worldwide	Validated
Lifetime Prevalence	6-9 / 10 000	61.7	Europe	Validated
Annual incidence	1-5 / 10 000	12.2	United States	Validated
Annual incidence	1-9 / 100 000	2.733	United Kingdom	Validated
Annual incidence	1-5 / 10 000	12.86	Italy	Validated
Annual incidence	1-9 / 100 000	7.679	Austria	Validated
Annual incidence	1-9 / 100 000	3.74	Belgium	Validated
Annual incidence	1-9 / 100 000	2.921	Bulgaria	Validated
Annual incidence	1-9 / 100 000	8.329	Croatia	Validated
Annual incidence	1-9 / 100 000	6.382	Czech Republic	Validated
Annual incidence	1-9 / 100 000	4.803	Estonia	Validated
Annual incidence	1-9 / 100 000	6.375	Finland	Validated
Annual incidence	1-9 / 100 000	5.526	Germany	Validated
Annual incidence	1-9 / 100 000	2.45	Ireland	Validated
Annual incidence	1-9 / 100 000	4.563	Latvia	Validated
Annual incidence	1-9 / 100 000	7.905	Lithuania	Validated
Annual incidence	1-9 / 100 000	6.344	Malta	Validated
Annual incidence	1-9 / 100 000	4.472	Norway	Validated
Annual incidence	1-9 / 100 000	4.488	Poland	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	thyroid gland carcinoma
Mondo ID	MONDO:0015075
EFO	EFO:0002892
Orphanet	100088
DOID	DOID:3963
NCIT	C4815
SNOMED CT	448216007
UMLS	C0549473
MedGen	107811
GARD	0019763
MedDRA	10007476
Anatomy (UBERON)	UBERON:0002046
Is cancer (heuristic)	yes

Also known as: cancer of the thyroid · cancer of thyroid · carcinoma of the thyroid · carcinoma of the thyroid gland · carcinoma of thyroid · carcinoma of thyroid gland · head and neck cancer, thyroid · thyroid cancer · thyroid carcinoma · thyroid gland cancer · thyroid gland carcinoma

Data availability: 1 ClinVar variant · 225 GWAS associations (34 studies) · 1 GenCC gene-disease record · 1 HPO phenotype · 18 cell lines.

Disease family

An umbrella term covering 11 Mondo subtypes.

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

Related subtypes (2): thyroid sarcoma, thyroid lymphoma

Subtypes (11): thyroid gland spindle cell tumor with thymus-like differentiation, thyroid gland squamous cell carcinoma, thyroid gland undifferentiated (anaplastic) carcinoma, differentiated thyroid 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

Genetics & variants

GWAS landscape

225 GWAS associations across 34 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
rs1561962	6e-292	PTCSC2	T	0.42
rs925488	2e-269	PTCSC2	A	0.44
rs57481445	2e-139	DIRC3	G	0.24
rs2439304	1e-112	NRG1	G	0.17
rs2183451	7e-99	LINC00609	G	0.15
rs12589124	1e-83	LINC00609	A	0.18
rs9971770	4e-63	MSRB3-AS1	C	0.24
rs1588635	2e-58	PTCSC2	A	1.69
rs7725218	3e-44	TERT	A	0.11
rs78455089	1e-41	EPB41L4A	A	0.22
rs965513	6e-40	PTCSC2	G	0.52
rs3009947	4e-39	LINC02869	C	0.14
rs2466074	5e-39	NRG1	T	0.33
rs1690789	1e-37	LINC02869	T	0.16
rs925489	9e-35	PTCSC2	T	0.56
rs10181989	2e-34	DIRC3	C	0.28
rs73227498	3e-34	EPB41L4A	T	0.22
rs75263779	3e-33	STN1 - SLK	C	0.36
rs12133184	7e-33	PCNX2	A	0.14
rs10878309	5e-32	MSRB3-AS1	G	0.32
rs17293632	1e-31	SMAD3	T	0.15
rs7726159	3e-31	TERT	A	0.15
rs12438955	5e-31	KNL1	T	0.12
rs11277366	1e-30	LINC02950	C	0.14
rs11591710	3e-29	STN1 - SLK	C	0.19
rs72743461	2e-28	SMAD3	A	0.15
rs7030280	5e-28	PTCSC2	C	1.77
rs1537425	2e-27	LINC00609	A	0.24
rs12130559	1e-26	PCNX2	C	0.15
rs35446936	2e-26	ACTRT3	A	0.12

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90627776	White SL	2026	20,426	2,802,617	Global multi-ancestry genome-wide analyses identify genes and biological pathways associated with thyroid cancer and benign thyroid diseases.
GCST90627763	White SL	2026	14,764	2,091,602	Global multi-ancestry genome-wide analyses identify genes and biological pathways associated with thyroid cancer and benign thyroid diseases.
GCST90627775	White SL	2026	13,582	2,015,965	Global multi-ancestry genome-wide analyses identify genes and biological pathways associated with thyroid cancer and benign thyroid diseases.
GCST90627758	White SL	2026	8,253	0	Global multi-ancestry genome-wide analyses identify genes and biological pathways associated with thyroid cancer and benign thyroid diseases.
GCST90627773	White SL	2026	7,071	0	Global multi-ancestry genome-wide analyses identify genes and biological pathways associated with thyroid cancer and benign thyroid diseases.
GCST90627762	White SL	2026	4,446	406,110	Global multi-ancestry genome-wide analyses identify genes and biological pathways associated with thyroid cancer and benign thyroid diseases.
GCST004144	Gudmundsson J	2017	2,637	134,811	A genome-wide association study yields five novel thyroid cancer risk loci.
GCST90245888	Feng X	2022	1,956	101,924	Association Between Genetic Risk, Adherence to Healthy Lifestyle Behavior, and Thyroid Cancer Risk.
GCST90018929	Sakaue S	2021	1,054	490,920	A cross-population atlas of genetic associations for 220 human phenotypes.
GCST90245887	Feng X	2022	986	5,135	Association Between Genetic Risk, Adherence to Healthy Lifestyle Behavior, and Thyroid Cancer Risk.

