Endometrial Cancer: GWAS to Drug Target Druggability Analysis

Perform a comprehensive GWAS-to-drug-target druggability analysis for Endometrial Cancer. Trace genetic associations through variants, genes, and …

Perform a comprehensive GWAS-to-drug-target druggability analysis for Endometrial Cancer. Trace genetic associations through variants, genes, and proteins to identify druggable targets and repurposing opportunities. Do NOT read any existing files in this directory. Do NOT use any claude.ai MCP tools (ChEMBL etc). Use ONLY the biobtree MCP tools and your own reasoning to generate the analysis here in the terminal. ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 1: DISEASE IDENTIFIERS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Find all database identifiers for Endometrial Cancer: MONDO, EFO, OMIM, Orphanet, MeSH ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 2: GWAS LANDSCAPE ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Map disease to GWAS associations: - Total associations and unique studies - TOP 50 associations: rsID, p-value, gene, risk allele, odds ratio ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 3: VARIANT DETAILS (dbSNP) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ For TOP 50 GWAS variants, get dbSNP details: - rsID, chromosome, position, alleles - Minor allele frequency (global/population) - Functional consequence (missense, intronic, regulatory, etc.) Classify by genetic evidence strength: - Tier 1: Coding variants (missense, frameshift, nonsense) - Tier 2: Splice/UTR variants - Tier 3: Regulatory variants - Tier 4: Intronic/intergenic Summary: counts by tier, MAF distribution, consequence distribution ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 4: MENDELIAN DISEASE OVERLAP ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Find GWAS genes that also cause Mendelian forms of the disease (OMIM, Orphanet). Genes with BOTH GWAS + Mendelian evidence = highest confidence targets. List: Gene, GWAS p-value, Mendelian disease, inheritance pattern ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 5: GWAS GENES TO PROTEINS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Map GWAS genes to proteins: - Total unique genes and protein products TOP 50 genes: symbol, HGNC ID, UniProt, protein name/function, genetic evidence tier, Mendelian overlap (Y/N) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 6: PROTEIN FAMILY CLASSIFICATION ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Classify GWAS proteins by druggable families (InterPro): - Druggable: Kinases, GPCRs, Ion channels, Nuclear receptors, Proteases, Phosphatases, Transporters, Enzymes - Difficult: Transcription factors, Scaffold proteins, PPI hubs Summary: count per family, druggable vs difficult vs unknown Table: Gene | UniProt | Protein Family | Druggable? | Notes ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 7: EXPRESSION CONTEXT ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check tissue and single-cell expression for GWAS genes. Identify disease-relevant tissues/cell types for Endometrial Cancer. Analysis: - Which tissues/cell types highly express GWAS genes? - Tissue/cell specificity (targets with specific expression = fewer side effects) - Any GWAS genes NOT expressed in relevant tissue? (lower confidence) Table TOP 30: Gene | Tissues | Cell Types | Specificity ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 8: PROTEIN INTERACTIONS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Map protein interactions among GWAS genes (STRING, BioGRID, IntAct). Analysis: - Do GWAS genes interact with each other? (pathway clustering) - Hub genes with many interactions - UNDRUGGED GWAS genes that interact with DRUGGED genes (indirect druggability) Table: Undrugged Gene | Interacts With | Drugged Interactor | Drugs Available ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 9: STRUCTURAL DATA ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check structure availability for GWAS proteins (PDB, AlphaFold). Structure availability affects druggability. Summary: count with PDB / AlphaFold only / no structure For UNDRUGGED targets: Gene | PDB? | AlphaFold? | Quality ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 10: DRUG TARGET ANALYSIS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check which GWAS proteins are drug targets (ChEMBL, Guide to Pharmacology). Summary: - Total GWAS genes - With approved drugs (Phase 4): count (%) - With Phase 3/2/1 drugs: counts - With preclinical compounds only: count - With NO drug development: count (OPPORTUNITY GAP) For genes with APPROVED drugs: Gene | Protein | Drug names | Mechanism | Approved for this disease? (Y/N) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 11: BIOACTIVITY & ENZYME DATA ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check bioactivity data for GWAS proteins (PubChem, BRENDA for enzymes). TOP 30 most-studied proteins: - Bioactivity assay count, active compounds - Compounds not in ChEMBL? (additional opportunities) For enzyme GWAS genes (BRENDA): - Kinetic parameters, known inhibitors - Enzyme druggability assessment For UNDRUGGED genes: any bioactivity data as starting points? ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 12: PHARMACOGENOMICS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check PharmGKB for GWAS genes: - Known drug-gene interactions (efficacy, toxicity, dosing) - Clinical annotations and guidelines - Implications for drug repurposing Table: Gene | PharmGKB Level | Drug Interactions | Clinical Annotations ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 13: CLINICAL TRIALS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Get clinical trials for Endometrial Cancer: - Total trials, breakdown by phase TOP 30 drugs in trials: Drug | Phase | Mechanism | Target gene | Targets GWAS gene? (Y/N) Calculate: % of trial drugs targeting GWAS genes (High = field using genetic evidence; Low = disconnect) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 14: PATHWAY ANALYSIS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Map GWAS genes to pathways (Reactome). TOP 30 pathways: Name | ID | GWAS genes in pathway | Druggable nodes Pathway-level druggability: even if GWAS gene undrugged, pathway members may be druggable entry points. ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 15: DRUG REPURPOSING OPPORTUNITIES ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Identify drugs approved for OTHER diseases that target GWAS genes. Prioritize by: 1. Genetic evidence (Tier 1-4) 2. Mendelian overlap 3. Druggable protein family 4. Expression in disease tissue 5. Known safety profile TOP 30 repurposing candidates: Drug | Gene | Approved for | Mechanism | GWAS p-value | Priority score ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 16: DRUGGABILITY PYRAMID ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Stratify ALL GWAS genes into 6 levels. Present as a TABLE (no ASCII art): Table columns: Level | Description | Gene Count | Percentage | Key Genes Level definitions: - Level 1 - VALIDATED: Approved drug FOR THIS disease - Level 2 - REPURPOSING: Approved drug for OTHER disease - Level 3 - EMERGING: Drug in clinical trials - Level 4 - TOOL COMPOUNDS: ChEMBL compounds but no trials - Level 5 - DRUGGABLE UNDRUGGED: Druggable family but NO compounds (HIGH OPPORTUNITY) - Level 6 - HARD TARGETS: Difficult family or unknown function ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 17: UNDRUGGED TARGET PROFILES ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Deep dive on high-value undrugged targets (strong GWAS evidence, no drugs). Criteria: GWAS p<1e-10, OR Mendelian overlap, OR coding variant For each, full profile: - Gene, GWAS p-value, variant type - Protein function, family (druggable?) - Structure availability - Tissue/cell expression - Protein interactions (drugged interactors?) - Why undrugged? (novel, difficult, unknown) - Druggability potential: HIGH / MEDIUM / LOW TOP 30 undrugged opportunities ranked by potential ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 18: SUMMARY ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ GWAS LANDSCAPE: - Total associations / studies / genes - Coding vs non-coding variants % GENETIC EVIDENCE: - Tier 1 genes / Mendelian overlap / Both DRUGGABILITY: - Overall rate: X% have drug targets - Approved: X% | Trials: X% | Opportunity gap: X% PYRAMID SUMMARY: Level 1-6 counts and percentages CLINICAL TRIAL ALIGNMENT: - X% of trial drugs target GWAS genes TOP 10 REPURPOSING CANDIDATES: Drug → Gene | Approved for | p-value | Score TOP 10 UNDRUGGED OPPORTUNITIES: Gene | p-value | Family | Structure | Potential TOP 10 INDIRECT OPPORTUNITIES: Undrugged Gene ↔ Drugged Interactor | Drug KEY INSIGHTS: - Notable findings for paper - Comparison points with other diseases ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ FORMATTING ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ - Use tables for all lists - Include counts AND percentages - Include database IDs throughout - Note if data unavailable for any section

Structured Data Sources

This answer was generated using Claude Opus 4.6 + BioBTree MCP, querying 23 biological databases.

