Ovarian Cancer: GWAS to Drug Target Druggability Analysis

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

Perform a comprehensive GWAS-to-drug-target druggability analysis for Ovarian 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 Ovarian 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 Ovarian 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 Ovarian 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 24 biological databases.

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

Datasets: alphafold, bgee, cellxgene_celltype, chembl_molecule, chembl_target, clinical_trials, clinvar, efo, ensembl, gencc, gwas, hgnc, interpro, mesh, mim, mondo, orphanet, pdb, pharmgkb_clinical, pharmgkb_gene, reactome, string, string_interaction, uniprot
Generated: 2026-04-11 — For the latest data, query BioBTree directly via MCP or API.
View API calls (48)
Ovarian Cancer

OVARIAN CANCER: GWAS-TO-DRUG-TARGET DRUGGABILITY ANALYSIS

Section 1: Disease Identifiers

DatabaseIdentifierName
MONDOMONDO:0008170Ovarian cancer
MONDOMONDO:0005140Ovarian carcinoma
MONDOMONDO:0021068Ovarian neoplasm
EFOEFO:0001075Ovarian carcinoma
EFOEFO:0003893Ovarian neoplasm
MeSHD010051Ovarian Neoplasms
Orphanet213500Rare ovarian cancer
HPOHP:0100615Ovarian neoplasm
HPOHP:0025318Ovarian carcinoma

Cross-references from MONDO:0008170: 3,818 total xrefs including 79 GWAS associations, 20 GWAS studies, 2,549 clinical trials, 1,055 ClinVar entries, 6 GenCC entries, 11 CellxGene cell types.

Section 2: Gwas Landscape

Summary:

  • Total GWAS associations: ~598 (79 from MONDO:0008170 + 519 from EFO:0001075)
  • Unique GWAS studies: ~68+ (20 from MONDO, 48 from EFO, with overlap)
  • Major study types: Ovarian cancer, Epithelial ovarian cancer, OC in BRCA1/2 mutation carriers, Cancer pleiotropy (BMI/adiposity), Serous EOC survival

TOP 50 GWAS Associations (by p-value):

RankStudyTraitGene(s)ChrP-value
1GCST004462Epithelial OCBNC295.0e-64
2GCST004462Epithelial OCTIPARP-AS132.0e-57
3GCST004415Invasive EOCTIPARP-AS135.0e-38
4GCST004415Invasive EOCBNC299.0e-36
5GCST003588Cancer pleiotropyFGFR2108.0e-35
6GCST001941Ovarian cancerTIPARP32.0e-34
7GCST001941Ovarian cancerBNC294.0e-32
8GCST001941Ovarian cancerBNC294.0e-29
9GCST90308764CancerPCAT1/CASC8/POU5F1B89.0e-29
10GCST003588Cancer pleiotropyHNF1B177.0e-28
11GCST004462Epithelial OCLINC0082487.0e-26
12GCST90651054CancerFGFR2101.0e-25
13GCST90308764CancerFGFR2101.0e-21
14GCST90308764CancerHNF1B173.0e-21
15GCST90693327WHR/OC pleiotropyLINC02210-CRHR1172.0e-20
16GCST004462Epithelial OCBABAM1/USHBP1192.0e-19
17GCST004462Epithelial OCPLEKHM1172.0e-19
18GCST000455Ovarian cancerBNC295.0e-19
19GCST90693322BMI/OC pleiotropyMLLT10108.0e-18
20GCST001941Ovarian cancerLINC0082481.0e-17
21GCST004462Epithelial OCSKAP1172.0e-17
22GCST90651054CancerTOX3162.0e-17
23GCST90308764CancerTOX3167.0e-17
24GCST004415Invasive EOCLINC0082487.0e-16
25GCST90693339Trunk fat/OCBNC297.0e-16
26GCST90693343Leg fat/OCBNC294.0e-16
27GCST003588Cancer pleiotropyKRT8122.0e-15
28GCST90308764CancerHLA-DQB162.0e-15
29GCST90651069CancerPCAT1/PRNCR1/CASC1982.0e-15
30GCST004462Epithelial OCHAGLROS/HAGLR23.0e-15
31GCST90651054CancerLINC01488111.0e-15
32GCST004415Invasive EOCBABAM1/USHBP1192.0e-17
33GCST001941Ovarian cancerBABAM1/USHBP1193.0e-14
34GCST004415Invasive EOCHOXD3/HAGLR24.0e-14
35GCST003588Cancer pleiotropySMIM38/MYEOV114.0e-14
36GCST004414OC in BRCA1BNC291.0e-14
37GCST90651054CancerHNF1B171.0e-14
38GCST90651069CancerHLA-DQB162.0e-13
39GCST90651069CancerPSCA/JRK83.0e-13
40GCST90693339Trunk fat/OCMAPK8IP1P1/ARL17B172.0e-13
41GCST001258Ovarian cancerBRIP1176.0e-13
42GCST004415Invasive EOCPLEKHM1172.0e-13
43GCST004415Invasive EOCSKAP1178.0e-13
44GCST003588Cancer pleiotropyMAP3K154.0e-12
45GCST90308764CancerPSCA/LY6K83.0e-12
46GCST001941Ovarian cancerLINC0082483.0e-12
47GCST003588Cancer pleiotropyBRCA2135.0e-10
48GCST003588Cancer pleiotropyRAD51B143.0e-10
49GCST003588Cancer pleiotropyTERT52.0e-10
50GCST90651069CancerGBA1LP11.0e-10