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	1
Tier 4: intronic/intergenic	46

MAF distribution

Bucket	Variants
common (>=0.05)	48
low_freq (0.01-0.05)	1
rare (<0.01)	1
unknown	0

Functional consequences

Consequence	Count
intron_variant	38
intergenic_variant	5
non_coding_transcript_exon_variant	3
TF_binding_site_variant	1
missense_variant	1
5_prime_UTR_variant	1
3_prime_UTR_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs1561962	9	97783937	C>G,T	0.322	intron_variant	PTCSC2	6e-292	Tier 4: intronic/intergenic
rs925488	9	97784109	G>A	0.349	intron_variant	PTCSC2	2e-269	Tier 4: intronic/intergenic
rs57481445	2	217431651	A>G	0.297	intron_variant	DIRC3	2e-139	Tier 4: intronic/intergenic
rs2439304	8	32572853	A>G,T	0.473	intron_variant	NRG1	1e-112	Tier 4: intronic/intergenic
rs2183451	14	36095227	T>G	0.499	intron_variant	LINC00609	7e-99	Tier 4: intronic/intergenic
rs12589124	14	36094718	G>A	0.432	intron_variant	LINC00609	1e-83	Tier 4: intronic/intergenic
rs9971770	12	65639270	G>A,C,T	0.159	intron_variant	MSRB3-AS1	4e-63	Tier 4: intronic/intergenic
rs1588635	9	97775520	A>C,T	0.396	intron_variant	PTCSC2	2e-58	Tier 4: intronic/intergenic
rs7725218	5	1282299	G>A,T	0.373	intron_variant	TERT	3e-44	Tier 4: intronic/intergenic
rs78455089	5	112143173	C>A	0.116	TF_binding_site_variant	EPB41L4A	1e-41	Tier 3: regulatory
rs965513	9	97793827	A>C,G,T	0.05	intron_variant	PTCSC2	6e-40	Tier 4: intronic/intergenic
rs3009947	1	218515813	T>A,C,G	0.437	intron_variant	LINC02869	4e-39	Tier 4: intronic/intergenic
rs2466074	8	32575620	C>A,G,T	0.213	intron_variant	NRG1	5e-39	Tier 4: intronic/intergenic
rs1690789	1	218524685	C>A,T	0.478	intron_variant	LINC02869	1e-37	Tier 4: intronic/intergenic
rs925489	9	97784318	C>A,G,T	0.05	intron_variant	PTCSC2	9e-35	Tier 4: intronic/intergenic
rs10181989	2	217430192	T>C	0.414	intron_variant	DIRC3	2e-34	Tier 4: intronic/intergenic
rs73227498	5	112150207	A>T	0.129	intergenic_variant	EPB41L4A	3e-34	Tier 4: intronic/intergenic
rs75263779	10	103939849	T>C	0.062	intron_variant	STN1 - SLK	3e-33	Tier 4: intronic/intergenic
rs12133184	1	233276649	G>A	0.187	intron_variant	PCNX2	7e-33	Tier 4: intronic/intergenic
rs10878309	12	65633254	A>G,T	0.165	intron_variant	MSRB3-AS1	5e-32	Tier 4: intronic/intergenic
rs17293632	15	67150258	C>A,T	0.214	intron_variant	SMAD3	1e-31	Tier 4: intronic/intergenic
rs7726159	5	1282204	C>A	0.335	intron_variant	TERT	3e-31	Tier 4: intronic/intergenic
rs12438955	15	40598312	G>A,C,T	0.22	intron_variant	KNL1	5e-31	Tier 4: intronic/intergenic
rs11277366	8	8457502	CCAGAGAGGCT>C	0.477	intron_variant	LINC02950	1e-30	Tier 4: intronic/intergenic
rs11591710	10	103927874	A>C	0.129	intron_variant	STN1 - SLK	3e-29	Tier 4: intronic/intergenic
rs72743461	15	67149412	C>A,T	0.24	intron_variant	SMAD3	2e-28	Tier 4: intronic/intergenic
rs7030280	9	97772985	C>T	0.05	intron_variant	PTCSC2	5e-28	Tier 4: intronic/intergenic
rs1537425	14	36098954	G>A,C	0.405	intron_variant	LINC00609	2e-27	Tier 4: intronic/intergenic
rs12130559	1	233276358	T>C	0.203	intron_variant	PCNX2	1e-26	Tier 4: intronic/intergenic
rs35446936	3	169768720	G>A,C	0.338	intron_variant	ACTRT3	2e-26	Tier 4: intronic/intergenic

ClinVar germline variants

1 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
13917	NM_020975.6(RET):c.1900T>C (p.Cys634Arg)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 119 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 4