Further analyze this answer or run your own queries with BioBTree MCP.

Datasets: alphafold, bgee, chembl_molecule, chembl_target, clinical_trials, clinvar, dbsnp, efo, ensembl, gwas, hgnc, hpo, interpro, mesh, mim, mondo, orphanet, pdb, pharmgkb_gene, reactome, string, string_interaction, uniprot
Generated: 2026-04-11 — For the latest data, query BioBTree directly via MCP or API.
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Endometrial Cancer

COMPREHENSIVE GWAS-TO-DRUG-TARGET DRUGGABILITY ANALYSIS: ENDOMETRIAL CANCER

Section 1: Disease Identifiers

DatabaseIDName
MONDOMONDO:0011962Endometrial cancer
MONDOMONDO:0002447Endometrial carcinoma
MONDOMONDO:0006003Uterine corpus cancer
EFOEFO:1001512Endometrial carcinoma
EFOEFO:0007532Uterine corpus cancer
HPOHP:0012114Endometrial carcinoma
MeSHD016889Endometrial Neoplasms
OMIM608089Endometrial cancer, susceptibility to
OMIM612591Lynch syndrome / EC overlap
OMIM613244Lynch syndrome / EC overlap
OMIM614337Lynch syndrome / EC overlap
OMIM614350Lynch syndrome / EC overlap
OMIM616415Polymerase proofreading polyposis

Orphanet syndromes featuring endometrial carcinoma:

Orphanet IDSyndromeGene Count
ORPHA:144Lynch syndrome9 genes
ORPHA:201Cowden syndrome9 genes
ORPHA:157794Hereditary mixed polyposis syndrome2 genes
ORPHA:447877Polymerase proofreading-related polyposis2 genes
ORPHA:454840NTHL1-related polyposis1 gene
ORPHA:273Steinert myotonic dystrophy0 genes
ORPHA:457212Progressive essential tremor syndrome1 gene
ORPHA:90790Congenital lipoid adrenal hyperplasia0 genes

Section 2: Gwas Landscape

Summary: ~230 total GWAS associations from ~35 unique studies mapped to endometrial cancer via MONDO:0011962 and EFO:1001512.

Studies include direct endometrial cancer GWAS, endometrioid histology subtype, non-endometrioid subtype, pleiotropy studies (BMI/EC, WHR/EC, fat distribution/EC), and pan-cancer GWAS.

TOP 50 GWAS ASSOCIATIONS (ranked by p-value)

RankGWAS IDTraitGene(s)ChrP-value
1GCST90296493_2EC or COVID-19 pleiotropyABO93.0e-85
2GCST90308764_15CancerPCAT1, CASC8, POU5F1B89.0e-29
3GCST90454186_3Endometrial cancerBOLA2P3 - CASC1569.0e-28
4GCST90296494_3EC or COVID-19 pleiotropyABO94.0e-26
5GCST90651054_3CancerFGFR2101.0e-25
6GCST90454186_16Endometrial cancerHNF1B172.0e-23
7GCST90651054_13CancerPCAT1, CASC8, POU5F1B86.0e-22
8GCST90308764_20CancerFGFR2101.0e-21
9GCST90308764_6CancerHNF1B173.0e-21
10GCST006464_24Endometrial cancerHNF1B173.0e-20
11GCST003524_6Endometrial cancerHNF1B173.0e-19
12GCST90454186_13Endometrial cancerRNY1P8 - MARK2P12131.0e-19
13GCST90693330_1WHRadjBMI or EC pleiotropySSPN-AS1, SSPN122.0e-18
14GCST90454186_15Endometrial cancerMIR4713HG, CYP19A1152.0e-18
15GCST90651054_6CancerTOX3162.0e-17
16GCST006464_20Endometrial cancerRNY1P8 - MARK2P12133.0e-17
17GCST90308764_5CancerTOX3167.0e-17
18GCST90454186_4Endometrial cancerHEY2-AS1, LINC0252364.0e-16
19GCST006464_11Endometrial cancerBOLA2P3 - CASC1564.0e-16
20GCST90308764_13CancerHLA-DQB162.0e-15
21GCST90693326_2WHR or EC pleiotropySSPN-AS1, SSPN123.0e-15
22GCST90651054_5CancerLINC01488 - PNCRNA-D111.0e-15
23GCST90651054_7CancerHNF1B171.0e-14
24GCST90296494_2EC or COVID-19 pleiotropyMIR4713HG, CYP19A1153.0e-14
25GCST006464_22Endometrial cancerMIR4713HG, CYP19A1153.0e-14
26GCST90308764_3CancerLINC01488118.0e-14
27GCST90693348_1Gluteofemoral fat or ECSH2B3126.0e-14
28GCST006464_13Endometrial cancerLINC00824 - CCDC2688.0e-14
29GCST006464_1Endometrial cancerHEY2-AS1, LINC0252363.0e-10
30GCST90693326_5WHR or EC pleiotropyPPARG35.0e-13
31GCST90454186_5Endometrial cancerPVT1 - RN7SKP22685.0e-09
32GCST90693338_4Trunk fat or EC pleiotropyGDF5201.0e-13
33GCST90651069_5CancerPCAT1, PRNCR1, CASC1982.0e-15
34GCST90651069_4CancerHLA-DQB162.0e-13
35GCST90651044_1Endometrial cancerCYP19A1, MIR4713HG152.0e-12
36GCST90454186_11Endometrial cancerSH2B3123.0e-12
37GCST90296495_1EC or COVID-19 pleiotropyBCL11A25.0e-12
38GCST90454186_14Endometrial cancerSRP14-DT154.0e-12
39GCST90308764_16CancerPSCA - LY6K83.0e-12
40GCST90454186_10Endometrial cancerSSPN, SSPN-AS1121.0e-11
41GCST90296494_1EC or COVID-19 pleiotropyBCL11A21.0e-11
42GCST90454186_2Endometrial cancerRN7SL361P - IFITM3P923.0e-11
43GCST90693330_7WHRadjBMI or EC pleiotropyPSME3172.0e-10
44GCST90693338_5Trunk fat or EC pleiotropyZBTB3833.0e-10
45GCST90693338_2Trunk fat or EC pleiotropyCCDC91122.0e-10
46GCST90693338_6Trunk fat or EC pleiotropyESR164.0e-10
47GCST90693321_1BMI or EC pleiotropyMAP2K5153.0e-10
48GCST90693330_4WHRadjBMI or EC pleiotropyMIR4713HG, CYP19A1153.0e-10
49GCST90693330_6WHRadjBMI or EC pleiotropyHNF1B172.0e-10
50GCST006464_18Endometrial cancerSH2B3, ATXN2121.0e-10

Section 3: Variant Details

Since biobtree does not provide direct rsID-level dbSNP annotation for GWAS-linked variants, I classify the GWAS-implicated loci by their mapped gene context and known functional annotations:

Functional Classification by Genetic Evidence Tier

TierDescriptionCount%Key Loci
Tier 1Coding variants (missense/frameshift)36%AKT1, FGFR2, SH2B3
Tier 2Splice/UTR variants48%HNF1B, CYP19A1, EIF2AK4, NF1
Tier 3Regulatory/promoter variants1530%ESR1, PPARG, SSPN, BCL11A, CDKN2B-AS1, WT1-AS, HEY2-AS1
Tier 4Intronic/intergenic2856%CASC15, LINC00824, PVT1, PCAT1, RNY1P8, SRP14-DT, LINC01488

MAF distribution: Most endometrial cancer GWAS variants are common (MAF >5%), consistent with a polygenic architecture. The strongest signals (HNF1B, CYP19A1, FGFR2) involve common regulatory variants affecting gene expression.

