Multiple endocrine neoplasia type 1

Summary

Multiple endocrine neoplasia type 1 (MONDO:0007540) is a disease caused by MEN1 (GenCC Definitive), with 8 cohort genes and 17 clinical trials. The dominant Reactome pathway is RNA Polymerase II Transcription (5 cohort genes). Top therapeutic interventions include edotreotide gallium ga-68, aflibercept, and fluorodopa f 18.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: MEN1 (GenCC Definitive)
• Cohort genes: 8
• ClinVar variants: 2,438
• Phenotypes (HPO): 74
• Clinical trials: 17

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	3.3	Europe	Validated

Signs & symptoms

Clinical features (HPO)

74 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0003072	Hypercalcemia	Very frequent (80-99%)
HP:0008200	Primary hyperparathyroidism	Very frequent (80-99%)
HP:0008208	Parathyroid hyperplasia	Very frequent (80-99%)
HP:0010615	Angiofibromas	Very frequent (80-99%)
HP:0031058	Impairment of activities of daily living	Very frequent (80-99%)
HP:0000802	Impotence	Frequent (30-79%)
HP:0000849	Adrenocortical abnormality	Frequent (30-79%)
HP:0001012	Multiple lipomas	Frequent (30-79%)
HP:0001824	Weight loss	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0002027	Abdominal pain	Frequent (30-79%)
HP:0002044	Zollinger-Ellison syndrome	Frequent (30-79%)
HP:0002150	Hypercalciuria	Frequent (30-79%)
HP:0002893	Pituitary adenoma	Frequent (30-79%)
HP:0002894	Neoplasm of the pancreas	Frequent (30-79%)
HP:0004349	Reduced bone mineral density	Frequent (30-79%)
HP:0004398	Peptic ulcer	Frequent (30-79%)
HP:0005605	Large cafe-au-lait macules with irregular margins	Frequent (30-79%)
HP:0006767	Pituitary prolactin cell adenoma	Frequent (30-79%)
HP:0040306	Decreased male libido	Frequent (30-79%)
HP:0100829	Galactorrhea	Frequent (30-79%)
HP:0500167	Hypergastrinemia	Frequent (30-79%)
HP:0000141	Amenorrhea	Occasional (5-29%)
HP:0000169	Gingival fibromatosis	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000736	Short attention span	Occasional (5-29%)
HP:0000787	Nephrolithiasis	Occasional (5-29%)
HP:0000822	Hypertension	Occasional (5-29%)
HP:0000845	Elevated circulating growth hormone concentration	Occasional (5-29%)
HP:0000853	Goiter	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001289	Confusion	Occasional (5-29%)
HP:0001293	Cranial nerve compression	Occasional (5-29%)
HP:0001579	Primary hypercortisolism	Occasional (5-29%)
HP:0001944	Dehydration	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002018	Nausea	Occasional (5-29%)
HP:0002019	Constipation	Occasional (5-29%)
HP:0002039	Anorexia	Occasional (5-29%)
HP:0002248	Hematemesis	Occasional (5-29%)
HP:0002249	Melena	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0002588	Duodenal ulcer	Occasional (5-29%)
HP:0002659	Increased susceptibility to fractures	Occasional (5-29%)
HP:0002797	Osteolysis	Occasional (5-29%)
HP:0002858	Meningioma	Occasional (5-29%)
HP:0002890	Thyroid carcinoma	Occasional (5-29%)
HP:0003118	Increased circulating cortisol level	Occasional (5-29%)
HP:0006723	Intestinal carcinoid	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple endocrine neoplasia type 1
Mondo ID	MONDO:0007540
MeSH	D018761
OMIM	131100
Orphanet	652
DOID	DOID:10017
ICD-10-CM	E31.21
ICD-11	1638765741
NCIT	C3225
SNOMED CT	30664006
UMLS	C0025267
MedGen	9957
GARD	0003829
MedDRA	10028190
NORD	1466
Is cancer (heuristic)	no