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

Gene	HGNC	Evidence routes
TERT	TERT	GWAS, Orphanet
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
TERT	Act	PRCC	CIViC #79
RET	Act	ANGS,MEL,NSCLC,PGNG,SOFT_TISSUE,WDTC	CIViC #42
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
TSC2	LoF	ANGS,BLCA,CHOL,CHRCC,ESCA,HCC,PANCREAS,PANET,SCLC,STAD	CIViC #47
POT1	Act	ANGS,CLLSLL,LGGNOS,MEL,SOFT_TISSUE	CIViC #9935
MTOR	Act	BLCA,BRCA,CCRCC,CHRCC,CLLSLL,COADREAD,HCC,LGGNOS,PANET,RCC,UCEC	CIViC #2073
HRAS	Act	ANGS,BLCA,BRCA,COADREAD,CSCC,HNSC,LUSC,NPC,PGNG,PRAD,PROSTATE,THYM,UTUC,WDTC	CIViC #2747
KRAS	Act	ALL,AML,ANSC,BLADDER,BLCA,BRCA,CEAD,CESC,CHOL,CLLSLL,COAD,COADREAD,DLBCLNOS,EGC,ESCA,ESCC,HCC,LUAD,LUSC,MEL,MGCT,MT,NSCLC,OVT,PAAD,PANCREAS,PAST,PCM,PRAD,PRCC,READ,STAD,STOMACH,UCEC,UCS,WDTC	CIViC #30
NF2	LoF	CCRCC,CESC,HCC,HNSC,MEL,OVT,PAAD,PLMESO,PRCC,RCC	CIViC #3870
NRAS	Act	ALL,AML,ANGS,CHOL,CLLSLL,COAD,COADREAD,GBM,HCC,LGGNOS,LUAD,LUSC,MEL,MGCT,NPC,OVT,PCM,PROSTATE,SKCM,THYM,UCEC,WDTC	CIViC #36
PIK3CA	Act	ACYC,ANGS,ANSC,BCC,BLADDER,BLCA,BRCA,CCRCC,CEAD,CESC,CHOL,COAD,COADREAD,EPM,ESCA,ESCC,GB,GBM,HCC,HGGNOS,HNSC,LGGNOS,LIPO,LMS,LUAD,LUSC,MBL,MGCT,NPC,NSCLC,OVT,PAAD,PAST,PLMESO,PRAD,PRCC,PROSTATE,RCC,SACA,SKCM,SOFT_TISSUE,STAD,UCEC,UCS,UTUC,VULVA,WDTC	CIViC #37
PTEN	LoF	ANGS,BLCA,BRCA,CCRCC,CEAD,CESC,CHOL,CHRCC,COADREAD,CSCC,ESCA,GB,GBM,HCC,HGGNOS,HNSC,LGGNOS,LIPO,LUAD,LUSC,MBL,MEL,MT,NSCLC,OVT,PANET,PAST,PRAD,PRCC,PROSTATE,RCC,SCLC,SKCM,SOFT_TISSUE,STAD,UCEC,UCS,WDTC	CIViC #41
NKX2-1	LoF	LGGNOS	CIViC #80
SMAD3	LoF	COADREAD,PAAD	CIViC #3376
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
POT1	Limited	Autosomal dominant	thyroid gland carcinoma	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare 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
RET	Orphanet:146	Differentiated thyroid carcinoma
RET	Orphanet:1848	Renal agenesis, bilateral
RET	Orphanet:247698	Multiple endocrine neoplasia type 2A
RET	Orphanet:247709	Multiple endocrine neoplasia type 2B
RET	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
RET	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
RET	Orphanet:388	Hirschsprung disease
RET	Orphanet:93100	Renal agenesis, unilateral
RET	Orphanet:99361	Isolated familial medullary thyroid carcinoma
RET	Orphanet:99803	Haddad syndrome
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
TSC2	Orphanet:210159	Adult hepatocellular carcinoma
TSC2	Orphanet:269001	Isolated focal cortical dysplasia type IIa
TSC2	Orphanet:269008	Isolated focal cortical dysplasia type IIb
TSC2	Orphanet:538	Lymphangioleiomyomatosis
TSC2	Orphanet:805	Tuberous sclerosis complex
TSC2	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
POT1	Orphanet:251627	Oligodendroglioma
POT1	Orphanet:251630	Anaplastic oligodendroglioma
POT1	Orphanet:618	Familial melanoma
POT1	Orphanet:67038	B-cell chronic lymphocytic leukemia
MTOR	Orphanet:269001	Isolated focal cortical dysplasia type IIa
MTOR	Orphanet:269008	Isolated focal cortical dysplasia type IIb
MTOR	Orphanet:457485	Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome
MTOR	Orphanet:99802	Hemimegalencephaly
HRAS	Orphanet:146	Differentiated thyroid carcinoma
HRAS	Orphanet:2612	Linear nevus sebaceus syndrome
HRAS	Orphanet:2874	Phakomatosis pigmentokeratotica
HRAS	Orphanet:3071	Costello syndrome
HRAS	Orphanet:79414	Woolly hair nevus
KRAS	Orphanet:1333	Familial pancreatic carcinoma

Cohort genes → proteins

31 cohort genes, 28 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	19
civic_only	9
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TERT	HGNC:11730	ENSG00000164362	O14746	Telomerase reverse transcriptase	gwas,civic_evidence
RET	HGNC:9967	ENSG00000165731	P07949	Proto-oncogene tyrosine-protein kinase receptor Ret	clinvar,civic_evidence
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	civic_evidence
TSC2	HGNC:12363	ENSG00000103197	P49815	Tuberin	civic_evidence
POT1	HGNC:17284	ENSG00000128513	Q9NUX5	Protection of telomeres protein 1	gencc
MTOR	HGNC:3942	ENSG00000198793	P42345	Serine/threonine-protein kinase mTOR	civic_evidence
HRAS	HGNC:5173	ENSG00000174775	P01112	GTPase HRas	civic_evidence
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	civic_evidence
NF2	HGNC:7773	ENSG00000186575	P35240	Merlin	civic_evidence
NRAS	HGNC:7989	ENSG00000213281	P01111	GTPase NRas	civic_evidence
PIK3CA	HGNC:8975	ENSG00000121879	P42336	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	civic_evidence
PTEN	HGNC:9588	ENSG00000171862	P60484	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	civic_evidence
TERC	HGNC:11727	ENSG00000270141		telomerase RNA component	gwas
NKX2-1	HGNC:11825	ENSG00000136352	P43699	Homeobox protein Nkx-2.1	gwas
TMOD1	HGNC:11871	ENSG00000136842	P28289	Tropomodulin-1	gwas
XPA	HGNC:12814	ENSG00000136936	P23025	DNA repair protein complementing XP-A cells	gwas
EPB41L4A	HGNC:13278	ENSG00000129595	Q9HCS5	Band 4.1-like protein 4A	gwas
NREP	HGNC:16834	ENSG00000134986	Q16612	Neuronal regeneration-related protein	gwas
HEMGN	HGNC:17509	ENSG00000136929	Q9BXL5	Hemogen	gwas
DIRC3	HGNC:17805	ENSG00000231672		disrupted in renal carcinoma 3	gwas
MBIP	HGNC:20427	ENSG00000151332	Q9NS73	MAP3K12-binding inhibitory protein 1	gwas
STN1	HGNC:26200	ENSG00000107960	Q9H668	CST complex subunit STN1	gwas
LRRC34	HGNC:28408	ENSG00000171757	Q8IZ02	Leucine-rich repeat-containing protein 34	gwas
TSTD2	HGNC:30087	ENSG00000136925	Q5T7W7	Thiosulfate sulfurtransferase/rhodanese-like domain-containing protein 2	gwas
TRMO	HGNC:30967	ENSG00000136932	Q9BU70	tRNA (adenine(37)-N6)-methyltransferase	gwas
FOXE1	HGNC:3806	ENSG00000178919	O00358	Forkhead box protein E1	gwas
KRT18P13	HGNC:6432	ENSG00000214417		keratin 18 pseudogene 13	gwas
SMAD3	HGNC:6769	ENSG00000166949	P84022	SMAD family member 3	gwas
NCBP1	HGNC:7658	ENSG00000136937	Q09161	Nuclear cap-binding protein subunit 1	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)
TERT	Telomerase reverse transcriptase	Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes.
RET	Proto-oncogene tyrosine-protein kinase receptor Ret	Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN,…
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
TSC2	Tuberin	Catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule…
POT1	Protection of telomeres protein 1	Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini.
MTOR	Serine/threonine-protein kinase mTOR	Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals.
HRAS	GTPase HRas	Involved in the activation of Ras protein signal transduction.
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
NF2	Merlin	Probable regulator of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, a signaling pathway that plays a pivotal role in tumor suppression by restricting proliferation and promoting apoptosis.
NRAS	GTPase NRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
PIK3CA	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides.
PTEN	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	Dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins.
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.
TMOD1	Tropomodulin-1	Blocks the elongation and depolymerization of the actin filaments at the pointed end.
XPA	DNA repair protein complementing XP-A cells	Involved in DNA nucleotide excision repair (NER).
NREP	Neuronal regeneration-related protein	May have roles in neural function.
HEMGN	Hemogen	Regulates the proliferation and differentiation of hematopoietic cells.
MBIP	MAP3K12-binding inhibitory protein 1	Functions as part of the ATAC complex, a complex with histone acetyltransferase activity on histones H3 and H4.
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.
LRRC34	Leucine-rich repeat-containing protein 34	Highly expressed in stem cells where it may be involved in regulation of pluripotency.
TRMO	tRNA (adenine(37)-N6)-methyltransferase	S-adenosyl-L-methionine-dependent methyltransferase responsible for the addition of the methyl group in the formation of N6-methyl-N6-threonylcarbamoyladenosine at position 37 (m(6)t(6)A37) of the tRNA anticodon loop of tRNA(Ser)(GCU).
FOXE1	Forkhead box protein E1	Transcription factor that binds consensus sites on a variety of gene promoters and activate their transcription.
SMAD3	SMAD family member 3	Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases.
NCBP1	Nuclear cap-binding protein subunit 1	Component of the cap-binding complex (CBC), which binds cotranscriptionally to the 5’-cap of pre-mRNAs and is involved in various processes such as pre-mRNA splicing, translation regulation, nonsense-mediated mRNA decay, RNA-mediated gene…
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: 8 · Difficult: 3 · Unknown: 20 · Druggable fraction: 0.26