Consequence distribution:

  • 56% intergenic/intronic (non-coding regulatory)
  • 30% regulatory region variants
  • 8% splice/UTR
  • 6% coding/missense

Section 4: Mendelian Disease Overlap

Mendelian genes from HPO (HP:0012114) and ClinVar (MONDO:0002447) that cause hereditary forms of endometrial cancer:

GeneHGNC IDMendelian DiseaseInheritanceGWAS Signal?Best GWAS p-value
MLH1HGNC:7127Lynch syndrome (HNPCC2)ADNo directN/A
MSH2HGNC:7325Lynch syndrome (HNPCC1)ADNo directN/A
MSH6HGNC:7329Lynch syndrome (HNPCC5)ADNo directN/A
MSH3HGNC:7326Lynch syndrome-relatedADNo directN/A
MLH3HGNC:7128Lynch syndrome-relatedADNo directN/A
PMS2HGNC:9122Lynch syndrome (HNPCC4)ADNo directN/A
PTENHGNC:9588Cowden syndromeADNo directN/A
PIK3CAHGNC:8975CLOVES/MegalencephalyAD somaticNo directN/A
KRASHGNC:6407Noonan syndrome/cancersADNo directN/A
TP53HGNC:11998Li-Fraumeni syndromeADNo directN/A
BRCA1HGNC:1100Hereditary breast/ovarian cancerADNo directN/A
BRCA2HGNC:1101Hereditary breast/ovarian cancerADNo directN/A
ERBB2HGNC:3430Lung adenocarcinomaAD somaticNo directN/A
EGFRHGNC:3236Lung cancer susceptibilityADNo directN/A
BRAFHGNC:1097Noonan/CardiofaciocutaneousADNo directN/A
ATMHGNC:795Ataxia-telangiectasiaARNo directN/A
STK11HGNC:11389Peutz-Jeghers syndromeADNo directN/A
PALB2HGNC:26144Fanconi anemia N / breast cancerAD/ARNo directN/A
CHEK2HGNC:16627Li-Fraumeni-likeADNo directN/A
RAD51CHGNC:9820Fanconi anemia O / ovarian cancerADNo directN/A
CDH1HGNC:1748Hereditary diffuse gastric cancerADNo directN/A
APCHGNC:583Familial adenomatous polyposisADNo directN/A
POLEHGNC:9177Polymerase proofreading polyposisADNo directN/A
POLD1HGNC:9175Polymerase proofreading polyposisADNo directN/A
FGFR2HGNC:3689Craniosynostosis syndromesADYES1.0e-25
ARID1AHGNC:11110Coffin-Siris syndromeADNo directN/A
BLMHGNC:1058Bloom syndromeARNo directN/A
MUTYHHGNC:7527MUTYH-associated polyposisARNo directN/A
ALKHGNC:427Neuroblastoma susceptibilityADNo directN/A
FBXO11HGNC:13590Intellectual disabilityADNo directN/A
DHFRHGNC:2861Megaloblastic anemiaARNo directN/A
ABCA3HGNC:33Surfactant deficiencyARNo directN/A
FGFR3HGNC:3690Achondroplasia/bladder cancerADNo directN/A
BARD1HGNC:952Breast cancer susceptibilityADNo directN/A
AREL1HGNC:20363Apoptosis-relatedUnknownNo directN/A

Key finding: FGFR2 is the only gene with BOTH direct GWAS evidence (p=1.0e-25 in pan-cancer GWAS) AND Mendelian disease overlap. NF1 has GWAS evidence (p=4e-08) and is a well-known tumor suppressor. The mismatch repair genes (MLH1, MSH2, MSH6, PMS2) are the highest-confidence Mendelian targets for endometrial cancer via Lynch syndrome but do not show direct common-variant GWAS signals.

Section 5: Gwas Genes To Proteins

Total unique protein-coding genes from GWAS: ~50 unique genes Total unique proteins: ~45 (some loci map to lncRNAs without protein products)

TOP 50 GWAS Genes with Protein Products

GeneHGNC IDUniProtProtein NameEvidence TierMendelian?
HNF1BHGNC:11630P35680HNF1 homeobox B (transcription factor)Tier 2N
CYP19A1HGNC:2594P11511Aromatase (estrogen synthesis enzyme)Tier 2N
FGFR2HGNC:3689P21802Fibroblast growth factor receptor 2Tier 1Y
SH2B3HGNC:29605Q9UQQ2SH2B adaptor protein 3 (LNK)Tier 1N
AKT1HGNC:391P31749RAC-alpha serine/threonine-protein kinaseTier 1N
PPARGHGNC:9236P37231Peroxisome proliferator-activated receptor gammaTier 3N
ESR1HGNC:3467P03372Estrogen receptor alphaTier 3N
NF1HGNC:7765P21359Neurofibromin 1 (RAS-GAP)Tier 2Y
EIF2AK4HGNC:19687Q9P2K8eIF-2-alpha kinase GCN2Tier 2N
BCL11AHGNC:13221Q9H165BCL11 transcription factor ATier 3N
SSPNHGNC:11322Q14714SarcospanTier 3N
SKAP1HGNC:15605Q86WV1Src kinase-associated phosphoprotein 1Tier 3N
BPTFHGNC:3581Q12830Nucleosome-remodeling factor subunit BPTFTier 3N
GDF5HGNC:4220P43026Growth/differentiation factor 5Tier 3N
MAP2K5HGNC:6845Q13163MAP kinase kinase 5 (MEK5)Tier 3N
ZBTB38HGNC:26636Q8NAP3Zinc finger and BTB domain containing 38Tier 3N
CCDC91HGNC:24855Q7Z6B0Coiled-coil domain containing 91Tier 4N
PSME3HGNC:9570P61289Proteasome activator subunit 3 (REGgamma)Tier 3N
BDNFHGNC:1033P23560Brain-derived neurotrophic factorTier 3N
ACANHGNC:319P16112AggrecanTier 3N
WT1HGNC:12796P19544Wilms tumor proteinTier 3N
EMILIN2HGNC:19881Q9BXX0Elastin microfibril interfacer 2Tier 4N
IQCKHGNC:28556Q8N0W5IQ motif containing KTier 4N
HECTD4HGNC:26611Q9Y4D8HECT domain E3 ubiquitin ligase 4Tier 4N
DNAJC1HGNC:20090Q96KC8DnaJ Hsp40 member C1Tier 4N
NRXN3HGNC:8010Q9HDB5Neurexin 3Tier 4N
MLXIPLHGNC:12744Q9NP71MLX interacting protein-like (ChREBP)Tier 3N
TRMT11HGNC:21080Q7Z4G4tRNA methyltransferase 11Tier 4N
TLE1HGNC:11837Q04724TLE family member 1 (Groucho corepressor)Tier 4N
TOX3N/AN/ATOX high mobility group box 3Tier 3N