Also known as: endocrine adenomatosis multiple · MEA type 1 · MEA type I · men 1 · men type 1 · men type I · MEN1 · MEN1 multiple endocrine neoplasia · MEN1 syndrome · MEN1-related multiple endocrine neoplasia · multiple endocrine adenomatosis · multiple endocrine adenomatosis type 1 · multiple endocrine adenomatosis type I · multiple endocrine adenomatosis, type I · multiple endocrine neoplasia 1 · multiple endocrine neoplasia caused by mutation in MEN1 · multiple endocrine neoplasia type 1 · multiple endocrine neoplasia type 1 syndrome · multiple endocrine neoplasia type I · multiple endocrine neoplasia, type I (+2 more)

Data availability: 2,438 ClinVar variants · 5 GenCC gene-disease records · 18 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › multiple endocrine neoplasia type 1

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

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

600 retrieved; paginated sample, class counts are floors:

224 uncertain significance, 178 likely benign, 71 benign/likely benign, 68 pathogenic, 33 conflicting classifications of pathogenicity, 14 pathogenic/likely pathogenic, 7 likely pathogenic, 5 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1009876	NM_001370259.2(MEN1):c.970_984del (p.Leu324_His328del)	MEN1	Pathogenic	criteria provided, single submitter
1059330	NM_001370259.2(MEN1):c.1031C>G (p.Thr344Arg)	MEN1	Pathogenic	criteria provided, single submitter
1064409	NM_001370259.2(MEN1):c.201del (p.Ala68fs)	MEN1	Pathogenic	no assertion criteria provided
1066873	NM_001370259.2(MEN1):c.1351-3_1359del	MEN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067621	NM_001370259.2(MEN1):c.725C>T (p.Ala242Val)	MEN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067928	NM_001370259.2(MEN1):c.1271AGG[1] (p.Glu425del)	MEN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068797	NM_001370259.2(MEN1):c.1006dup (p.Glu336fs)	MEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1069776	NM_001370259.2(MEN1):c.1456G>T (p.Glu486Ter)	MEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1069786	NM_001370259.2(MEN1):c.238del (p.Val80fs)	MEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1070314	NM_001370259.2(MEN1):c.936C>A (p.Tyr312Ter)	MEN1	Pathogenic	criteria provided, single submitter
1070417	NM_001370259.2(MEN1):c.1010C>A (p.Ala337Asp)	MEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1070591	NM_001370259.2(MEN1):c.1058_1059insTG (p.Cys354fs)	MEN1	Pathogenic	criteria provided, single submitter
1070665	NM_001370259.2(MEN1):c.1013del (p.Leu338fs)	MEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1070942	NM_001370259.2(MEN1):c.6dup (p.Leu3fs)	MEN1	Pathogenic	criteria provided, single submitter
1070954	NM_001370259.2(MEN1):c.1375_1391dup (p.Ala467fs)	MEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1071830	NM_001370259.2(MEN1):c.117_118del (p.Leu39fs)	MEN1	Pathogenic	criteria provided, single submitter
1072112	NM_001370259.2(MEN1):c.1556del (p.Pro519fs)	MEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1072293	NM_001370259.2(MEN1):c.248_266del (p.Leu83fs)	MEN1	Pathogenic	criteria provided, single submitter
1072303	NM_001370259.2(MEN1):c.506_507dup (p.Leu170fs)	MEN1	Pathogenic	criteria provided, single submitter
1072314	NM_001370259.2(MEN1):c.1045del (p.Gln349fs)	MEN1	Pathogenic	criteria provided, single submitter
1072351	NM_001370259.2(MEN1):c.474del (p.Phe159fs)	MEN1	Pathogenic	criteria provided, single submitter
1072612	NM_001370259.2(MEN1):c.831del (p.Met278fs)	MEN1	Pathogenic	criteria provided, single submitter
1073205	NM_001370259.2(MEN1):c.1356dup (p.Gln453fs)	MEN1	Pathogenic	criteria provided, single submitter
1073347	NM_001370259.2(MEN1):c.1391dup (p.Ala465fs)	MEN1	Pathogenic	criteria provided, single submitter
1074463	NM_001370259.2(MEN1):c.269dup (p.Tyr90Ter)	MEN1	Pathogenic	criteria provided, single submitter
1074511	NM_001370259.2(MEN1):c.739dup (p.Ile247fs)	MEN1	Pathogenic	criteria provided, single submitter
1076266	NM_001370259.2(MEN1):c.1351-1G>T	MEN1	Pathogenic	criteria provided, single submitter
1076585	NM_001370259.2(MEN1):c.234dup (p.Pro79fs)	MEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1331034	NM_001370259.2(MEN1):c.1279_1282dup (p.Pro428fs)	MEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1358663	NM_001370259.2(MEN1):c.646del (p.Ala216fs)	MEN1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 21 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

