Endometrial hyperplasia without atypia

Summary

Endometrial hyperplasia without atypia (MONDO:0006193) is a disease with 2 cohort genes and 5 clinical trials. Top therapeutic interventions include dydrogesterone, etonogestrel, and medroxyprogesterone acetate.

At a glance

• Cohort genes: 2
• ClinVar variants: 2
• Clinical trials: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	endometrial hyperplasia without atypia
Mondo ID	MONDO:0006193
EFO	EFO:1000234
NCIT	C40157
SNOMED CT	134031000119108
UMLS	C1516855
MedGen	274011
Is cancer (heuristic)	no

Also known as: typical endometrial hyperplasia

Data availability: 2 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › hyperplasia › endometrial hyperplasia without atypia

Related subtypes (13): adrenal medullary hyperplasia, atypical endometrial hyperplasia, atypical lobular breast hyperplasia, C-cell hyperplasia, columnar cell hyperplasia of the breast, complex endometrial hyperplasia, parathyroid hyperplasia, simple endometrial hyperplasia, usual ductal breast hyperplasia, focal epithelial hyperplasia, benign prostatic hyperplasia, neuroendocrine cell hyperplasia of infancy, urothelial hyperplasia

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

2 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
12582	NM_004985.5(KRAS):c.35G>A (p.Gly12Asp)	KRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2447221	NM_000314.8(PTEN):c.332G>A (p.Trp111Ter)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 25 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
PTEN	Orphanet:109	Bannayan-Riley-Ruvalcaba syndrome
PTEN	Orphanet:137608	Segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome
PTEN	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
PTEN	Orphanet:201	Cowden syndrome
PTEN	Orphanet:210548	Macrocephaly-intellectual disability-autism syndrome
PTEN	Orphanet:2969	Proteus-like syndrome
PTEN	Orphanet:494547	Squamous cell carcinoma of the hypopharynx
PTEN	Orphanet:494550	Squamous cell carcinoma of the larynx
PTEN	Orphanet:500464	Squamous cell carcinoma of the nasal cavity and paranasal sinuses
PTEN	Orphanet:500478	Squamous cell carcinoma of the oropharynx
PTEN	Orphanet:502363	Squamous cell carcinoma of the oral cavity
PTEN	Orphanet:502366	Squamous cell carcinoma of the lip
PTEN	Orphanet:65285	Lhermitte-Duclos disease
PTEN	Orphanet:79076	Juvenile polyposis of infancy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	clinvar
PTEN	HGNC:9588	ENSG00000171862	P60484	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
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.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Phosphatase	1	42.0×	0.047
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
PTEN	Phosphatase	yes	3.1.3.16	Tyr_Pase_dom, Tyr_Pase_cat, Tensin_C2-dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
nipple	1
pylorus	1
trigeminal ganglion	1
calcaneal tendon	1
endothelial cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple
PTEN	256	ubiquitous	marker	sperm, endothelial cell, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRAS	14,509
PTEN	11,626