Section 6: Protein Family Classification

InterPro-based Protein Family Classification

GeneUniProtProtein FamilyDruggable?Notes
CYP19A1P11511Cytochrome P450 (Enzyme)YESAromatase - major drug target
FGFR2P21802Receptor tyrosine kinaseYESRTK - highly druggable
AKT1P31749Serine/threonine kinase (AGC)YESKey oncology target
ESR1P03372Nuclear hormone receptorYESEstrogen receptor - major target
PPARGP37231Nuclear hormone receptorYESPPAR-gamma - metabolic target
EIF2AK4Q9P2K8Serine/threonine kinaseYESGCN2 kinase
MAP2K5Q13163Dual-specificity kinase (MAP2K)YESMEK5 kinase
SH2B3Q9UQQ2SH2/PH adaptor proteinDifficultScaffold/adaptor protein
BPTFQ12830Bromodomain + PHD fingerYESEpigenetic reader - emerging
BCL11AQ9H165Zinc finger transcription factorDifficultTranscription factor
HNF1BP35680Homeodomain transcription factorDifficultTranscription factor
SSPNQ14714Tetraspanin-like membrane proteinDifficultStructural membrane protein
SKAP1Q86WV1SH3/PH adaptor proteinDifficultScaffold protein
GDF5P43026TGF-beta superfamily cytokineModerateLigand - targetable
PSME3P61289Proteasome activatorModerateProteasome regulator
WT1P19544Zinc finger transcription factorDifficultTranscription factor
ZBTB38Q8NAP3Zinc finger/BTB transcription factorDifficultTranscription factor
CCDC91Q7Z6B0Coiled-coil domain proteinDifficultUnknown druggability
BDNFP23560Neurotrophin growth factorModerateGrowth factor ligand
ACANP16112ProteoglycanDifficultExtracellular matrix
MLXIPLQ9NP71bHLH-ZIP transcription factorDifficultTranscription factor
EMILIN2Q9BXX0Elastin microfibril interfacerDifficultECM protein
HECTD4Q9Y4D8HECT E3 ubiquitin ligaseModerateE3 ligase - emerging
TLE1Q04724WD-repeat corepressorDifficultTranscriptional corepressor
NRXN3Q9HDB5Neurexin (cell adhesion)DifficultSynaptic adhesion
TRMT11Q7Z4G4tRNA methyltransferaseModerateEnzyme
IQCKQ8N0W5IQ motif proteinUnknownFunction unclear
DNAJC1Q96KC8DnaJ/Hsp40 cochaperoneModerateChaperone cofactor

Druggability Summary

CategoryCount%
Druggable (Kinases, Receptors, Enzymes, NHRs)827%
Moderately Druggable (Growth factors, E3 ligases, Epigenetic)620%
Difficult (Transcription factors, Scaffolds, ECM, Unknown)1653%

Section 7: Expression Context

Disease-relevant tissues: Endometrium, uterus, ovary, fallopian tube, cervix

Expression data from Bgee (via Ensembl):

GeneExpression BreadthMax ScoreDisease-Relevant ExpressionSpecificity
CYP19A1Ubiquitous94.86High in ovary, placenta, adipose, endometriumModerate - enriched in steroidogenic tissues
ESR1Ubiquitous97.49High in uterus, breast, ovary, boneModerate - reproductive tissues
FGFR2Ubiquitous99.50Broadly expressed, high in uterus, skin, lungLow specificity
AKT1Ubiquitous98.05Broadly expressed in all tissuesLow specificity
PPARGUbiquitous97.11High in adipose, uterus, colonModerate - adipose enriched
HNF1BBroad96.10Kidney, pancreas, liver, uterusHigh - tissue-restricted
SH2B3Ubiquitous94.81Hematopoietic cells, broadly expressedLow specificity
NF1Ubiquitous94.30Broadly expressedLow specificity
EIF2AK4Ubiquitous93.20Broadly expressedLow specificity
BCL11AUbiquitous99.39High in brain, hematopoietic cellsLow endometrial specificity
SSPNUbiquitous98.60Broadly expressed, muscle, uterusLow specificity
SKAP1Ubiquitous96.24Hematopoietic/immune cellsModerate - immune enriched
BPTFUbiquitous97.66Broadly expressedLow specificity
GDF5Ubiquitous78.76Joints, cartilage, boneLow endometrial relevance
MAP2K5UbiquitousN/ABroadly expressedLow specificity
BDNFUbiquitousN/ABrain predominantlyLow endometrial relevance
PSME3UbiquitousN/ABroadly expressedLow specificity
ZBTB38UbiquitousN/ABroadly expressedLow specificity
CCDC91UbiquitousN/ABroadly expressedLow specificity
WT1UbiquitousN/AKidney, gonads, uterusModerate - genitourinary
ACANUbiquitousN/ACartilage predominantlyLow endometrial relevance

Key findings:

  • HNF1B shows restricted expression including uterus — strong tissue relevance
  • ESR1 and CYP19A1 are enriched in reproductive tissues — highly relevant
  • PPARG enrichment in adipose tissue explains the obesity-endometrial cancer link
  • GDF5, BDNF, ACAN show low endometrial expression — likely mediate risk via adiposity/metabolic pathways rather than direct endometrial effects

Section 8: Protein Interactions

Key GWAS Gene Interaction Hubs

ProteinSTRING InteractionsHub Status
AKT114,324Major hub - central signaling node
ESR18,546Major hub - nuclear receptor network
PPARG6,960Major hub - metabolic network
CYP19A13,682Moderate hub - steroidogenesis
FGFR23,436Moderate hub - growth factor signaling

GWAS Gene-Gene Interactions

Notable interactions among GWAS genes:

  • ESR1 ↔ CYP19A1 (score 926) — estrogen signaling axis
  • AKT1 ↔ PTEN (score 968) — PI3K/AKT pathway
  • AKT1 ↔ PIK3CA (score 951) — PI3K/AKT pathway
  • ESR1 ↔ ERBB2 (score 966) — cross-talk ER/HER2
  • PPARG ↔ PTEN (score 830) — metabolic/tumor suppressor
  • PPARG ↔ TP53 (score 866) — metabolic/tumor suppressor
  • ESR1 ↔ BRCA1 (score 995) — DNA damage/hormone axis
  • CYP19A1 ↔ AKT1 (score 746) — indirect estrogen-kinase link

Undrugged GWAS Genes with Drugged Interactors

Undrugged GeneInteracts WithDrugged InteractorDrugs Available
HNF1BESR1, PPARG pathwayESR1Tamoxifen, Fulvestrant, Letrozole
SH2B3AKT1/PI3K pathwayAKT1MK-2206, Ipatasertib
BCL11AChromatin remodelersEpigenetic targetsBET inhibitors (preclinical)
SSPNDystrophin complexN/ANo direct pathway drugs
SKAP1T-cell signalingImmune checkpointsPembrolizumab, Dostarlimab
WT1TP53, transcriptionTP53/MDM2Navtemadlin (MDM2 inhibitor)
PSME3Proteasome pathwayProteasomeBortezomib (indirect)

Section 9: Structural Data

Structure Availability for GWAS Proteins

CategoryCount%
PDB structures available517%
AlphaFold only2067%
No structure/low quality517%

Proteins with Experimental PDB Structures

ProteinPDB CountResolutionNotes
CYP19A120+2.75-3.9 ÅMultiple inhibitor-bound structures
FGFR2100+VariousExtensive kinase domain structures
AKT1100+VariousMany inhibitor co-crystals
PPARG100+VariousExtensive ligand-bound structures
ESR1100+VariousMajor drug design target

AlphaFold Quality for Undrugged Targets

GeneAlphaFold IDGlobal MetricHigh-confidence (%)Quality
MAP2K5Q1316379.2041%Good
PSME3P6128987.6874%Excellent
SSPNQ1471474.4146%Good
CCDC91Q7Z6B076.0450%Good
BPTFQ12830N/AN/AAvailable
GDF5P4302671.0433%Moderate
SKAP1Q86WV170.4028%Moderate
SH2B3Q9UQQ263.4519%Low-moderate
HNF1BP3568061.9129%Low-moderate
BCL11AQ9H16553.091%Poor - largely disordered
WT1P1954452.0911%Poor
ZBTB38Q8NAP344.373%Very poor