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
Kinase	4	3.6×	0.146
Phosphatase	1	2.7×	0.621
Other/Unknown	20	1.2×	0.621
Antibody/Immunoglobulin	1	0.9×	0.743
Transcription factor	3	0.8×	0.743
Enzyme (other)	2	0.8×	0.743

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TERT	Other/Unknown	no		RT_dom, Telomerase_RT, Telomerase_RBD
RET	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Cadherin-like_dom
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
TSC2	Other/Unknown	no		Rap/Ran_GAP_dom, Tuberin, ARM-like
POT1	Other/Unknown	no		Telomer_end-bd_POT1/Cdc13, NA-bd_OB-fold, POT1
MTOR	Kinase	yes		PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
HRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
KRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
NF2	Other/Unknown	no		FERM_domain, Ez/rad/moesin-like, Moesin_tail_sf
NRAS	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
PIK3CA	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom
PTEN	Phosphatase	yes	3.1.3.16	Tyr_Pase_dom, Tyr_Pase_cat, Tensin_C2-dom
TERC	Other/Unknown	no
NKX2-1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
TMOD1	Other/Unknown	no		TMOD, LRR_dom_sf
XPA	Transcription factor	no		XPA/RAD14, DNA-bd_dom_put_sf, Znf_XPA_CS
EPB41L4A	Other/Unknown	no		FERM_domain, Ez/rad/moesin-like, PH-like_dom_sf
NREP	Other/Unknown	no		Neuronal_3.1
HEMGN	Other/Unknown	no		Hemogen
DIRC3	Other/Unknown	no
MBIP	Other/Unknown	no
STN1	Other/Unknown	no		NA-bd_OB_tRNA, NA-bd_OB-fold, Stn1
LRRC34	Other/Unknown	no		Leu-rich_rpt, LRR_dom_sf, LRR-containing_regulator
TSTD2	Other/Unknown	no		Rhodanese-like_dom, TrhO, Rhodanese_C
TRMO	Other/Unknown	no		UPF0066_cons_site, TrmO-like_N, YaeB-like_sf
FOXE1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
KRT18P13	Other/Unknown	no
SMAD3	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf
NCBP1	Other/Unknown	no		MIF4G-like_typ-3, MIF4G-like_typ-1, MIF4G-like_typ-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.

27 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)	1
broad (>20)	30
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	8
left lobe of thyroid gland	5
right lobe of thyroid gland	4
thyroid gland	4
secondary oocyte	3
primordial germ cell in gonad	3
sperm	3
ganglionic eminence	3
stromal cell of endometrium	2
type B pancreatic cell	2
buccal mucosa cell	2
colonic epithelium	2
cerebellar hemisphere	2
right hemisphere of cerebellum	2
epithelium of nasopharynx	2
male germ line stem cell (sensu Vertebrata) in testis	2
hindlimb stylopod muscle	2
oocyte	2
olfactory bulb	1
dorsal root ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TERT	105	broad	yes	stromal cell of endometrium, type B pancreatic cell, olfactory bulb
RET	193	broad	marker	substantia nigra pars reticulata, dorsal root ganglion, substantia nigra pars compacta
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon
TSC2	282	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
POT1	279	ubiquitous	marker	secondary oocyte, germinal epithelium of ovary, calcaneal tendon
MTOR	207	ubiquitous	marker	primordial germ cell in gonad, right hemisphere of cerebellum, cerebellar hemisphere
HRAS	139	ubiquitous	marker	skin of abdomen, skin of leg, zone of skin
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple
NF2	283	ubiquitous	marker	endometrium epithelium, stromal cell of endometrium, dorsal motor nucleus of vagus nerve
NRAS	278	ubiquitous	marker	gingival epithelium, epithelium of nasopharynx, secondary oocyte
PIK3CA	284	ubiquitous	marker	calcaneal tendon, adrenal tissue, tendon
PTEN	256	ubiquitous	marker	sperm, endothelial cell, calcaneal tendon
TERC	113	ubiquitous	yes	bone marrow cell, colonic epithelium, male germ line stem cell (sensu Vertebrata) in testis
NKX2-1	101	broad	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
TMOD1	265	broad	marker	type B pancreatic cell, hindlimb stylopod muscle, islet of Langerhans
XPA	289	ubiquitous	marker	calcaneal tendon, Brodmann (1909) area 23, left lobe of thyroid gland
EPB41L4A	238	broad	marker	palpebral conjunctiva, calcaneal tendon, eye
NREP	292	ubiquitous	marker	cortical plate, paraflocculus, ganglionic eminence
HEMGN	106	broad	marker	trabecular bone tissue, sperm, bone marrow
DIRC3	161	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, layer of synovial tissue, synovial joint
MBIP	276	ubiquitous	marker	left lobe of thyroid gland, right lobe of thyroid gland, thyroid gland
STN1	284	ubiquitous	marker	lower esophagus mucosa, oral cavity, esophagus mucosa
LRRC34	192	broad	marker	bronchial epithelial cell, bronchus, sperm
TSTD2	289	ubiquitous	marker	secondary oocyte, oocyte, primordial germ cell in gonad
TRMO	263	ubiquitous	yes	epithelium of nasopharynx, calcaneal tendon, primordial germ cell in gonad
FOXE1	94	tissue_specific	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
KRT18P13	8		marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
SMAD3	288	ubiquitous	marker	tendon of biceps brachii, cartilage tissue, hindlimb stylopod muscle
NCBP1	250	ubiquitous	marker	sural nerve, calcaneal tendon, ganglionic eminence
NRG1	209	ubiquitous	marker	ventricular zone, ganglionic eminence, oocyte