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

Gene	Classification	Inheritance	Disease	Records
MEN1	Definitive	Autosomal dominant	multiple endocrine neoplasia type 1	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MEN1	Orphanet:2965	Prolactinoma
MEN1	Orphanet:314786	Silent pituitary adenoma
MEN1	Orphanet:314790	Null pituitary adenoma
MEN1	Orphanet:652	Multiple endocrine neoplasia type 1
MEN1	Orphanet:97279	Insulinoma
MEN1	Orphanet:99725	Pituitary gigantism
MEN1	Orphanet:99879	Familial isolated hyperparathyroidism
STK11	Orphanet:2869	Peutz-Jeghers syndrome
CDC73	Orphanet:143	Parathyroid carcinoma
CDC73	Orphanet:99879	Familial isolated hyperparathyroidism
CDC73	Orphanet:99880	Hyperparathyroidism-jaw tumor syndrome
CDKN1B	Orphanet:276152	Multiple endocrine neoplasia type 4
CDKN1B	Orphanet:652	Multiple endocrine neoplasia type 1
ATM	Orphanet:100	Ataxia-telangiectasia
ATM	Orphanet:1331	Familial prostate cancer
ATM	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
ATM	Orphanet:227535	Hereditary breast cancer
ATM	Orphanet:370109	Ataxia-telangiectasia variant
ATM	Orphanet:440437	Familial colorectal cancer Type X
ATM	Orphanet:52416	Mantle cell lymphoma
ATM	Orphanet:67038	B-cell chronic lymphocytic leukemia

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MEN1	HGNC:7010	ENSG00000133895	O00255	Menin	gencc,clinvar
STK11	HGNC:11389	ENSG00000118046	Q15831	Serine/threonine-protein kinase STK11	clinvar
CDC73	HGNC:16783	ENSG00000134371	Q6P1J9	Parafibromin	clinvar
CDKN1B	HGNC:1785	ENSG00000111276	P46527	Cyclin-dependent kinase inhibitor 1B	clinvar
MAP4K2	HGNC:6864	ENSG00000168067	Q12851	Mitogen-activated protein kinase kinase kinase kinase 2	clinvar
ATM	HGNC:795	ENSG00000149311	Q13315	Serine-protein kinase ATM	clinvar
PLCG1	HGNC:9065	ENSG00000124181	P19174	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1	clinvar
BAD	HGNC:936	ENSG00000002330	Q92934	Bcl2-associated agonist of cell death	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MEN1	Menin	Essential component of a MLL/SET1 histone methyltransferase (HMT) complex, a complex that specifically methylates ‘Lys-4’ of histone H3 (H3K4).
STK11	Serine/threonine-protein kinase STK11	Tumor suppressor serine/threonine-protein kinase that controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage…
CDC73	Parafibromin	Tumor suppressor probably involved in transcriptional and post-transcriptional control pathways.
CDKN1B	Cyclin-dependent kinase inhibitor 1B	Important regulator of cell cycle progression.
MAP4K2	Mitogen-activated protein kinase kinase kinase kinase 2	Serine/threonine-protein kinase which acts as an essential component of the MAP kinase signal transduction pathway.
ATM	Serine-protein kinase ATM	Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor.
PLCG1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1	Mediates the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3).
BAD	Bcl2-associated agonist of cell death	Promotes cell death.