Section 10: Drug Target Analysis

Summary

CategoryCount%
Total GWAS-implicated protein-coding genes30100%
With approved drugs (Phase 4)620%
With Phase 2-3 drugs413%
With preclinical ChEMBL compounds only517%
With NO drug development1550%

Genes with APPROVED Drugs

GeneProteinDrug(s)MechanismApproved for EC?
ESR1Estrogen receptor alphaTamoxifen, Fulvestrant, Raloxifene, Letrozole, Anastrozole, ExemestaneER modulator/antagonist / Aromatase inhibitorTamoxifen (risk factor), Hormonal therapy (Y)
CYP19A1AromataseLetrozole, Anastrozole, ExemestaneAromatase inhibitorY (off-label / trials)
FGFR2FGFR2 kinasePemigatinib, Erdafitinib, Futibatinib, LenvatinibFGFR inhibitor / Multi-kinaseY (Lenvatinib approved in combo)
AKT1AKT kinaseMK-2206, Ipatasertib, CapivasertibAKT inhibitorTrials (Phase 2-3)
PPARGPPAR-gammaPioglitazone, RosiglitazonePPAR-gamma agonistN (approved for diabetes)
EIF2AK4GCN2 kinasePreclinical inhibitorsKinase inhibitorN

Genes with Phase 2-3 Drugs (Not Yet Approved for EC)

GeneProteinDrug(s)PhaseMechanism
MAP2K5MEK5BIX-02189 (tool), SC-1-151PreclinicalMEK5 inhibitor
BPTFBPTF bromodomainAU-15330 (preclinical)PreclinicalBromodomain inhibitor
BDNFBDNFTrkB agonists (indirect)VariousNeurotrophin modulator
PSME3REGgammaNo specific drugsN/AProteasome activator

Section 11: Bioactivity & Enzyme Data

TOP Proteins by ChEMBL Bioactivity Data

GeneChEMBL TargetTypeBioactivity Level
ESR1CHEMBL206Single proteinVery high - thousands of compounds
PPARGCHEMBL235Single proteinVery high - thousands of compounds
FGFR2CHEMBL4142Single proteinHigh - hundreds of compounds
AKT1CHEMBL4282Single proteinHigh - hundreds of compounds
CYP19A1CHEMBL1978Single proteinHigh - aromatase inhibitors well-studied
EIF2AK4CHEMBL5358Single proteinModerate - emerging target
BPTFCHEMBL3085621Single proteinLow - few compounds
MAP2K5CHEMBL4948Single proteinModerate - kinase screening hits
TP53CHEMBL4096Single proteinHigh - p53 reactivators, MDM2 inhibitors
ERBB2CHEMBL1824Single proteinVery high - HER2 inhibitors
EGFRCHEMBL203Single proteinVery high - EGFR inhibitors
BRAFCHEMBL5145Single proteinVery high - RAF inhibitors
KRASCHEMBL2189121Single proteinHigh - RAS inhibitors (sotorasib, etc.)
PIK3CACHEMBL4005Single proteinVery high - PI3K inhibitors
ATMCHEMBL3797Single proteinModerate - ATM inhibitors in development

Enzyme GWAS Genes (BRENDA-relevant)

GeneEnzyme ClassKnown InhibitorsDruggability
CYP19A1Cytochrome P450 oxidoreductaseLetrozole, Anastrozole, ExemestaneHIGH - approved drugs
AKT1Serine/threonine kinaseMK-2206, Ipatasertib, CapivasertibHIGH - clinical candidates
EIF2AK4Serine/threonine kinase (GCN2)Tool compounds availableMODERATE - emerging
MAP2K5Dual-specificity kinase (MEK5)BIX-02189, SC-1-151MODERATE - tool stage
TRMT11tRNA methyltransferaseNone reportedLOW - no compounds
HECTD4HECT E3 ubiquitin ligaseNone specificLOW - difficult class

Undrugged Genes with Bioactivity Starting Points

GeneBioactivity Data?Starting Points
BCL11AChEMBL target existsVery few compounds, mostly screening hits
WT1ChEMBL target existsPeptide-based approaches
PSME3ChEMBL target existsLimited screening data
SH2B3No ChEMBL targetNo compounds — pure opportunity gap
SSPNNo ChEMBL targetNo compounds
SKAP1No ChEMBL targetNo compounds
HNF1BNo ChEMBL targetNo compounds — transcription factor

Section 12: Pharmacogenomics

All 14 key genes queried are PharmGKB VIP (Very Important Pharmacogenes):

GenePharmGKB IDVIP?CPIC Guideline?Key Drug Interactions
ESR1PA156YesNoTamoxifen response, aromatase inhibitor efficacy
PPARGPA281YesNoThiazolidinedione response, diabetes pharmacogenomics
AKT1PA24684YesNoPI3K/AKT inhibitor response prediction
FGFR2PA28128YesNoFGFR inhibitor sensitivity
CYP19A1PA27091YesNoAromatase inhibitor metabolism, estrogen levels
PTENPA33942YesNoPI3K inhibitor sensitivity prediction
PIK3CAPA33308YesNoAlpelisib response (PIK3CA mutations)
KRASPA30196YesNoEGFR inhibitor resistance, KRAS inhibitor eligibility
TP53PA36679YesNoChemotherapy response, p53 pathway drugs
ERBB2PA27844YesNoTrastuzumab eligibility (HER2 amplification)
EGFRPA7360YesNoEGFR inhibitor response
BRAFPA25408YesNoBRAF inhibitor eligibility (V600E mutation)
ATMPA61YesNoPARP inhibitor/platinum sensitivity
NF1PA31572YesNoMEK inhibitor sensitivity

Implications for endometrial cancer:

  • PIK3CA mutations (present in ~40% of EC) predict response to alpelisib
  • MSI-H/dMMR status (Lynch genes) predicts response to pembrolizumab/dostarlimab
  • ERBB2 amplification (~5% of EC) predicts response to trastuzumab
  • FGFR2 alterations predict response to FGFR inhibitors (pemigatinib)

Section 13: Clinical Trials

Total clinical trials for endometrial cancer: >1,000 (via MONDO:0011962 → clinical_trials)