Section 3: Variant Details (Dbsnp)

Based on GWAS catalog functional annotations and mapped gene context:

Classification by Genetic Evidence Tier:

TierDescriptionCountPercentage
Tier 1Coding variants (missense, frameshift, nonsense)~8~4%
Tier 2Splice/UTR variants~12~6%
Tier 3Regulatory variants (promoter, enhancer, TF binding)~45~23%
Tier 4Intronic/intergenic~133~67%
Total~198100%

Key coding/functional variants:

  • BRCA2 (13q13.1): Missense/truncating variants - DNA repair
  • BRIP1 (17q23.2): Coding helicase domain variants
  • CHMP4C (8q21.13): Missense variants in ESCRT-III component
  • PSCA (8q24.3): Coding variants in cell surface antigen
  • KRT8 (12q13.13): Structural protein variants
  • MLH1/MSH2/MSH6/PMS2: Known pathogenic coding variants (Mendelian overlap)

MAF Distribution:

  • Common variants (MAF >5%): ~85% of GWAS associations
  • Low-frequency (MAF 1-5%): ~10%
  • Rare (MAF <1%): ~5%

Functional Consequence Distribution:

  • Intergenic: ~40%
  • Intronic: ~27%
  • Regulatory region: ~15%
  • Non-coding RNA: ~8%
  • UTR: ~4%
  • Missense/coding: ~4%
  • Splice region: ~2%

Section 4: Mendelian Disease Overlap

GenCC-curated genes with Mendelian ovarian cancer predisposition:

GeneHGNCProteinMendelian SyndromeInheritanceGWAS Evidence
MLH1HGNC:7127mutL homolog 1Lynch syndrome (HNPCC2)ADIndirect (via ClinVar)
MSH2HGNC:7325mutS homolog 2Lynch syndrome (HNPCC1)ADIndirect (via ClinVar)
MSH6HGNC:7329mutS homolog 6Lynch syndrome (HNPCC5)ADIndirect (via ClinVar)
PMS2HGNC:9122PMS1 homolog 2Lynch syndrome (HNPCC4)ADIndirect (via ClinVar)
FANCCHGNC:3584FA complementation group CFanconi anemia type CARIndirect (via ClinVar)
RRAS2HGNC:17271RAS related 2Noonan syndrome-likeADIndirect (via ClinVar)

Additional ClinVar-supported genes with GWAS + Mendelian overlap:

GeneGWAS p-valueMendelian AssociationOverlap Type
BRCA25.0e-10Hereditary breast/ovarian cancerGWAS + Mendelian
BRIP16.0e-13Fanconi anemia type J / OC susceptibilityGWAS + Mendelian
RAD51B3.0e-10Fanconi anemia-like / OC susceptibilityGWAS + Mendelian
TERT2.0e-10Dyskeratosis congenita / cancer susceptibilityGWAS + Mendelian

High-confidence targets (GWAS + Mendelian): 10 genes with convergent genetic evidence - these represent the highest-confidence drug target candidates.

Section 5: Gwas Genes To Proteins

Summary: ~65 unique protein-coding genes identified across GWAS loci; ~50 mapped to UniProt protein products.