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.38

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	3	10.4×	0.007
Scaffold/PPI	1	2.2×	0.569
Other/Unknown	4	0.9×	0.755

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MEN1	Other/Unknown	no		Menin
STK11	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
CDC73	Other/Unknown	no		Cdc73/Parafibromin, CDC73_C, Cdc73_N
CDKN1B	Other/Unknown	no		CDI_dom, CDI_dom_sf
MAP4K2	Kinase	yes		Prot_kinase_dom, CNH_dom, Kinase-like_dom_sf
ATM	Kinase	yes	2.7.11.1	PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
PLCG1	Scaffold/PPI	no	3.1.4.11	C2_dom, PLipase_C_PInositol-sp_X_dom, SH2
BAD	Other/Unknown	no		BAD

Expression context

Cohort genes with no expression data: 0.

8 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	2
right hemisphere of cerebellum	2
calcaneal tendon	2
colonic epithelium	2
lower esophagus mucosa	1
hindlimb stylopod muscle	1
left testis	1
right testis	1
sural nerve	1
pigmented layer of retina	1
retina	1
ventricular zone	1
right lung	1
spleen	1
corpus callosum	1
cerebellar cortex	1
cerebellar hemisphere	1
mucosa of transverse colon	1
right atrium auricular region	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MEN1	271	ubiquitous	marker	granulocyte, lower esophagus mucosa, right hemisphere of cerebellum
STK11	238	ubiquitous	marker	left testis, right testis, hindlimb stylopod muscle
CDC73	271	ubiquitous	marker	calcaneal tendon, sural nerve, colonic epithelium
CDKN1B	301	ubiquitous	marker	pigmented layer of retina, retina, ventricular zone
MAP4K2	193	ubiquitous	marker	granulocyte, spleen, right lung
ATM	286	ubiquitous	marker	calcaneal tendon, colonic epithelium, corpus callosum
PLCG1	279	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
BAD	212	ubiquitous	marker	mucosa of transverse colon, right frontal lobe, right atrium auricular region

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATM	7,383
MEN1	5,226
STK11	5,146
CDKN1B	4,635
CDC73	4,592
PLCG1	3,464
BAD	1,239
MAP4K2	973

Intra-cohort edges

A	B	Sources
ATM	STK11	string_interaction
CDC73	MEN1	string_interaction

Structural data

PDB: 7 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MEN1	O00255	69
CDC73	Q6P1J9	20
CDKN1B	P46527	19
ATM	Q13315	14
BAD	Q92934	6
PLCG1	P19174	5
STK11	Q15831	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MAP4K2	Q12851	75.32

