Thyroid cancer, nonmedullary, 1

Summary

Thyroid cancer, nonmedullary, 1 (MONDO:0008567) is a cancer with 7 cohort genes (3 CIViC-evidence somatic drivers; 9 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Cohort genes: 7
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thyroid cancer, nonmedullary, 1
Mondo ID	MONDO:0008567
OMIM	188550
UMLS	C4721429
MedGen	1648293
GARD	0024632
Is cancer (heuristic)	yes

Also known as: NMTC1 · thyroid cancer, nonmedullary, 1 · thyroid cancer, nonmedullary, type 1

Data availability: 9 ClinVar variants.

Disease family

Classification path: human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › cancer › carcinoma › adenocarcinoma › papillary adenocarcinoma › thyroid gland papillary carcinoma › thyroid cancer, nonmedullary, 1

Related subtypes (5): 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

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

9 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 established risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
3576568	NM_001079668.3(NKX2-1):c.572G>T (p.Arg191Leu)	NKX2-1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1327505	NM_004985.5(KRAS):c.445A>T (p.Arg149Ter)	KRAS	Likely pathogenic	no assertion criteria provided
653869	NM_021930.6(RINT1):c.1107+1G>T	RINT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4077164	NC_000009.12:g.97793827A>G	PTCSC2	Established risk allele	criteria provided, single submitter
946956	NM_021930.6(RINT1):c.1021C>G (p.Leu341Val)	RINT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
487553	NM_001079668.3(NKX2-1):c.1106C>T (p.Ala369Val)	SFTA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
930341	NM_001079668.3(NKX2-1):c.463+4A>G	NKX2-1	Uncertain significance	criteria provided, single submitter
225430	NM_006197.4(PCM1):c.2935C>T (p.Gln979Ter)	PCM1	Uncertain significance	criteria provided, single submitter
1052297	NM_000546.6(TP53):c.1118del (p.Lys373fs)	TP53	Uncertain significance	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 37 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
NKX2-1	LoF	LGGNOS	CIViC #80
TP53	LoF	ACC,ALL,AML,ANGS,ANSC,BCC,BL,BLADDER,BLCA,BRCA,CCRCC,CEAD,CESC,CHOL,CHRCC,CLLSLL,COAD,COADREAD,CSCC,DLBCLNOS,EGC,ES,ESCA,ESCC,GB,GBC,GBM,GIST,HCC,HGGNOS,HNSC,LGGNOS,LIPO,LMS,LNM,LUAD,LUSC,MBL,MEL,MLYM,MT,NBL,NETNOS,NHL,NPC,NSCLC,OS,OVT,PAAD,PANCREAS,PAST,PCM,PLMESO,PRAD,PRCC,PROSTATE,RCC,READ,SACA,SARCNOS,SCLC,SIC,SKCM,SKIN,SOFT_TISSUE,STAD,STOMACH,THYM,UCEC,UCS,UTUC,VULVA,WDTC,WT	CIViC #45
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

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
TP53	Orphanet:1333	Familial pancreatic carcinoma
TP53	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
TP53	Orphanet:1501	Adrenocortical carcinoma
TP53	Orphanet:210159	Adult hepatocellular carcinoma
TP53	Orphanet:251576	Gliosarcoma
TP53	Orphanet:251579	Giant cell glioblastoma
TP53	Orphanet:251899	Choroid plexus carcinoma
TP53	Orphanet:2807	Papilloma of choroid plexus
TP53	Orphanet:293199	Pleomorphic rhabdomyosarcoma
TP53	Orphanet:3318	Essential thrombocythemia
TP53	Orphanet:524	Li-Fraumeni syndrome
TP53	Orphanet:52688	Myelodysplastic syndrome
TP53	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
TP53	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
TP53	Orphanet:668	Osteosarcoma
TP53	Orphanet:67038	B-cell chronic lymphocytic leukemia
TP53	Orphanet:70573	Small cell lung cancer
TP53	Orphanet:96253	Cushing disease
TP53	Orphanet:99756	Alveolar rhabdomyosarcoma
TP53	Orphanet:99757	Embryonal rhabdomyosarcoma
RINT1	Orphanet:464724	Fever-associated acute infantile liver failure syndrome
KRAS	Orphanet:1333	Familial pancreatic carcinoma
KRAS	Orphanet:1340	Cardiofaciocutaneous syndrome
KRAS	Orphanet:144	Lynch syndrome
KRAS	Orphanet:146	Differentiated thyroid carcinoma
KRAS	Orphanet:2396	Encephalocraniocutaneous lipomatosis
KRAS	Orphanet:251615	Pilomyxoid astrocytoma
KRAS	Orphanet:2612	Linear nevus sebaceus syndrome
KRAS	Orphanet:268114	RAS-associated autoimmune leukoproliferative disease
KRAS	Orphanet:3339	Oculoectodermal syndrome
KRAS	Orphanet:648	Noonan syndrome
KRAS	Orphanet:86834	Juvenile myelomonocytic leukemia
PCM1	Orphanet:146	Differentiated thyroid carcinoma