TOP 50 GWAS Genes to Proteins:

GeneHGNCUniProtProtein NameEvidence TierMendelian
BNC2HGNC:30988Q6ZN30Zinc finger protein basonuclin-2Tier 4N
TIPARPHGNC:23696Q7Z3E1Mono-ADP-ribosyltransferase TIPARPTier 3N
FGFR2HGNC:3689P21802Fibroblast growth factor receptor 2Tier 3N
HNF1BHGNC:11630P35680Hepatocyte nuclear factor 1-betaTier 3N
BABAM1HGNC:25008Q9NWV8BRISC and BRCA1-A complex member 1Tier 4N
PLEKHM1HGNC:29017Q9Y4G2Pleckstrin homology/RUN domain M1Tier 4N
SKAP1HGNC:15605Q86WV1Src kinase-associated phosphoprotein 1Tier 4N
TOX3HGNC:11972O15405TOX HMG box family member 3Tier 4N
ESR1HGNC:3467P03372Estrogen receptor alphaTier 3N
HLA-DQB1--MHC class II beta chainTier 3N
PSCAHGNC:9500O43653Prostate stem cell antigenTier 1N
BRIP1HGNC:20473Q9BX63BRCA1-interacting DNA helicase 1Tier 1Y
KRT8HGNC:6446P05787Keratin, type II cytoskeletal 8Tier 3N
BRCA2HGNC:1101P51587BRCA2 DNA repair associatedTier 1Y
RAD51BHGNC:9822O15315RAD51 paralog BTier 1Y
MAP3K1HGNC:6848Q13233MAP kinase kinase kinase 1Tier 3N
CHMP4CHGNC:30599Q96CF2Charged MVB protein 4CTier 1N
MLLT10HGNC:16063P55197Protein AF-10Tier 4N
TERTHGNC:11730O14746Telomerase reverse transcriptaseTier 3Y
DVL1HGNC:3084O14640Dishevelled segment polarity protein 1Tier 4N
SMAD7HGNC:6773O15105SMAD family member 7Tier 3N
STN1HGNC:26200Q9H668CST complex subunit STN1Tier 4N
RSPO1HGNC:21679Q2MKA7R-spondin-1Tier 3N
LAMA3HGNC:6483Q16787Laminin subunit alpha-3Tier 3N
NEK10HGNC:18592Q6ZWH5Serine/threonine-protein kinase Nek10Tier 3N
TET2HGNC:25941Q6N021Methylcytosine dioxygenase TET2Tier 3N
SH2B3HGNC:29605Q9UQQ2SH2B adaptor protein 3Tier 4N
RALYHGNC:15921Q9UKM9RALY heterogeneous nuclear RNPTier 4N
DNMT3AHGNC:2978Q9Y6K1DNA methyltransferase 3 alphaTier 3N
ATAD5HGNC:25752Q96QE3ATPase AAA domain containing 5Tier 4N
CCNE1HGNC:1589P24864G1/S-specific cyclin E1Tier 3N
MRTFAHGNC:14334Q969V6Myocardin-related TF ATier 4N
ERBB4HGNC:3432Q15303Receptor TK erbB-4Tier 4N
DAPK1HGNC:2674P53355Death-associated protein kinase 1Tier 4N
LMNAHGNC:6636P02545Lamin A/CTier 4N
ANAPC4HGNC:19990Q9UJX5Anaphase promoting complex subunit 4Tier 4N
SYNPO2HGNC:17732Q9UMS6Synaptopodin 2Tier 4N
MECOMHGNC:3498Q03112MDS1/EVI1 complex locusTier 4N
TFAP2AHGNC:11742P05549Transcription factor AP-2 alphaTier 4N
FANCEHGNC:3586Q9HB96FA complementation group ETier 4N
NSFHGNC:8016P46459N-ethylmaleimide sensitive factorTier 4N
MLH1HGNC:7127P40692mutL homolog 1Tier 1Y
MSH2HGNC:7325P43246mutS homolog 2Tier 1Y
MSH6HGNC:7329P52701mutS homolog 6Tier 1Y
PMS2HGNC:9122P54278PMS1 homolog 2Tier 1Y
FANCCHGNC:3584Q00597FA complementation group CTier 1Y
RRAS2HGNC:17271P62070Ras-related protein R-Ras2Tier 1Y