TOP 30 Drugs in Endometrial Cancer Trials

DrugPhaseMechanismTarget GeneTargets GWAS Gene?
Pembrolizumab4 (Approved)PD-1 inhibitorPDCD1N
Dostarlimab4 (Approved)PD-1 inhibitorPDCD1N
Lenvatinib4 (Approved)Multi-kinase (VEGFR/FGFR)FGFR2, VEGFRY
Carboplatin4 (Approved)DNA crosslinkerDNAN
Paclitaxel4 (Approved)Tubulin stabilizerTubulinN
Doxorubicin4 (Approved)Topoisomerase IITOP2AN
Trastuzumab4 (Approved)Anti-HER2ERBB2Y (Mendelian)
Olaparib4 (Approved)PARP inhibitorPARP1N (indirect BRCA)
Selinexor4 (Approved)XPO1 inhibitorXPO1N
Pemigatinib4 (Approved)FGFR inhibitorFGFR2Y
Everolimus4 (Approved)mTOR inhibitorMTORN (AKT1 pathway)
Letrozole4 (Approved)Aromatase inhibitorCYP19A1Y
Tamoxifen4 (Approved)ER modulatorESR1Y
Medroxyprogesterone4 (Approved)Progesterone receptorPGRN
Bevacizumab4 (Approved)Anti-VEGFVEGFAN
Atezolizumab4 (Approved)PD-L1 inhibitorCD274N
Durvalumab4 (Approved)PD-L1 inhibitorCD274N
Nivolumab4 (Approved)PD-1 inhibitorPDCD1N
Tislelizumab4 (Approved)PD-1 inhibitorPDCD1N
Alpelisib4 (Approved)PI3K-alpha inhibitorPIK3CAY (Mendelian)
Palbociclib4 (Approved)CDK4/6 inhibitorCDK4/6N
Trastuzumab deruxtecan4 (Approved)Anti-HER2 ADCERBB2Y (Mendelian)
Buparlisib3Pan-PI3K inhibitorPIK3CAY (Mendelian)
Gedatolisib3PI3K/mTOR inhibitorPIK3CA/MTORY (Mendelian)
Catequentinib3Multi-kinaseVEGFR/cMETN
Navtemadlin3MDM2 inhibitorMDM2→TP53Y (Mendelian)
Dordaviprone3MDM2 degraderMDM2→TP53Y (Mendelian)
Ipatasertib3AKT inhibitorAKT1Y
Fruquintinib4 (Approved)VEGFR inhibitorVEGFRN
Sacituzumab govitecan4 (Approved)Anti-TROP2 ADCTACSTD2N

Clinical Trial Alignment with GWAS

  • Drugs targeting GWAS genes: ~10 of 30 (33%)
  • GWAS-aligned targets: FGFR2, ESR1, CYP19A1, AKT1, ERBB2, PIK3CA, TP53
  • Non-GWAS targets dominating trials: PD-1/PD-L1 checkpoint inhibitors, cytotoxic agents
  • Assessment: Moderate alignment — key hormone and kinase GWAS targets are well-represented, but immune checkpoint focus is orthogonal to GWAS signals

Section 14: Pathway Analysis

TOP 30 Reactome Pathways Enriched in GWAS Genes

PathwayReactome IDGWAS GenesDruggable Nodes
PI3K/AKT signalingR-HSA-1257604AKT1, FGFR2, ESR1AKT, PI3K, mTOR
Estrogen-dependent gene expressionR-HSA-9018519ESR1ESR1, coactivators
ESR-mediated signalingR-HSA-8939211ESR1ESR1
Extra-nuclear estrogen signalingR-HSA-9009391ESR1, AKT1ESR1, AKT, SRC
Estrogen biosynthesisR-HSA-193144CYP19A1CYP19A1 (aromatase)
Signaling by FGFR2 in diseaseR-HSA-5655253FGFR2FGFR2
FGFR2 amplification mutantsR-HSA-2023837FGFR2FGFR2
Activated point mutants FGFR2R-HSA-2033519FGFR2FGFR2
PI-3K cascade: FGFR2R-HSA-5654695FGFR2PI3K, AKT
RAF/MAP kinase cascadeR-HSA-5673001FGFR2RAF, MEK, ERK
Constitutive PI3K signaling in cancerR-HSA-2219530FGFR2, ESR1PI3K, AKT, mTOR
Constitutive AKT1 E17K signalingR-HSA-5674400AKT1AKT1
MTOR signallingR-HSA-165159AKT1mTOR
Nuclear receptor transcriptionR-HSA-383280PPARG, ESR1NHRs, coactivators
PPARA gene expressionR-HSA-1989781PPARGPPARs
White adipocyte differentiationR-HSA-381340PPARGPPARG
Regulation of PTEN stabilityR-HSA-8948751AKT1PTEN, AKT
TP53 metabolic genesR-HSA-5628897AKT1p53 pathway
TP53 degradationR-HSA-6804757AKT1MDM2
Interleukin-4/13 signalingR-HSA-6785807AKT1JAK/STAT
FLT3 signalingR-HSA-9607240AKT1FLT3
Downregulation of ERBB2:ERBB3R-HSA-1358803AKT1ERBB2/3
SHC-mediated cascade: FGFR2R-HSA-5654699FGFR2RAS/MAPK
FRS-mediated FGFR2 signalingR-HSA-5654700FGFR2FRS2/RAS
PLC-mediated cascade: FGFR2R-HSA-5654221FGFR2PLC, PKC
Co-inhibition by CTLA4R-HSA-389513AKT1CTLA4 (ipilimumab)
VEGFR2 vascular permeabilityR-HSA-5218920AKT1VEGFR2
Nuclear signaling by ERBB4R-HSA-1251985ESR1ERBB4
RUNX1 regulates ER-mediated transcriptionR-HSA-8931987ESR1RUNX1
SUMOylation of intracellular receptorsR-HSA-4090294PPARG, ESR1SUMO pathway

Pathway druggability: Even undrugged GWAS genes (HNF1B, SH2B3, BCL11A) can be targeted indirectly through pathway members. The PI3K/AKT/mTOR and estrogen signaling pathways are the most druggable convergence points for endometrial cancer GWAS genes.

Section 15: Drug Repurposing Opportunities

TOP 30 Repurposing Candidates

RankDrugGeneApproved ForMechanismBest GWAS p-valuePriority Score
1PioglitazonePPARGType 2 diabetesPPAR-gamma agonist5.0e-13★★★★★
2RosiglitazonePPARGType 2 diabetesPPAR-gamma agonist5.0e-13★★★★★
3CapivasertibAKT1Breast cancer (HR+)AKT inhibitor4.0e-08★★★★★
4FulvestrantESR1Breast cancerER degrader (SERD)4.0e-10★★★★★
5GiredestrantESR1Breast cancer (trials)Oral SERD4.0e-10★★★★☆
6PemigatinibFGFR2CholangiocarcinomaFGFR inhibitor1.0e-25★★★★★
7ErdafitinibFGFR2Bladder cancerFGFR inhibitor1.0e-25★★★★★
8FutibatinibFGFR2CholangiocarcinomaFGFR inhibitor1.0e-25★★★★★
9AlpelisibPIK3CA (pathway)Breast cancerPI3K-alpha inhibitorN/A (Mendelian)★★★★☆
10InavolisibPIK3CA (pathway)Breast cancerPI3K-alpha inhibitorN/A (Mendelian)★★★★☆
11EnzalutamideAR/ESR1 pathwayProstate cancerAR antagonist4.0e-10 (ESR1)★★★☆☆
12TalazoparibBRCA1/2 (Mendelian)Breast cancerPARP inhibitorN/A (Mendelian)★★★★☆
13NiraparibBRCA1/2 (Mendelian)Ovarian cancerPARP inhibitorN/A (Mendelian)★★★★☆
14DabrafenibBRAF (Mendelian)MelanomaBRAF inhibitorN/A (Mendelian)★★★☆☆
15VemurafenibBRAF (Mendelian)MelanomaBRAF inhibitorN/A (Mendelian)★★★☆☆
16SotorasibKRAS (Mendelian)Lung cancer (G12C)KRAS G12C inhibitorN/A (Mendelian)★★★☆☆
17AdagrasibKRAS (Mendelian)Lung cancer (G12C)KRAS G12C inhibitorN/A (Mendelian)★★★☆☆
18TrametinibNF1 pathwayMelanomaMEK inhibitor4.0e-08★★★★☆
19SelumetinibNF1 pathwayNeurofibromatosisMEK inhibitor4.0e-08★★★★☆
20NintedanibFGFR2 (multi-kinase)IPFFGFR/VEGFR/PDGFR1.0e-25★★★☆☆
21DovitinibFGFR2 (multi-kinase)TrialsFGFR/VEGFR/PDGFR1.0e-25★★★☆☆
22MetforminAMPK/mTOR pathwayType 2 diabetesAMPK activatorN/A (pathway)★★★☆☆
23CelecoxibCOX-2 pathwayOA/painCOX-2 inhibitorN/A (pathway)★★☆☆☆
24ImatinibMulti-kinaseCMLBCR-ABL/KITN/A★★☆☆☆
25DasatinibMulti-kinaseCMLSRC/ABLN/A★★☆☆☆
26CrizotinibALK/METNSCLCALK inhibitorN/A (Mendelian)★★☆☆☆
27MifepristonePGR/GREmergency contraceptionProgesterone antagonistN/A (pathway)★★★☆☆
28AspirinCOX pathwayCV preventionCOX inhibitorN/A★★☆☆☆
29AtorvastatinHMGCR/cholesterolHyperlipidemiaHMG-CoA reductaseN/A (metabolic)★★☆☆☆
30ThalidomideCereblon/angiogenesisMultiple myelomaImmunomodulatoryN/A★★☆☆☆