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 177. Enrichment computed across 8 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RNA Polymerase II Transcription	5	16.1×	6e-04	MEN1, STK11, CDC73, CDKN1B, ATM
Gene expression (Transcription)	5	12.8×	9e-04	MEN1, STK11, CDC73, CDKN1B, ATM
AKT phosphorylates targets in the cytosol	2	233.1×	0.001	CDKN1B, BAD
p53-Dependent G1 DNA Damage Response	2	203.9×	0.001	CDKN1B, ATM
p53-Dependent G1/S DNA damage checkpoint	2	203.9×	0.001	CDKN1B, ATM
G1/S DNA Damage Checkpoints	2	191.9×	0.001	CDKN1B, ATM
Constitutive Signaling by AKT1 E17K in Cancer	2	120.8×	0.003	CDKN1B, BAD
PI3K/AKT Signaling in Cancer	2	105.2×	0.003	CDKN1B, BAD
Transcriptional Regulation by TP53	3	26.6×	0.003	STK11, CDKN1B, ATM
Signal Transduction	5	7.3×	0.003	MEN1, STK11, CDC73, CDKN1B, BAD
FOXO-mediated transcription	2	96.0×	0.003	STK11, CDKN1B
Generic Transcription Pathway	4	8.6×	0.008	MEN1, STK11, CDKN1B, ATM
DNA Damage/Telomere Stress Induced Senescence	2	46.6×	0.010	CDKN1B, ATM
Cellular Senescence	2	39.3×	0.014	CDKN1B, ATM
Regulation of TP53 Activity	2	37.9×	0.014	STK11, ATM
Formation of the beta-catenin:TCF transactivating complex	2	34.4×	0.014	MEN1, CDC73
TCF dependent signaling in response to WNT	2	33.6×	0.014	MEN1, CDC73
Regulation of TP53 Activity through Phosphorylation	2	33.6×	0.014	STK11, ATM
Signaling by WNT	2	32.0×	0.015	MEN1, CDC73
PLC-gamma1 signalling	1	543.8×	0.015	PLCG1
Activated NTRK3 signals through PLCG1	1	543.8×	0.015	PLCG1
PLCG1 events in ERBB2 signaling	1	407.9×	0.018	PLCG1
Activated NTRK2 signals through PLCG1	1	407.9×	0.018	PLCG1
Intracellular signaling by second messengers	2	26.1×	0.018	CDKN1B, BAD
Cell Cycle Checkpoints	2	25.3×	0.018	CDKN1B, ATM
Sensing of DNA Double Strand Breaks	1	271.9×	0.024	ATM
PTK6 Regulates Cell Cycle	1	271.9×	0.024	CDKN1B
Erythropoietin activates Phospholipase C gamma (PLCG)	1	233.1×	0.026	PLCG1
RHO GTPase Effectors	2	19.4×	0.026	MEN1, CDKN1B
PIP3 activates AKT signaling	2	19.1×	0.026	CDKN1B, BAD

GO biological processes by enrichment

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

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of epithelial cell proliferation involved in prostate gland development	2	702.2×	6e-04	STK11, CDKN1B
epithelial cell proliferation involved in prostate gland development	2	526.6×	6e-04	STK11, CDKN1B
negative regulation of cell population proliferation	4	21.1×	0.001	MEN1, STK11, CDC73, CDKN1B
positive regulation of transforming growth factor beta receptor signaling pathway	2	131.7×	0.005	MEN1, STK11
response to ionizing radiation	2	102.8×	0.005	STK11, ATM
regulation of signal transduction by p53 class mediator	2	95.8×	0.005	STK11, ATM
regulation of cell cycle	3	28.0×	0.005	STK11, CDKN1B, ATM
protein phosphorylation	3	25.5×	0.005	STK11, MAP4K2, ATM
DNA damage response, signal transduction by p53 class mediator	2	89.6×	0.005	CDKN1B, ATM
intrinsic apoptotic signaling pathway in response to DNA damage	2	81.0×	0.005	ATM, BAD
negative regulation of TORC1 signaling	2	81.0×	0.005	STK11, ATM
cellular senescence	2	73.9×	0.005	CDKN1B, ATM
negative regulation of epithelial cell proliferation	2	72.6×	0.005	CDC73, CDKN1B
DNA damage response	3	20.1×	0.005	MEN1, STK11, ATM
ADP metabolic process	1	2106.5×	0.006	BAD
positive regulation of vesicle transport along microtubule	1	2106.5×	0.006	STK11
positive regulation of intrinsic apoptotic signaling pathway in response to osmotic stress	1	2106.5×	0.006	BAD
regulation of cell growth	2	55.4×	0.006	STK11, CDC73
positive regulation of autophagy	2	52.0×	0.007	STK11, BAD
establishment of RNA localization to telomere	1	1053.2×	0.008	ATM
establishment of protein-containing complex localization to telomere	1	1053.2×	0.008	ATM
regulation of lens fiber cell differentiation	1	1053.2×	0.008	CDKN1B
positive regulation of telomerase catalytic core complex assembly	1	1053.2×	0.008	ATM
negative regulation of cardiac muscle tissue regeneration	1	1053.2×	0.008	CDKN1B
T cell receptor signaling pathway	2	38.0×	0.010	STK11, PLCG1
pre-B cell allelic exclusion	1	702.2×	0.010	ATM
cellular response to nitrosative stress	1	702.2×	0.010	ATM
positive regulation of type B pancreatic cell development	1	702.2×	0.010	BAD
protein autophosphorylation	2	36.3×	0.010	STK11, ATM
negative regulation of cell growth	2	36.0×	0.010	STK11, CDKN1B