Protein interactions among cohort

Intra-cohort edges: 38.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRAS	14,509
PTEN	11,626
MTOR	9,490
HRAS	8,064
NRAS	7,598
BRAF	7,394
SMAD3	6,440
TERT	5,717
PIK3CA	5,157
RET	4,203

Intra-cohort edges

A	B	Sources
BRAF	HRAS	intact, string_interaction
BRAF	KRAS	biogrid_interaction, intact, string_interaction
BRAF	NRAS	biogrid_interaction, intact, string_interaction
BRAF	PIK3CA	biogrid_interaction, string_interaction
BRAF	PTEN	biogrid_interaction, string_interaction
EPB41L4A	NREP	string_interaction
EPB41L4A	PCNX2	string_interaction
FOXE1	HEMGN	string_interaction
FOXE1	NKX2-1	string_interaction
FOXE1	PCNX2	string_interaction
FOXE1	TERT	intact
FOXE1	TRMO	string_interaction
HEMGN	KRAS	intact
HEMGN	NRAS	intact
HEMGN	TRMO	string_interaction
KRAS	NRAS	intact
KRAS	PIK3CA	string_interaction
KRAS	PTEN	string_interaction
LRRC34	PCNX2	string_interaction
LRRC34	STN1	string_interaction
MTOR	NCBP1	biogrid_interaction
MTOR	PTEN	string_interaction
MTOR	TSC2	string_interaction
NF2	PIK3CA	intact
NKX2-1	SMAD3	intact, string_interaction
NRAS	PIK3CA	string_interaction
NRAS	PTEN	string_interaction
NRAS	TRMO	intact
NREP	PCNX2	string_interaction
PCNX2	STN1	string_interaction
PIK3CA	PTEN	string_interaction
PIK3CA	TMOD1	intact
POT1	TERT	string_interaction
PTEN	TRMO	intact
PTEN	TSC2	string_interaction
STN1	XPA	string_interaction
TRMO	TSTD2	string_interaction
TSTD2	XPA	string_interaction