Section 16: Druggability Pyramid

LevelDescriptionGene Count%Key Genes
LevelVALIDATED: Approved drug FOR endometrial48%ESR1 (tamoxifen), CYP19A1 (letrozole), FGFR2 (lenvatinib/pemigatinib), ERBB2 (trastuzumab)
1cancer
LevelREPURPOSING: Approved drug for OTHER714%PPARG (pioglitazone), AKT1 (capivasertib), PIK3CA (alpelisib), EGFR (erlotinib), BRAF (dabrafenib), KRAS (sotorasib),
2diseaseATM (olaparib/indirect)
LevelEMERGING: Drug in clinical trials36%EIF2AK4 (GCN2 inhibitors), NF1 (MEK inhibitors), TP53 (MDM2 inhibitors)
3
LevelTOOL COMPOUNDS: ChEMBL compounds, no trials48%MAP2K5, BPTF, BCL11A, PSME3
4
LevelDRUGGABLE UNDRUGGED: Druggable family, NO36%HECTD4 (HECT ligase), TRMT11 (methyltransferase), DNAJC1 (chaperone)
5compounds
LevelHARD TARGETS: Difficult family or unknown2958%HNF1B, SH2B3, BCL11A, SSPN, SKAP1, WT1, ZBTB38, CCDC91, IQCK, NRXN3, ACAN, EMILIN2, TLE1, MLXIPL, GDF5, BDNF, TOX3,
6lncRNAs

Section 17: Undrugged Target Profiles

TOP 30 Undrugged Opportunities Ranked by Potential

RankGeneGWAS p-valueVariant TypeFamilyStructureExpressionDrugged Interactors?Druggability
1SH2B36.0e-14RegulatorySH2/PH adaptorAlphaFold (moderate)Ubiquitous, hematopoieticAKT1, JAK2, LNK pathwayMEDIUM
2HNF1B2.0e-23RegulatoryHomeodomain TFAlphaFold (low)Kidney, uterus, pancreasER pathway (indirect)LOW (TF)
3BCL11A7.0e-10RegulatoryZinc finger TFAlphaFold (poor)Hematopoietic, brainChromatin remodelersLOW (TF)
4SSPN2.0e-18RegulatoryTetraspanin-likeAlphaFold (good)Ubiquitous, muscle, uterusDystrophin complexLOW
5SKAP15.0e-11RegulatorySH3/PH adaptorAlphaFold (moderate)Immune cellsT-cell signalingLOW
6WT14.0e-08Regulatory (WT1-AS)Zinc finger TFAlphaFold (poor)Kidney, gonads, uterusTP53, MDM2 (drugged)LOW (TF)
7PSME32.0e-10RegulatoryProteasome activatorAlphaFold (excellent)UbiquitousProteasome (bortezomib)MEDIUM
8ZBTB383.0e-10RegulatoryZinc finger/BTB TFAlphaFold (very poor)UbiquitousUnknownLOW
9CCDC912.0e-10IntergenicCoiled-coilAlphaFold (good)UbiquitousUnknownLOW
10GDF51.0e-13RegulatoryTGF-beta ligandAlphaFold (moderate)Joints, cartilageBMP receptors (drugged)MEDIUM
11IQCK1.0e-09IntergenicIQ motifUnknownUnknownUnknownUNKNOWN
12HECTD43.0e-10IntergenicHECT E3 ligaseUnknownUbiquitousUbiquitin pathwayMEDIUM
13NRXN36.0e-10IntergenicNeurexin (adhesion)UnknownBrain, synapticNeuronal proteinsLOW
14BDNF2.0e-08RegulatoryNeurotrophinAlphaFold (moderate)BrainTrkB receptor (drugged)MEDIUM
15DNAJC14.0e-09IntergenicDnaJ cochaperoneUnknownUbiquitousHSP70 (drugged)MEDIUM
16ACAN1.0e-08RegulatoryProteoglycanAlphaFold (poor)CartilageECM proteinsLOW
17MLXIPL2.0e-11RegulatorybHLH-ZIP TFUnknownLiver, adiposeMetabolic enzymesLOW (TF)
18EMILIN22.0e-08RegulatoryElastin microfibrilAlphaFold (low)ECMECM proteinsLOW
19TRMT118.0e-11RegulatorytRNA methyltransferaseUnknownUbiquitousNone knownMEDIUM (enzyme)
20TLE19.0e-08RegulatoryWD-repeat corepressorUnknownUbiquitousNotch pathwayLOW

Detailed Profiles for Top 5

  1. SH2B3 (LNK) — Druggability: MEDIUM
  • GWAS p-value: 6.0e-14 (gluteofemoral adipose/EC pleiotropy), 3.0e-12 (direct EC)
  • Function: Negative regulator of cytokine signaling; controls JAK2, KIT, PDGFR pathways
  • Family: SH2/PH adaptor — historically difficult, but SH2 domain PPI inhibitors emerging
  • Structure: AlphaFold available (pLDDT 63), PH domain likely foldable
  • Expression: Ubiquitous, strong in hematopoietic cells
  • Drugged interactors: JAK2 (ruxolitinib), KIT (imatinib)
  • Why undrugged: Adaptor protein, no enzymatic activity; PPI interface targeting needed
  • Opportunity: Loss of SH2B3 activates JAK/STAT — JAK inhibitors may phenocopy
  1. HNF1B — Druggability: LOW
  • GWAS p-value: 2.0e-23 (most replicated EC locus across studies)
  • Function: Transcription factor controlling kidney, pancreas, uterine development
  • Family: POU homeodomain — no precedent for small molecule modulation
  • Structure: AlphaFold (pLDDT 62), DNA-binding domain likely structured
  • Expression: Tissue-restricted to kidney, uterus, pancreas — ideal for specificity
  • Drugged interactors: None direct; ER pathway cross-talk
  • Why undrugged: Transcription factor — historically undruggable
  • Opportunity: PROTAC/degrader approaches; epigenetic modulation of HNF1B expression
  1. SSPN — Druggability: LOW
  • GWAS p-value: 2.0e-18 (WHRadjBMI/EC pleiotropy)
  • Function: Sarcospan — tetraspanin-like membrane protein in dystrophin complex
  • Family: Tetraspanin-like — no drug precedent for this specific protein
  • Structure: AlphaFold (pLDDT 74), transmembrane topology
  • Expression: Ubiquitous, enriched in muscle and uterus
  • Why undrugged: Structural membrane protein; no enzymatic activity
  • Opportunity: Antibody-drug conjugate if surface-expressed on tumor cells
  1. PSME3 — Druggability: MEDIUM
  • GWAS p-value: 2.0e-10 (WHRadjBMI/EC pleiotropy)
  • Function: REGgamma — activates proteasome for ubiquitin-independent degradation
  • Family: Proteasome activator — related to proteasome inhibitor class
  • Structure: AlphaFold (excellent, pLDDT 88, 74% high confidence)
  • Expression: Ubiquitous
  • Why undrugged: Niche target; less attention than 20S/26S proteasome
  • Opportunity: Excellent structure + proteasome biology = screenable target
  1. GDF5 — Druggability: MEDIUM
  • GWAS p-value: 1.0e-13 (trunk fat/EC pleiotropy)
  • Function: BMP family ligand; bone/joint morphogenesis; links height/adiposity to cancer
  • Family: TGF-beta superfamily cytokine — ligand targeting is feasible
  • Structure: AlphaFold (pLDDT 71); mature domain likely structured
  • Expression: Low in endometrium — mediates risk via systemic metabolic effects
  • Why undrugged: Low disease-area attention for cancer
  • Opportunity: Anti-GDF5 antibodies; receptor-level targeting via BMP receptor inhibitors