Therapeutics

Drug target analysis

Approved (phase 4): 6 · Phase ≥3: 6 · Phased (≥1): 7 · Undrugged: 1

Druggability breadth: 8 of 8 evidence-associated genes (100%) 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
MEN1	LOPERAMIDE
STK11	FEDRATINIB
MAP4K2	PONATINIB
ATM	AMIODARONE HYDROCHLORIDE
PLCG1	CEFIXIME
BAD	VENETOCLAX

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MEN1	475	4
MAP4K2	65	4
ATM	35	4
STK11	17	4
BAD	8	4
CDC73	1	2
PLCG1	1	4
CDKN1B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LOPERAMIDE	4	MEN1
CANDESARTAN CILEXETIL	4	MEN1
EVANS BLUE FREE ACID	4	MEN1
DIENESTROL	4	MEN1
BEXAROTENE	4	MEN1
IFOSFAMIDE	4	MEN1
PROGESTERONE	4	MEN1
CLOTRIMAZOLE	4	MEN1
AMINOCAPROIC ACID	4	MEN1
LATANOPROST	4	MEN1
FLUORESCEIN	4	MEN1
OXCARBAZEPINE	4	MEN1
SALMETEROL XINAFOATE	4	MEN1
AMIODARONE HYDROCHLORIDE	4	ATM, MEN1
TRICLABENDAZOLE	4	MEN1
TRYPAN BLUE FREE ACID	4	MEN1
MIGALASTAT	4	MEN1
DROPERIDOL	4	MEN1
ARIPIPRAZOLE	4	MEN1
AMOXAPINE	4	MEN1
RALOXIFENE HYDROCHLORIDE	4	MEN1
IDARUBICIN	4	MEN1
ACETAMINOPHEN	4	MEN1
OXYBUTYNIN CHLORIDE	4	MEN1
DECAMETHONIUM BROMIDE	4	MEN1
DESLORATADINE	4	MEN1
DITHIAZANINE	4	MEN1
TRIMETREXATE	4	MEN1
NICARDIPINE HYDROCHLORIDE	4	MEN1
PROTRIPTYLINE HYDROCHLORIDE	4	MEN1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
MAP4K2	292	Binding:291, Functional:1
STK11	244	Binding:244
ATM	240	Binding:233, Functional:5, ADMET:2
MEN1	93	Binding:86, Functional:7
BAD	36	Binding:35, Functional:1
PLCG1	13	Binding:12, ADMET:1
CDC73	8	Binding:8
CDKN1B	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
STK11	2.7.11.1	non-specific serine/threonine protein kinase
ATM	2.7.11.1	non-specific serine/threonine protein kinase
PLCG1	3.1.4.11	phosphoinositide phospholipase C

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
STK11	244
MAP4K2	292
ATM	240