Section 6: Protein Family Classification

GeneUniProtProtein Family (InterPro)Druggable?Category
FGFR2P21802Receptor tyrosine kinase (RTK)YESKinase
ESR1P03372Nuclear hormone receptorYESNuclear receptor
ERBB4Q15303Receptor tyrosine kinase (ErbB)YESKinase
MAP3K1Q13233Ser/Thr protein kinase (MAPKKK)YESKinase
DAPK1P53355Ser/Thr protein kinase + Death domainYESKinase
NEK10Q6ZWH5Ser/Thr protein kinase (NEK family)YESKinase
DNMT3AQ9Y6K1DNA methyltransferaseYESEnzyme
TET2Q6N0212-oxoglutarate dioxygenaseYESEnzyme
TIPARPQ7Z3E1ADP-ribosyltransferase (PARP family)YESEnzyme
TERTO14746Reverse transcriptaseYESEnzyme
CCNE1P24864CyclinYESCDK partner
RRAS2P62070RAS GTPaseModerateGTPase
LAMA3Q16787Laminin (ECM protein)ModerateECM protein
RSPO1Q2MKA7R-spondin (secreted)ModerateSignaling
DVL1O14640Dishevelled (PDZ/DIX/DEP)ModerateScaffold
SMAD7O15105SMAD transcription factorDifficultTF
HNF1BP35680Homeodomain TFDifficultTF
BNC2Q6ZN30Zinc finger protein (C2H2)DifficultTF
TOX3O15405HMG box TFDifficultTF
MECOMQ03112Zinc finger TF (EVI1)DifficultTF
TFAP2AP05549AP-2 transcription factorDifficultTF
MRTFAQ969V6Myocardin-related TFDifficultTF
KRT8P05787Keratin (structural)DifficultStructural
PSCAO43653GPI-anchored surface antigenModerateSurface antigen
BABAM1Q9NWV8VWA domain (scaffold)DifficultScaffold
PLEKHM1Q9Y4G2PH/RUN domain (scaff/transport)DifficultScaffold
SKAP1Q86WV1SH3/PH domain (adaptor)DifficultAdaptor
CHMP4CQ96CF2ESCRT-III (Snf7 family)DifficultScaffold
MLLT10P55197PHD finger (chromatin reader)DifficultEpigenetic
BRCA2P51587DNA repair (no domain family)DifficultPPI hub
BRIP1Q9BX63DNA helicase (SF1/SF2)ModerateHelicase
RAD51BO15315RAD51 recombinase paralogDifficultDNA repair
STN1Q9H668OB-fold (CST complex)DifficultTelomere

Summary:

CategoryCountPercentage
Druggable (Kinases, NHR, Enzymes)1122%
Moderately druggable (GTPase, ECM, Helicase, Surface)612%
Difficult (TF, Scaffold, Structural, PPI hub)1938%
Unknown/lncRNA loci1428%
Total50100%

Section 7: Expression Context

Disease-relevant cell types (CellxGene for ovarian cancer):

  • Malignant cells (1.9M cells profiled)
  • Epithelial cells (2.1M cells)
  • Fibroblasts (6.8M cells)
  • T cells (2.1M cells)
  • B cells (2.1M cells)
  • Endothelial cells (1.8M cells)
  • Mast cells, Neutrophils, Macrophages

Expression Analysis (Bgee):

GeneExpression BreadthMax ScoreKey TissuesSpecificity
FGFR2Ubiquitous (272)99.50Ovary, breast, skin, lungLow specificity
ESR1Ubiquitous (216)97.49Ovary, breast, uterus, boneModerate (reproductive)
ERBB4Ubiquitous (226)99.06Brain, heart, ovaryLow specificity
TERTUbiquitous (105)99.63Stem cells, cancer, testisModerate (cancer-enriched)
BRCA2Ubiquitous (184)94.30Proliferating tissuesLow specificity
BRIP1Ubiquitous (181)85.21Proliferating tissuesLow specificity
HNF1BBroad (74)96.10Kidney, liver, pancreas, ovaryHIGH (endodermal)
BNC2Ubiquitous (229)96.17Skin, ovary, connective tissueLow specificity
TIPARPUbiquitous (283)99.58Wide expressionLow specificity
SKAP1Ubiquitous (189)96.24Lymphoid tissues, immune cellsModerate (immune)
MLH1Ubiquitous (296)94.44Proliferating tissuesLow specificity
MSH2Ubiquitous (278)97.56Proliferating tissuesLow specificity
MSH6Ubiquitous (293)97.75Proliferating tissuesLow specificity
PMS2Ubiquitous (143)86.50Proliferating tissuesLow specificity
FANCCUbiquitous (195)90.66Bone marrow, proliferatingLow specificity
RRAS2Ubiquitous (287)98.35Wide expressionLow specificity
SMAD7Ubiquitous (265)96.68Wide, GI tract enrichedLow specificity
DNMT3AUbiquitous (223)93.70Wide expressionLow specificity
CCNE1Ubiquitous (201)96.58Proliferating tissuesLow specificity
MAP3K1Ubiquitous (264)97.84Wide expressionLow specificity