Intra-cohort edges

A	B	Sources
KRAS	PTEN	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
PTEN	P60484	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 84. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
PTEN Loss of Function in Cancer	1	2855.0×	0.007	PTEN
Signaling by RAS GAP mutants	1	1903.3×	0.007	KRAS
Signaling by RAS GTPase mutants	1	1903.3×	0.007	KRAS
Activation of RAS in B cells	1	1142.0×	0.007	KRAS
RAS signaling downstream of NF1 loss-of-function variants	1	815.7×	0.007	KRAS
Estrogen-stimulated signaling through PRKCZ	1	815.7×	0.007	KRAS
SOS-mediated signalling	1	713.8×	0.007	KRAS
Activated NTRK3 signals through RAS	1	634.4×	0.007	KRAS
EGFR Transactivation by Gastrin	1	571.0×	0.007	KRAS
SHC-related events triggered by IGF1R	1	571.0×	0.007	KRAS
Regulation of PTEN mRNA translation	1	571.0×	0.007	PTEN
RUNX3 regulates p14-ARF	1	571.0×	0.007	KRAS
Activated NTRK2 signals through RAS	1	571.0×	0.007	KRAS
MET activates RAS signaling	1	519.1×	0.007	KRAS
Regulation of PTEN localization	1	519.1×	0.007	PTEN
Signaling by FGFR4 in disease	1	475.8×	0.007	KRAS
Activated NTRK2 signals through FRS2 and FRS3	1	475.8×	0.007	KRAS
Constitutive Signaling by Overexpressed ERBB2	1	475.8×	0.007	KRAS
p38MAPK events	1	439.2×	0.007	KRAS
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	439.2×	0.007	KRAS
Signaling by PDGFRA extracellular domain mutants	1	439.2×	0.007	KRAS
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases	1	407.9×	0.007	KRAS
GRB2 events in EGFR signaling	1	380.7×	0.007	KRAS
Erythropoietin activates RAS	1	380.7×	0.007	KRAS
Signaling by FLT3 ITD and TKD mutants	1	380.7×	0.007	KRAS
SHC1 events in ERBB4 signaling	1	356.9×	0.007	KRAS
SHC1 events in EGFR signaling	1	356.9×	0.007	KRAS
Constitutive Signaling by EGFRvIII	1	356.9×	0.007	KRAS
Signalling to RAS	1	335.9×	0.007	KRAS
Insulin receptor signalling cascade	1	335.9×	0.007	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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to mineralocorticoid	1	8426.0×	0.005	KRAS
negative regulation of synaptic vesicle clustering	1	4213.0×	0.005	PTEN
forebrain astrocyte development	1	2808.7×	0.005	KRAS
negative regulation of keratinocyte migration	1	2808.7×	0.005	PTEN
response to isolation stress	1	2106.5×	0.005	KRAS
rhythmic synaptic transmission	1	2106.5×	0.005	PTEN
response to gravity	1	1404.3×	0.005	KRAS
central nervous system myelin maintenance	1	1404.3×	0.005	PTEN
negative regulation of cell cycle G1/S phase transition	1	1203.7×	0.005	PTEN
negative regulation of wound healing, spreading of epidermal cells	1	1203.7×	0.005	PTEN
spindle assembly involved in female meiosis	1	936.2×	0.005	PTEN
central nervous system neuron axonogenesis	1	936.2×	0.005	PTEN
postsynaptic density assembly	1	936.2×	0.005	PTEN
neuron-neuron synaptic transmission	1	842.6×	0.005	PTEN
negative regulation of peptidyl-serine phosphorylation	1	842.6×	0.005	PTEN
negative regulation of cell size	1	842.6×	0.005	PTEN
presynaptic membrane assembly	1	842.6×	0.005	PTEN
type I pneumocyte differentiation	1	766.0×	0.005	KRAS
negative regulation of organ growth	1	702.2×	0.005	PTEN
forebrain morphogenesis	1	702.2×	0.005	PTEN
myoblast proliferation	1	702.2×	0.005	KRAS
multicellular organismal response to stress	1	648.1×	0.005	PTEN
negative regulation of axonogenesis	1	648.1×	0.005	PTEN
cellular response to electrical stimulus	1	648.1×	0.005	PTEN
negative regulation of excitatory postsynaptic potential	1	648.1×	0.005	PTEN
positive regulation of cellular senescence	1	648.1×	0.005	KRAS
negative regulation of epithelial cell differentiation	1	601.9×	0.005	KRAS
maternal behavior	1	561.7×	0.005	PTEN
prepulse inhibition	1	561.7×	0.005	PTEN
regulation of synaptic transmission, GABAergic	1	526.6×	0.005	KRAS

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
KRAS	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KRAS	11	4
PTEN	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	KRAS
DABRAFENIB	4	KRAS
LONAFARNIB	4	KRAS
SOTORASIB	4	KRAS
ADAGRASIB	4	KRAS
OPNURASIB	3	KRAS
DIVARASIB	2	KRAS
GLECIRASIB	2	KRAS
BMS-214662	1	KRAS
LY-3009120	1	KRAS
MRTX-1133	1	KRAS

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
KRAS	861	Binding:829, Functional:32
PTEN	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KRAS	3.6.5.2	small monomeric GTPase
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
KRAS	861

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

11 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)
VEMURAFENIB	4	KRAS
DABRAFENIB	4	KRAS
LONAFARNIB	4	KRAS
SOTORASIB	4	KRAS
ADAGRASIB	4	KRAS
OPNURASIB	3	KRAS
DIVARASIB	2	KRAS
GLECIRASIB	2	KRAS
BMS-214662	1	KRAS
LY-3009120	1	KRAS
MRTX-1133	1	KRAS

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KRAS
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PTEN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
PTEN	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE3	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03675139	PHASE3	COMPLETED	MPA Versus Dydrogesterone for Management of Endometrial Hyperplasia Without Atypia
NCT01685762	EARLY_PHASE1	COMPLETED	Metformin for the Treatment of Endometrial Hyperplasia
NCT03992937	Not specified	COMPLETED	Vaginal Micronized Progesterone Versus Levonorgestrel for Treatment of Non-atypical Endometrial Hyperplasia
NCT06115577	Not specified	COMPLETED	Endometrial Tissues and Mononuclear Cells Receptivity in Pathogenesis of Endometrial Proliferative Processes
NCT06378489	Not specified	UNKNOWN	The Use of Etonogestrel Contraceptive Implant as Treatment for Endometrial Hyperplasia Without Atypia: A Cohort Study

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DYDROGESTERONE	4	1
ETONOGESTREL	4	1
MEDROXYPROGESTERONE ACETATE	4	1
METFORMIN	4	1
CHEMBL287148	0	1
CHEMBL430483	0	1