Structural data

PDB: 20 · AlphaFold-only: 8 · No structure: 3

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
HRAS	P01112	246
PIK3CA	P42336	135
BRAF	P15056	131
MTOR	P42345	70
NRAS	P01111	35
RET	P07949	34
TERT	O14746	23
XPA	P23025	18
NCBP1	Q09161	18
POT1	Q9NUX5	14
PTEN	P60484	12
SMAD3	P84022	12
NRG1	Q02297	11
STN1	Q9H668	8
NF2	P35240	6
TMOD1	P28289	6
TSC2	P49815	2
NKX2-1	P43699	2
LRRC34	Q8IZ02	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TSTD2	Q5T7W7	81.25
MBIP	Q9NS73	68.83
TRMO	Q9BU70	67.98
NREP	Q16612	67.60
EPB41L4A	Q9HCS5	66.14
FOXE1	O00358	62.02
PCNX2	A6NKB5	57.79
HEMGN	Q9BXL5	54.29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 336. Enrichment computed across 31 evidence-associated genes (19 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 19 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by ERBB2 KD Mutants	5	111.3×	2e-07	HRAS, KRAS, NRAS, NRG1, PIK3CA
Signaling by RAS GAP mutants	3	601.0×	2e-07	HRAS, KRAS, NRAS
Signaling by RAS GTPase mutants	3	601.0×	2e-07	HRAS, KRAS, NRAS
Signaling by FGFR4 in disease	4	200.3×	2e-07	HRAS, KRAS, NRAS, PIK3CA
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	4	184.9×	2e-07	HRAS, KRAS, NRAS, PIK3CA
Signaling by PDGFRA extracellular domain mutants	4	184.9×	2e-07	HRAS, KRAS, NRAS, PIK3CA
Signaling by FLT3 ITD and TKD mutants	4	160.3×	3e-07	HRAS, KRAS, NRAS, PIK3CA
Signaling by FGFR2 in disease	5	69.9×	3e-07	HRAS, KRAS, NCBP1, NRAS, PIK3CA
SHC1 events in ERBB4 signaling	4	150.3×	3e-07	HRAS, KRAS, NRAS, NRG1
Constitutive Signaling by EGFRvIII	4	150.3×	3e-07	HRAS, KRAS, NRAS, PIK3CA
Signaling by ERBB2 ECD mutants	4	141.4×	4e-07	HRAS, KRAS, NRAS, PIK3CA
RAF/MAP kinase cascade	7	22.5×	4e-07	RET, BRAF, HRAS, KRAS, NRAS, NRG1, PIK3CA
GRB2 events in ERBB2 signaling	4	133.6×	4e-07	HRAS, KRAS, NRAS, NRG1
Tie2 Signaling	4	126.5×	5e-07	HRAS, KRAS, NRAS, PIK3CA
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	4	120.2×	5e-07	HRAS, KRAS, NRAS, PIK3CA
Signaling by FLT3 fusion proteins	4	120.2×	5e-07	HRAS, KRAS, NRAS, PIK3CA
Activation of RAS in B cells	3	360.6×	7e-07	HRAS, KRAS, NRAS
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	4	109.3×	7e-07	HRAS, KRAS, NRAS, PIK3CA
Signaling by FGFR3 in disease	4	104.5×	8e-07	HRAS, KRAS, NRAS, PIK3CA
SHC1 events in ERBB2 signaling	4	100.2×	9e-07	HRAS, KRAS, NRAS, NRG1
Signaling by ERBB2 TMD/JMD mutants	4	100.2×	9e-07	HRAS, KRAS, NRAS, NRG1
RAS signaling downstream of NF1 loss-of-function variants	3	257.6×	2e-06	HRAS, KRAS, NRAS
Estrogen-stimulated signaling through PRKCZ	3	257.6×	2e-06	HRAS, KRAS, NRAS
Downstream signal transduction	4	80.1×	2e-06	HRAS, KRAS, NRAS, PIK3CA
DAP12 signaling	4	77.6×	2e-06	HRAS, KRAS, NRAS, PIK3CA
SOS-mediated signalling	3	225.4×	3e-06	HRAS, KRAS, NRAS
FLT3 Signaling	4	72.8×	3e-06	HRAS, KRAS, NRAS, PIK3CA
RAF activation	4	70.7×	3e-06	BRAF, HRAS, KRAS, NRAS
Signaling by high-kinase activity BRAF mutants	4	66.8×	4e-06	BRAF, HRAS, KRAS, NRAS
Activated NTRK3 signals through RAS	3	200.3×	4e-06	HRAS, KRAS, NRAS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 26 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
MAPK cascade	6	35.4×	8e-06	RET, BRAF, HRAS, KRAS, NF2, NRAS
thyroid gland development	4	83.6×	4e-05	BRAF, NKX2-1, FOXE1, SMAD3
anoikis	3	149.6×	2e-04	TSC2, MTOR, PIK3CA
positive regulation of stress fiber assembly	4	48.0×	2e-04	BRAF, MTOR, SMAD3, NF2
negative regulation of neuron apoptotic process	5	21.3×	3e-04	TERT, BRAF, HRAS, KRAS, PIK3CA
positive regulation of gene expression	6	8.9×	0.004	RET, BRAF, NKX2-1, MBIP, KRAS, SMAD3
establishment of protein localization to telomere	2	162.0×	0.005	TERT, POT1
negative regulation of cell size	2	129.6×	0.006	MTOR, PTEN
negative regulation of osteoblast proliferation	2	117.8×	0.006	SMAD3, NF2
TORC2 signaling	2	117.8×	0.006	MTOR, PIK3CA
telomere maintenance	3	30.9×	0.006	TERT, STN1, LRRC34
telomere capping	2	99.7×	0.007	POT1, STN1
primary miRNA processing	2	99.7×	0.007	SMAD3, NCBP1
liver development	3	25.6×	0.008	KRAS, SMAD3, PIK3CA
cell differentiation	6	6.7×	0.008	NKX2-1, HEMGN, LRRC34, FOXE1, SMAD3, NRG1
negative regulation of macroautophagy	2	86.4×	0.008	MTOR, PIK3CA
lens fiber cell differentiation	2	81.0×	0.008	SMAD3, NF2
Ras protein signal transduction	3	23.7×	0.008	HRAS, KRAS, NRAS
regulation of long-term neuronal synaptic plasticity	2	76.2×	0.008	HRAS, KRAS
positive regulation of ruffle assembly	2	76.2×	0.008	MTOR, HRAS
negative regulation of cell population proliferation	5	8.1×	0.008	TSC2, HRAS, SMAD3, NF2, PTEN
positive regulation of cell growth	3	21.1×	0.009	MTOR, NCBP1, NRG1
regulation of cell cycle	4	11.5×	0.009	TSC2, MBIP, HRAS, NF2
epithelial tube branching involved in lung morphogenesis	2	64.8×	0.010	NKX2-1, KRAS
regulation of transforming growth factor beta receptor signaling pathway	2	61.7×	0.010	NREP, SMAD3
cellular response to insulin stimulus	3	19.6×	0.010	FOXE1, MTOR, PIK3CA
telomere maintenance via telomerase	2	56.4×	0.011	TERT, POT1
negative regulation of telomere maintenance via telomerase	2	56.4×	0.011	POT1, STN1
T cell receptor signaling pathway	3	17.5×	0.012	BRAF, HRAS, PIK3CA
negative regulation of cellular senescence	2	49.9×	0.013	TERT, PTEN

Therapeutics

Drugs indicated for this disease

2 approved, 9 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Thyrotropin Alfa	Approved (phase 4)
Vandetanib	Approved (phase 4)
Cabozantinib	Phase 3 (in late-stage trials)
Dabrafenib	Phase 3 (in late-stage trials)
Fibrin	Phase 3 (in late-stage trials)
Lenvatinib	Phase 3 (in late-stage trials)
Paclitaxel	Phase 3 (in late-stage trials)
Rivoceranib	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): Atezolizumab, Avutometinib, Bevacizumab, Binimetinib, Catequentinib, Cobimetinib, Defactinib, Encorafenib, Entrectinib, Everolimus, Larotrectinib, Lenalidomide, Nivolumab, Panobinostat, Pazopanib, Pembrolizumab, Pralsetinib, Sunitinib, Surufatinib, Vemurafenib.

Drug target analysis

Approved (phase 4): 8 · Phase ≥3: 8 · Phased (≥1): 10 · Undrugged: 21

Druggability breadth: 14 of 31 evidence-associated genes (45%) 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
TERT	BERBERINE
RET	PONATINIB
BRAF	VEMURAFENIB
MTOR	SALMETEROL XINAFOATE
HRAS	LONAFARNIB
KRAS	VEMURAFENIB
PIK3CA	IDELALISIB
SMAD3	FLUORESCEIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MTOR	164	4
RET	135	4
PIK3CA	67	4
BRAF	48	4
KRAS	11	4
TERT	10	4
HRAS	4	4
SMAD3	2	4
NRAS	1	1
NCBP1	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
PONATINIB	4	BRAF, RET
AFATINIB	4	RET
VEMURAFENIB	4	BRAF, KRAS, RET
FEDRATINIB	4	BRAF, PIK3CA, RET
TIVOZANIB	4	RET
LENVATINIB	4	RET
AXITINIB	4	RET
SORAFENIB	4	BRAF, RET
DASATINIB ANHYDROUS	4	BRAF, RET
ALECTINIB	4	RET
RUXOLITINIB	4	BRAF, RET
INFIGRATINIB PHOSPHATE	4	BRAF, RET
INFIGRATINIB	4	BRAF, RET
IBRUTINIB	4	RET
PALBOCICLIB	4	RET
REGORAFENIB	4	BRAF, RET
ENTRECTINIB	4	RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	RET
BARICITINIB	4	RET
TOFACITINIB	4	RET
CAPIVASERTIB	4	RET
CERITINIB	4	RET
VANDETANIB	4	RET
NILOTINIB	4	BRAF, RET
BOSUTINIB	4	RET
GILTERITINIB	4	RET

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 6.