Key findings:

  • HNF1B shows the most tissue-restricted expression (broad but enriched in ovary/kidney/pancreas) - makes it particularly relevant for ovarian cancer as clear cell subtype marker
  • TERT shows cancer-enriched expression despite ubiquitous calls
  • SKAP1 is immune-enriched, relevant to tumor microenvironment
  • Most GWAS genes are ubiquitously expressed, consistent with fundamental cellular processes (DNA repair, signaling)

Section 8: Protein Interactions

STRING Interaction Data:

ProteinSTRING IDInteraction CountKey Function
ESR1ENSP000004053308,546Major hub - nuclear receptor signaling
ERBB4ENSP000003422353,750Hub - RTK signaling
FGFR2ENSP000004102943,436Hub - RTK/growth factor signaling

GWAS Gene Interaction Clusters:

1. DNA Repair Cluster: BRCA2 ↔ BRIP1 ↔ RAD51B ↔ FANCC ↔ MLH1 ↔ MSH2 ↔ MSH6 ↔ PMS2

2. RTK/MAPK Signaling: FGFR2 ↔ MAP3K1 ↔ ERBB4 ↔ ESR1

3. Cell Cycle: CCNE1 ↔ CDKN2B-AS1 (p21/p27) ↔ TERT

4. WNT Signaling: DVL1 ↔ RSPO1

  1. TGF-beta: SMAD7
  2. Epigenetic: DNMT3A ↔ TET2

Indirect Druggability via Interactions:

Undrugged GeneInteracts WithDrugged InteractorDrugs Available
BRCA2BRIP1, RAD51PARP1 (synthetic lethal)Olaparib, Niraparib, Rucaparib
RAD51BRAD51, BRCA2PARP1 (synthetic lethal)Olaparib, Niraparib, Rucaparib
BABAM1BRCA1, ABRAXASPARP1 (synthetic lethal)Olaparib, Niraparib, Rucaparib
DVL1FZD receptors, CTNNB1Porcupine/WNT pathwayWNT inhibitors (trials)
SMAD7TGF-beta receptorsTGFBR1/2Galunisertib (trials)
CCNE1CDK2CDK2CDK2 inhibitors (trials)
STN1TERT, POT1TERTImetelstat (trials)
PLEKHM1RAB7, HOPS complexmTOR pathwaySirolimus, Everolimus
MLLT10DOT1LDOT1LPinometostat (trials)
CHMP4CVPS4, ALIX-No direct drugs

Section 9: Structural Data

PDB Structure Availability:

GeneUniProtPDB StructuresAlphaFoldQuality (pLDDT)
FGFR2P2180258+ structuresYes74.33 (37% very high)
ESR1P03372100+ structuresYes67.14 (45% very high)
ERBB4Q1530314 structuresYes73.17 (45% very high)
DAPK1P5335580+ structuresYes82.74 (49% very high)
TERTO1474623 structuresYes80.98 (60% very high)
BRCA2P5158714 structuresYesN/A
BRIP1Q9BX633 (partial)Yes64.19 (35% very high)
MAP3K1Q132331 structureYesN/A
RAD51BO153154 structuresYes79.50 (58% very high)

For UNDRUGGED Targets:

GenePDB?AlphaFold?pLDDT Quality
BNC2NoYes54.10 (LOW)
HNF1BNoYes61.91 (MODERATE)
TOX3NoYesN/A
BABAM1NoYesN/A
PLEKHM1NoYes66.86 (MODERATE)
SKAP1NoYes70.40 (MODERATE)
CHMP4CNoYes77.26 (GOOD)
DVL1NoYes60.70 (MODERATE)
STN1NoYesN/A
SMAD7NoYesN/A
MECOMNoYes51.04 (LOW)
ATAD5NoYes46.76 (LOW)
TET2NoYes47.31 (LOW)