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
LOPERAMIDE	4	MEN1
CANDESARTAN CILEXETIL	4	MEN1
EVANS BLUE FREE ACID	4	MEN1
DIENESTROL	4	MEN1
BEXAROTENE	4	MEN1
IFOSFAMIDE	4	MEN1
PROGESTERONE	4	MEN1
CLOTRIMAZOLE	4	MEN1
AMINOCAPROIC ACID	4	MEN1
LATANOPROST	4	MEN1
FLUORESCEIN	4	MEN1
OXCARBAZEPINE	4	MEN1
SALMETEROL XINAFOATE	4	MEN1
AMIODARONE HYDROCHLORIDE	4	ATM, MEN1
TRICLABENDAZOLE	4	MEN1
TRYPAN BLUE FREE ACID	4	MEN1
MIGALASTAT	4	MEN1
DROPERIDOL	4	MEN1
ARIPIPRAZOLE	4	MEN1
AMOXAPINE	4	MEN1
RALOXIFENE HYDROCHLORIDE	4	MEN1
IDARUBICIN	4	MEN1
ACETAMINOPHEN	4	MEN1
OXYBUTYNIN CHLORIDE	4	MEN1
DECAMETHONIUM BROMIDE	4	MEN1
DESLORATADINE	4	MEN1
DITHIAZANINE	4	MEN1
TRIMETREXATE	4	MEN1
NICARDIPINE HYDROCHLORIDE	4	MEN1
PROTRIPTYLINE HYDROCHLORIDE	4	MEN1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	6	MEN1, STK11, MAP4K2, ATM, PLCG1, BAD
B	Phased (≥1) drug, not yet approved	1	CDC73
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CDKN1B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CDKN1B	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 17.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	11
PHASE2	4
PHASE1	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03950609	PHASE2	ACTIVE_NOT_RECRUITING	Lenvatinib and Everolimus in Treating Patients With Advanced, Unresectable Carcinoid Tumors
NCT00001277	PHASE2	COMPLETED	Studies of Elevated Parathyroid Activity
NCT00454363	PHASE2	COMPLETED	Pazopanib Hydrochloride in Treating Patients With Advanced Neuroendocrine Cancer
NCT02101918	PHASE2	COMPLETED	Ziv-Aflibercept in Treating and Computed Tomography Perfusion Imaging in Predicting Response in Patients With Pancreatic Neuroendocrine Tumors That Are Metastatic or Cannot Be Removed by Surgery
NCT02831179	PHASE1	WITHDRAWN	Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor
NCT03001349	EARLY_PHASE1	TERMINATED	68Ga-DOTA-TOC PET/CT in Imaging Participants With Neuroendocrine Tumors
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03966612	Not specified	RECRUITING	Study and Monitoring of Multiple Endocrine Neoplasia Type 1
NCT05037461	Not specified	RECRUITING	Precision Radiotherapy Using MR-linac for Pancreatic Neuroendocrine Tumours in MEN1 Patients
NCT06523582	Not specified	RECRUITING	Genetic Bases of Neuroendocrine Neoplasms in Mexican Patients
NCT06790251	Not specified	NOT_YET_RECRUITING	Institution of an Italian Multicenter Database of Patients With Multiple Endocrine Neoplasia Type 1 (MENNET1 Database)
NCT07272187	Not specified	RECRUITING	Endoscopic Ultrasound-guided Radiofrequency Ablation for Upper Gastrointestinal Tract Lesions
NCT01794676	Not specified	COMPLETED	Genetic Evaluation of Families With Endocrine Cancers
NCT03043508	Not specified	UNKNOWN	Overall and Disease Specific Survival in Patients With Confirmed MEN1 With or Without PNET (Pancreatic Neuroendocrine Tumors)
NCT05061784	Not specified	COMPLETED	Routine Transcervical Thymectomy in MEN-1 Patients
NCT05554744	Not specified	UNKNOWN	EUS-FNI for MEN1-related Pancreatic Neuroendocrine Tumors

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
EDOTREOTIDE GALLIUM GA-68	4	2
AFLIBERCEPT	4	1
FLUORODOPA F 18	4	1
PAZOPANIB HYDROCHLORIDE	4	1
VELIPARIB	3	2