Cohort genes → proteins

7 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NKX2-1	HGNC:11825	ENSG00000136352	P43699	Homeobox protein Nkx-2.1	clinvar
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	clinvar
SFTA3	HGNC:18387	ENSG00000229415	P0C7M3	Surfactant-associated protein 3	clinvar
RINT1	HGNC:21876	ENSG00000135249	Q6NUQ1	RAD50-interacting protein 1	clinvar
PTCSC2	HGNC:44086	ENSG00000236130		papillary thyroid carcinoma susceptibility candidate 2	clinvar
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	clinvar
PCM1	HGNC:8727	ENSG00000078674	Q15154	Pericentriolar material 1 protein	clinvar

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.
TP53	Cellular tumor antigen p53	Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence.
SFTA3	Surfactant-associated protein 3	Putative surfactant protein.
RINT1	RAD50-interacting protein 1	Involved in regulation of membrane traffic between the Golgi and the endoplasmic reticulum (ER); the function is proposed to depend on its association in the NRZ complex which is believed to play a role in SNARE assembly at the ER.
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
PCM1	Pericentriolar material 1 protein	Required for centrosome assembly and function.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 4 · Druggable fraction: 0.14

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	2	2.4×	0.613
Enzyme (other)	1	1.7×	0.626
Other/Unknown	4	1.0×	0.626

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NKX2-1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
TP53	Transcription factor	no		p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn
SFTA3	Other/Unknown	no
RINT1	Other/Unknown	no		RINT1_Tip20, EXOC6PINT-1/Sec15/Tip20_C_dom2
PTCSC2	Other/Unknown	no
KRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
PCM1	Other/Unknown	no		Pericentriolar_Pcm1, PCM1_C

Expression context

Cohort genes with no expression data: 0.

7 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left lobe of thyroid gland	3
right lobe of thyroid gland	3
thyroid gland	2
ventricular zone	2
ganglionic eminence	1
tendon of biceps brachii	1
body of pancreas	1
male germ line stem cell (sensu Vertebrata) in testis	1
tibia	1
bone marrow cell	1
nipple	1
pylorus	1
trigeminal ganglion	1
calcaneal tendon	1
left testis	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
TP53	223	ubiquitous	marker	ventricular zone, ganglionic eminence, tendon of biceps brachii
SFTA3	107	tissue_specific	marker	right lobe of thyroid gland, thyroid gland, left lobe of thyroid gland
RINT1	259	ubiquitous	marker	tibia, male germ line stem cell (sensu Vertebrata) in testis, body of pancreas
PTCSC2	120	tissue_specific	marker	bone marrow cell, right lobe of thyroid gland, left lobe of thyroid gland
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple
PCM1	292	ubiquitous	marker	calcaneal tendon, left testis, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP53	22,736
KRAS	14,509
PCM1	2,728
NKX2-1	2,403
RINT1	2,398
SFTA3	604
PTCSC2	0