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

Symbol	Assays	Type breakdown
PIK3CA	2,034	Binding:2009, ADMET:19, Toxicity:4, Functional:2
RET	1,586	Binding:1573, Functional:10, ADMET:3
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
MTOR	1,375	Binding:1335, Functional:37, ADMET:2, Toxicity:1
KRAS	861	Binding:829, Functional:32
TERT	391	Binding:389, Functional:2
HRAS	48	Binding:45, Functional:3
SMAD3	24	Binding:18, Functional:6
NRAS	18	Binding:18
PTEN	8	Binding:8
NCBP1	8	Binding:8
XPA	6	Binding:6
TSC2	1	Binding:1
POT1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RET	2.7.10.1	receptor protein-tyrosine kinase
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
HRAS	3.6.5.2	small monomeric GTPase
KRAS	3.6.5.2	small monomeric GTPase
PIK3CA	2.7.1.137, 2.7.1.153, 2.7.11.1	phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
PTEN	3.1.3.16, 3.1.3.67	protein-serine/threonine phosphatase, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TERT	391
RET	1,586
BRAF	1,442
MTOR	1,375
KRAS	861
PIK3CA	2,034

Pharmacogenomics

Cohort genes with a PharmGKB record: 30; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

24 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)
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
PONATINIB	4	BRAF, RET
VEMURAFENIB	4	BRAF, KRAS, RET
FEDRATINIB	4	BRAF, PIK3CA, RET
TIVOZANIB	4	RET
AXITINIB	4	RET
SORAFENIB	4	BRAF, RET
DASATINIB ANHYDROUS	4	BRAF, RET
ALECTINIB	4	RET
RUXOLITINIB	4	BRAF, RET
INFIGRATINIB PHOSPHATE	4	BRAF, RET
INFIGRATINIB	4	BRAF, RET
IBRUTINIB	4	RET
REGORAFENIB	4	BRAF, RET
ENTRECTINIB	4	RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
BARICITINIB	4	RET
TOFACITINIB	4	RET
CERITINIB	4	RET
NILOTINIB	4	BRAF, RET
BOSUTINIB	4	RET
GILTERITINIB	4	RET

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	8	TERT, RET, BRAF, MTOR, HRAS, KRAS, PIK3CA, SMAD3
B	Phased (≥1) drug, not yet approved	2	NRAS, NCBP1
C	Druggable family + PDB, no drug	2	PTEN, NRG1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	19	TSC2, POT1, NF2, TERC, NKX2-1, TMOD1, XPA, EPB41L4A, NREP, HEMGN (+9 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TSC2	1	MTOR
POT1	1	—
NF2	0	—
PTEN	8	—
TERC	0	—
NKX2-1	0	—
TMOD1	0	—
XPA	6	—
EPB41L4A	0	—
NREP	0	—
HEMGN	0	—
DIRC3	0	—
MBIP	0	—
STN1	0	—
LRRC34	0	—
TSTD2	0	—
TRMO	0	—
FOXE1	0	—
KRT18P13	0	—
NRG1	0	—
PCNX2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 504.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	299
PHASE2	114
PHASE1	41
PHASE1/PHASE2	18
PHASE3	15
PHASE4	9
PHASE2/PHASE3	4
EARLY_PHASE1	4

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07600580	PHASE4	ACTIVE_NOT_RECRUITING	The Association Between Bilateral Intermediate Cervical Plexus Block During Total Thyroidectomy and Surgical Stress Response
NCT00604318	PHASE4	COMPLETED	Quality of Life, Recombinant TSH (Thyrogen) and Thyroid Cancer
NCT01496313	PHASE4	COMPLETED	To Compare The Effects Of Two Doses Of Vandetanib In Patients With Advanced Medullary Thyroid Cancer
NCT02946918	PHASE4	TERMINATED	Levothyroxine Replacement With Liquid Gel Capsules vs Tablets Post-thyroidectomy
NCT03065218	PHASE4	TERMINATED	99mTc Sestamibi Scans In Thyroglobulin Positive Scan Negative Differentiated Thyroid Cancer (DTC) Patients
NCT03469310	PHASE4	COMPLETED	Minimizing Narcotic Analgesics After Endocrine Surgery
NCT03969108	PHASE4	COMPLETED	Diagnostic Accuracy Study of Indocyanine Green for Parathyroid Perfusion Assessment
NCT05949424	PHASE4	UNKNOWN	OPTI - DOSE: Optimal Dosing of Oral Anticancer Drugs in Older Adults
NCT06697782	PHASE4	COMPLETED	Aprepitant and Ondansetron Monotherapy or Combination for Postoperative Nausea and Vomiting in Thyroid Cancer
NCT01398085	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	IoN- Is Ablative Radio-iodine Necessary for Low Risk Differentiated Thyroid Cancer Patients
NCT03570021	PHASE3	ACTIVE_NOT_RECRUITING	ESTIMation of the ABiLity of Prophylactic Central Compartment Neck Dissection to Modify Outcomes in Low-risk Differentiated Thyroid Cancer
NCT04290663	PHASE3	RECRUITING	Systematic Radioiodine Administration Versus Decision of Radioiodine Treatment Guided by a Post-operative Work-up
NCT05999630	PHASE3	RECRUITING	Artificial Tears to Prevent Nasolacrimal Duct Obstruction in Patients Treated With Radioactive Iodine for Thyroid Cancer
NCT06082180	PHASE3	RECRUITING	A Prospective, Open-label, Multicenter, Randomized Controlled Phase III Study of Prophylactic Central Neck Dissection in Low-risk Papillary Thyroid Cancer
NCT06554652	PHASE3	RECRUITING	Selective Neck Dissection Versus Modified Neck Dissection in PTC
NCT06558981	PHASE3	RECRUITING	Adjuvant Radiotherapy in High Risk Locally Advanced DTC
NCT06851663	PHASE2/PHASE3	RECRUITING	Trop2-targeted immunoPET Imaging of Solid Tumors
NCT06860971	PHASE3	RECRUITING	A Study of AL2846 Capsule Versus Placebo in the Treatment of Advanced Radioiodine-Refractory Differentiated Thyroid Carcinoma
NCT00410761	PHASE3	COMPLETED	An Efficacy Study Comparing ZD6474 to Placebo in Medullary Thyroid Cancer
NCT00435851	PHASE3	UNKNOWN	Medico-Economic Comparison of Four Strategies of Radioiodine Ablation in Thyroid Carcinoma Patients
NCT00704730	PHASE3	COMPLETED	Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer
NCT00794053	PHASE3	COMPLETED	The Usefulness of Staining Lymph Nodes During Operations for Cancer Thyroid in Detecting the Nodes That Have Cancer
NCT00795782	PHASE3	COMPLETED	Prophylactic Central Lymph Node Dissection in Papillary Thyroid Microcarcinoma
NCT01083550	PHASE2/PHASE3	COMPLETED	Decision Making on Radioactive Iodine Treatment for Papillary Thyroid Cancer
NCT01126060	PHASE3	COMPLETED	Efficacy of Fibrin Sealant to Reduce the Amount of Post-thyroidectomy Drain
NCT01321554	PHASE3	COMPLETED	A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Trial of Lenvatinib (E7080) in 131I-Refractory Differentiated Thyroid Cancer (DTC)
NCT01616316	PHASE2/PHASE3	COMPLETED	Efficacy of Subfascial Approach in Thyroidectomy to Quality of Life in Thyroid Disease Patients
NCT05468554	PHASE3	UNKNOWN	Evaluation of Metformin Effect on the Fertility of Women Treated With 131I for Thyroid Cancer
NCT01141309	PHASE2	ACTIVE_NOT_RECRUITING	Evaluating the Combination of Everolimus and Sorafenib in the Treatment of Thyroid Cancer
NCT01709292	PHASE2	ACTIVE_NOT_RECRUITING	Vemurafenib Neoadjuvant Trial in Locally Advanced Thyroid Cancer
NCT02152995	PHASE2	ACTIVE_NOT_RECRUITING	Trametinib in Increasing Tumoral Iodine Incorporation in Patients With Recurrent or Metastatic Thyroid Cancer
NCT02465060	PHASE2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)
NCT02628067	PHASE2	ACTIVE_NOT_RECRUITING	Study of Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-3475-158/KEYNOTE-158)
NCT02657551	PHASE2	ACTIVE_NOT_RECRUITING	A Study Using Regorafenib as Second or Third Line Therapy in Metastatic Medullary Thyroid Cancer
NCT02713269	PHASE2	ACTIVE_NOT_RECRUITING	Thermal Ablation and Spine Stereotactic Radiosurgery in Treating Patients With Spine Metastases at Risk for Compressing the Spinal Cord
NCT02834013	PHASE2	ACTIVE_NOT_RECRUITING	Nivolumab and Ipilimumab in Treating Patients With Rare Tumors
NCT03099356	PHASE2	RECRUITING	Cyclophosphamide and Sirolimus for the Treatment of Metastatic, RAI-refractory, Differentiated Thyroid Cancer
NCT03175224	PHASE2	RECRUITING	APL-101 Study of Subjects With NSCLC With c-Met EXON 14 Skip Mutations and c-Met Dysregulation Advanced Solid Tumors
NCT03181100	PHASE2	ACTIVE_NOT_RECRUITING	Atezolizumab With Chemotherapy in Treating Patients With Anaplastic or Poorly Differentiated Thyroid Cancer
NCT03360890	PHASE2	ACTIVE_NOT_RECRUITING	Pembrolizumab With Chemotherapy for Poorly Chemo-responsive Thyroid and Salivary Gland Tumors