Section 18: Summary

GWAS LANDSCAPE

  • Total associations: ~230 across ~35 studies
  • Unique protein-coding genes: ~50
  • Coding vs non-coding variants: 14% coding/splice vs 86% regulatory/intergenic

GENETIC EVIDENCE

  • Mendelian genes (ClinVar/HPO): 35 genes
  • GWAS genes with Mendelian overlap: 1 (FGFR2) + NF1 partial
  • Lynch syndrome genes (highest confidence): MLH1, MSH2, MSH6, PMS2 — no common GWAS signal

DRUGGABILITY

  • Overall rate with ANY drug target: 47% (14/30 protein-coding GWAS genes)
  • Approved drugs: 20% (6 genes) — ESR1, CYP19A1, FGFR2, ERBB2, AKT1 (partially), PPARG
  • In trials: 13% (4 genes)
  • Opportunity gap (no drugs): 50% (15 genes)

PYRAMID SUMMARY

LevelCount%
Level 1 — Validated48%
Level 2 — Repurposing714%
Level 3 — Emerging36%
Level 4 — Tool compounds48%
Level 5 — Druggable undrugged36%
Level 6 — Hard targets2958%

CLINICAL TRIAL ALIGNMENT

  • 33% of trial drugs target GWAS genes — moderate alignment
  • Strongest alignment: estrogen pathway (ESR1/CYP19A1), FGFR2, PI3K/AKT

TOP 10 REPURPOSING CANDIDATES

DrugGeneApproved Forp-valueScore
PioglitazonePPARGDiabetes5.0e-13★★★★★
PemigatinibFGFR2Cholangiocarcinoma1.0e-25★★★★★
ErdafitinibFGFR2Bladder cancer1.0e-25★★★★★
CapivasertibAKT1Breast cancer4.0e-08★★★★★
FulvestrantESR1Breast cancer4.0e-10★★★★★
AlpelisibPIK3CABreast cancerMendelian★★★★☆
TrametinibNF1 pathwayMelanoma4.0e-08★★★★☆
TalazoparibBRCA1/2Breast cancerMendelian★★★★☆
SelumetinibNF1 pathwayNF14.0e-08★★★★☆
MetforminAMPK/mTORDiabetesPathway★★★☆☆

TOP 10 UNDRUGGED OPPORTUNITIES

Genep-valueFamilyStructurePotential
SH2B36.0e-14SH2 adaptorAlphaFoldMEDIUM
HNF1B2.0e-23Homeodomain TFAlphaFoldLOW
PSME32.0e-10Proteasome activatorAlphaFold (excellent)MEDIUM
SSPN2.0e-18Tetraspanin-likeAlphaFoldLOW
GDF51.0e-13TGF-beta ligandAlphaFoldMEDIUM
HECTD43.0e-10HECT E3 ligaseUnknownMEDIUM
TRMT118.0e-11MethyltransferaseUnknownMEDIUM
BCL11A7.0e-10Zinc finger TFAlphaFold (poor)LOW
ZBTB383.0e-10Zinc finger/BTB TFAlphaFold (poor)LOW
CCDC912.0e-10Coiled-coilAlphaFoldLOW

TOP 10 INDIRECT OPPORTUNITIES

Undrugged GeneDrugged InteractorDrug
SH2B3 ↔ JAK2JAK2Ruxolitinib
HNF1B ↔ ESR1 pathwayESR1Tamoxifen/Fulvestrant
NF1 ↔ RAS/MAPKMEK1/2Trametinib
WT1 ↔ TP53/MDM2MDM2Navtemadlin
SKAP1 ↔ T-cell signalingPD-1Pembrolizumab
BCL11A ↔ Chromatin remodelingBET/BRDPreclinical BRD inhibitors
PSME3 ↔ 20S Proteasome20SBortezomib
BDNF ↔ TrkB receptorNTRKLarotrectinib
GDF5 ↔ BMP receptorsBMPRLDN-193189 (preclinical)
DNAJC1 ↔ HSP70HSP70VER-155008 (preclinical)

KEY INSIGHTS

  1. Estrogen axis is the genetically best-supported druggable pathway — ESR1, CYP19A1, and PPARG all have strong GWAS signals and approved drugs, but are underexploited compared to checkpoint inhibitors in current EC trials.

  2. HNF1B is the strongest single GWAS locus (p=2e-23) but completely undruggable — this is the largest opportunity gap in endometrial cancer genetics. Indirect targeting through downstream pathways or epigenetic approaches is needed.

  3. The obesity-EC link is genetically validated through PPARG (p=5e-13), SSPN (p=2e-18), GDF5 (p=1e-13), and ZBTB38 (p=3e-10) in pleiotropy studies. Pioglitazone is the top repurposing candidate.

  4. FGFR2 is the only gene with BOTH GWAS evidence AND Mendelian disease overlap — it has the strongest pan-cancer signal (p=1e-25) and multiple approved inhibitors (pemigatinib, lenvatinib). Genetic evidence supports expanding FGFR-targeted therapy in EC.

  5. PI3K/AKT/mTOR pathway convergence — AKT1 (direct GWAS), PIK3CA (Mendelian/somatic), PTEN (Mendelian/somatic), and mTOR are all druggable nodes on the same pathway, genetically validated by multiple evidence streams.

  6. Lynch syndrome genes dominate Mendelian EC risk but have no GWAS common variant signals — this is consistent with rare high-penetrance variants driving hereditary EC vs. common regulatory variants in sporadic EC.

  7. 58% of GWAS genes are “hard targets” (transcription factors, scaffolds, unknown function) — this is typical for GWAS and highlights the importance of indirect druggability through interacting pathway members.

  8. Comparison with other cancers: Endometrial cancer GWAS shows notable overlap with breast cancer (ESR1, FGFR2, TOX3, CASC15 locus) and colorectal cancer (SMAD7, CDKN2B-AS1) loci, supporting shared hormonal and cell-cycle mechanisms.

  9. Immune checkpoint inhibitors dominate EC trials but are NOT genetically supported by GWAS — the disconnect between trial activity (checkpoint focus) and genetic evidence (hormone/kinase focus) represents a gap where genetics-informed drug development could yield new approaches.

  10. Novel target highlight: PSME3 (REGgamma proteasome activator) has excellent AlphaFold structure (pLDDT 88), moderate GWAS signal (p=2e-10), and biological relevance through p53 degradation — a strong candidate for drug discovery efforts.

Analysis completed using biobtree MCP tools accessing GWAS Catalog, MONDO, EFO, MeSH, HPO, OMIM, Orphanet, HGNC, UniProt, InterPro, STRING, Reactome, PDB, AlphaFold, ChEMBL, PharmGKB, and Bgee databases. Date: 2026-04-11.