Intra-cohort edges

A	B	Sources
KRAS	TP53	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
TP53	P04637	313
PCM1	Q15154	3
NKX2-1	P43699	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RINT1	Q6NUQ1	85.97
SFTA3	P0C7M3	61.17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 128. Enrichment computed across 7 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Loss of function of TP53 in cancer due to loss of tetramerization ability	1	2284.0×	0.019	TP53
Regulation of TP53 Expression	1	1142.0×	0.019	TP53
Signaling by RAS GAP mutants	1	761.3×	0.019	KRAS
Signaling by RAS GTPase mutants	1	761.3×	0.019	KRAS
Transcriptional activation of cell cycle inhibitor p21	1	571.0×	0.019	TP53
Activation of RAS in B cells	1	456.8×	0.019	KRAS
Activation of NOXA and translocation to mitochondria	1	380.7×	0.019	TP53
Defective CSF2RB causes SMDP5	1	326.3×	0.019	SFTA3
Defective CSF2RA causes SMDP4	1	326.3×	0.019	SFTA3
RAS signaling downstream of NF1 loss-of-function variants	1	326.3×	0.019	KRAS
RUNX3 regulates CDKN1A transcription	1	326.3×	0.019	TP53
Estrogen-stimulated signaling through PRKCZ	1	326.3×	0.019	KRAS
SOS-mediated signalling	1	285.5×	0.019	KRAS
PI5P Regulates TP53 Acetylation	1	253.8×	0.019	TP53
Activated NTRK3 signals through RAS	1	253.8×	0.019	KRAS
Activation of PUMA and translocation to mitochondria	1	228.4×	0.019	TP53
EGFR Transactivation by Gastrin	1	228.4×	0.019	KRAS
SHC-related events triggered by IGF1R	1	228.4×	0.019	KRAS
RUNX3 regulates p14-ARF	1	228.4×	0.019	KRAS
Activated NTRK2 signals through RAS	1	228.4×	0.019	KRAS
MET activates RAS signaling	1	207.6×	0.019	KRAS
Signaling by FGFR4 in disease	1	190.3×	0.019	KRAS
TP53 Regulates Transcription of Caspase Activators and Caspases	1	190.3×	0.019	TP53
TP53 Regulates Transcription of Death Receptors and Ligands	1	190.3×	0.019	TP53
Activated NTRK2 signals through FRS2 and FRS3	1	190.3×	0.019	KRAS
Constitutive Signaling by Overexpressed ERBB2	1	190.3×	0.019	KRAS
p38MAPK events	1	175.7×	0.019	KRAS
Urea cycle	1	175.7×	0.019	TP53
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	175.7×	0.019	KRAS
Signaling by PDGFRA extracellular domain mutants	1	175.7×	0.019	KRAS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of cellular senescence	2	432.1×	0.001	TP53, KRAS
glial cell proliferation	2	295.6×	0.001	TP53, KRAS
epithelial tube branching involved in lung morphogenesis	2	280.9×	0.001	NKX2-1, KRAS
negative regulation of helicase activity	1	2808.7×	0.007	TP53
response to mineralocorticoid	1	2808.7×	0.007	KRAS
cellular response to actinomycin D	1	2808.7×	0.007	TP53
regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1	2808.7×	0.007	TP53
negative regulation of G1 to G0 transition	1	2808.7×	0.007	TP53
Ras protein signal transduction	2	68.5×	0.007	TP53, KRAS
positive regulation of gene expression	3	19.4×	0.007	NKX2-1, TP53, KRAS
neuron apoptotic process	2	61.7×	0.008	TP53, KRAS
developmental induction	1	1404.3×	0.008	NKX2-1
positive regulation of mitochondrial membrane permeability	1	1404.3×	0.008	TP53
oligodendrocyte apoptotic process	1	1404.3×	0.008	TP53
protein-containing complex localization to centriolar satellite	1	1404.3×	0.008	PCM1
negative regulation of glucose catabolic process to lactate via pyruvate	1	1404.3×	0.008	TP53
negative regulation of pentose-phosphate shunt	1	1404.3×	0.008	TP53
negative regulation of transforming growth factor beta receptor signaling pathway	2	57.9×	0.008	NKX2-1, TP53
obsolete homolactic fermentation	1	936.2×	0.008	TP53
cerebral cortex GABAergic interneuron differentiation	1	936.2×	0.008	NKX2-1
forebrain astrocyte development	1	936.2×	0.008	KRAS
signal transduction by p53 class mediator	1	936.2×	0.008	TP53
negative regulation of miRNA processing	1	936.2×	0.008	TP53
intrinsic apoptotic signaling pathway in response to hypoxia	1	936.2×	0.008	TP53
regulation of fibroblast apoptotic process	1	936.2×	0.008	TP53
T cell proliferation involved in immune response	1	702.2×	0.009	TP53
response to isolation stress	1	702.2×	0.009	KRAS
positive regulation of programmed necrotic cell death	1	702.2×	0.009	TP53
oxidative stress-induced premature senescence	1	702.2×	0.009	TP53
B cell lineage commitment	1	561.7×	0.009	TP53

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 5

Druggability breadth: 2 of 7 evidence-associated genes (29%) 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
TP53	NITROFURANTOIN
KRAS	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TP53	196	4
KRAS	11	4
NKX2-1	0	0
SFTA3	0	0
RINT1	0	0
PTCSC2	0	0
PCM1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53
FURAZOLIDONE	4	TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53
AMITRIPTYLINE HYDROCHLORIDE	4	TP53
ETHOPROPAZINE HYDROCHLORIDE	4	TP53
MECHLORETHAMINE HYDROCHLORIDE	4	TP53
ECONAZOLE NITRATE	4	TP53
TRIFLUPROMAZINE HYDROCHLORIDE	4	TP53
PROCHLORPERAZINE EDISYLATE	4	TP53
DEQUALINIUM CHLORIDE	4	TP53

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
KRAS	861	Binding:829, Functional:32

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KRAS	3.6.5.2	small monomeric GTPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TP53	869
KRAS	861

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

30 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)
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53
FURAZOLIDONE	4	TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53
AMITRIPTYLINE HYDROCHLORIDE	4	TP53
ETHOPROPAZINE HYDROCHLORIDE	4	TP53
MECHLORETHAMINE HYDROCHLORIDE	4	TP53
ECONAZOLE NITRATE	4	TP53
TRIFLUPROMAZINE HYDROCHLORIDE	4	TP53
PROCHLORPERAZINE EDISYLATE	4	TP53
DEQUALINIUM CHLORIDE	4	TP53

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	TP53, KRAS
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	NKX2-1, SFTA3, RINT1, PTCSC2, PCM1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NKX2-1	0	—
SFTA3	0	—
RINT1	0	—
PTCSC2	0	—
PCM1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.