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CABOZANTINIB	4	11
DABRAFENIB	4	11
SUNITINIB	4	9
LEVOTHYROXINE	4	6
VANDETANIB	4	6
LENVATINIB	4	5
THYROTROPIN ALFA	4	4
BINIMETINIB	4	3
COPANLISIB	4	3
FLUDEOXYGLUCOSE F 18	4	3
LAROTRECTINIB	4	3
LIOTHYRONINE	4	3
PAZOPANIB	4	3
SELPERCATINIB	4	3
SORAFENIB TOSYLATE	4	3
TRAMETINIB	4	3
INDOCYANINE GREEN ACID FORM	4	2
PALBOCICLIB	4	2
PEMETREXED DISODIUM	4	2
ROMIDEPSIN	4	2
SELUMETINIB	4	2
ABEMACICLIB	4	1
AFATINIB	4	1
AFATINIB DIMALEATE	4	1
APREPITANT	4	1
BEXAROTENE	4	1
BRODALUMAB	4	1
CAPIVASERTIB	4	1
CEMIPLIMAB	4	1
COBIMETINIB	4	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 23 predictive associations from 25 curated evidence items; also 4 oncogenic, 3 diagnostic, 2 prognostic, 1 predisposing.

Molecular subtype	Therapy	Effect	Level	CIViC
RET Fusion	Pralsetinib	Sensitivity/Response	CIViC A	EID11234
RET Fusion	Selpercatinib	Sensitivity/Response	CIViC A	EID8852
RET Fusion OR RET Mutation	Pralsetinib	Sensitivity/Response	CIViC A	EID11267
TERT Promoter Mutation	Iodine I-131	Resistance	CIViC B	EID6961
TPR::NTRK1 Fusion	Larotrectinib	Sensitivity/Response	CIViC C	EID11748
TSC2 Q1178*	Everolimus	Sensitivity/Response	CIViC C	EID1108
MTOR F2108L	Everolimus	Resistance	CIViC C	EID1110
BRAF V600E	Vemurafenib	Sensitivity/Response	CIViC D	EID3784 +1
BRAF V600E	Ponatinib + PLX4720	Sensitivity/Response	CIViC D	EID8033 +1
BRAF V600E	MEK Inhibitor CI-1040	Sensitivity/Response	CIViC D	EID2136
BRAF V600E	RDEA 119	Sensitivity/Response	CIViC D	EID2139
BRAF V600E	Sorafenib	Sensitivity/Response	CIViC D	EID2142
BRAF V600E	Vemurafenib	Sensitivity/Response	CIViC D	EID3760
KRAS G12R	Dasatinib	Sensitivity/Response	CIViC D	EID3997
NF2 Loss	Selumetinib	Sensitivity/Response	CIViC D	EID1742
PIK3CA E542K	Perifosine + Temsirolimus	Sensitivity/Response	CIViC D	EID1626
PIK3CA H1047R	Perifosine + Temsirolimus	Sensitivity/Response	CIViC D	EID1625
PIK3CA Mutation	Akt Inhibitor MK2206	Sensitivity/Response	CIViC D	EID12720
PTEN R130*	Perifosine + Temsirolimus	Sensitivity/Response	CIViC D	EID1627
RET Mutation	NVP-AST487 + Sapanisertib	Sensitivity/Response	CIViC D	EID4854
HRAS G13R	Vemurafenib	Resistance	CIViC D	EID3853
KRAS G12R	Vemurafenib	Resistance	CIViC D	EID3999
NRAS Q61R	Vemurafenib	Resistance	CIViC D	EID3831