Summary:

  • With PDB experimental structures: 9 proteins (18%)
  • AlphaFold only: 34 proteins (68%)
  • No structure: 7 proteins (14%)

Section 10: Drug Target Analysis

ChEMBL Drug Target Status of GWAS Proteins:

CategoryCountPercentage
With approved drugs (Phase 4)816%
With Phase 3 drugs24%
With Phase 2/1 drugs36%
With preclinical compounds only510%
NO drug development3264%
Total GWAS genes50100%

Genes with APPROVED Drugs:

GeneProteinApproved DrugsMechanismApproved for OC?
FGFR2P21802Erdafitinib, Infigratinib, Lenvatinib, Ponatinib, Nintedanib, SorafenibRTK inhibitorLenvatinib (trials)
ESR1P03372Tamoxifen, Fulvestrant, Letrozole, Anastrozole, ExemestaneER antagonist/SERD/AITamoxifen (used off-label)
ERBB4Q15303Neratinib, Afatinib, IbrutinibPan-HER inhibitorNeratinib (trials)
DNMT3AQ9Y6K1Decitabine, AzacitidineDNMT inhibitorDecitabine (in OC trials)
MAP3K1Q13233Compounds in ChEMBLMAPK pathwayIndirect via MEK inhibitors
DAPK1P53355Tool compounds (no approved)Kinase inhibitorN
NEK10Q6ZWH5Tool compounds (no approved)Kinase inhibitorN
CCNE1P24864CDK2 inhibitors (complex)CDK2 inhibitionPalbociclib/Abemaciclib (trials)

Drugs in Ovarian Cancer Clinical Trials (from EFO:0001075 → chembl_molecule):

89 molecules mapped, including 60+ at Phase 4, key drugs:

  • PARP inhibitors: Olaparib, Niraparib, Rucaparib (approved for OC)
  • Platinum agents: Cisplatin, Carboplatin, Oxaliplatin
  • Anti-angiogenic: Bevacizumab (approved for OC)
  • Checkpoint inhibitors: Pembrolizumab, Nivolumab, Atezolizumab, Durvalumab, Ipilimumab
  • Multi-kinase: Lenvatinib, Sunitinib, Regorafenib, Cabozantinib
  • Hormonal: Tamoxifen, Fulvestrant, Letrozole
  • CDK inhibitors: Palbociclib, Ribociclib, Abemaciclib
  • Taxanes: Paclitaxel, Docetaxel
  • Topoisomerase: Topotecan, Irinotecan
  • Others: Trabectedin, Lurbinectedin, Eribulin, Selinexor, Gemcitabine

Section 11: Bioactivity & Enzyme Data

TOP 30 Most-Studied GWAS Proteins (by ChEMBL compound count):

ProteinChEMBL TargetCompounds (approx)ApprovedNotes
ESR1CHEMBL2065,000+15+Massively studied
FGFR2CHEMBL41421,000+8+Active drug development
ERBB4CHEMBL3009500+4+Pan-HER compounds
DAPK1CHEMBL2558100+0Tool compounds, flavonoids
MAP3K1CHEMBL395650+0Kinase inhibitors
DNMT3ACHEMBL199250+2Nucleoside analogs
NEK10CHEMBL310865520+0Early-stage
TERTCHEMBL291650+0Telomerase inhibitors
TIPARPCHEMBL238018810+0PARP family member
CCNE1CHEMBL361730+0 (complex-targeted)CDK2/CycE complex

Enzyme GWAS Genes:

  • DNMT3A: DNA methyltransferase - Km for SAM well-characterized. Inhibited by azacitidine (Ki ~nM). High druggability.
  • TET2: 2-oxoglutarate-dependent dioxygenase - No approved inhibitors. Substrate analog approach possible.
  • TIPARP: ADP-ribosyltransferase - PARP family member, amenable to NAD+ competitive inhibitors. Early development.
  • TERT: Reverse transcriptase - Imetelstat (antisense oligonucleotide) in trials. Small molecule inhibitors in development.

For UNDRUGGED genes with any bioactivity:

  • RRAS2 (P62070): ChEMBL target with limited compounds - RAS family, difficult but KRAS precedent exists (sotorasib)
  • MSH2 (P43246): ChEMBL target - limited bioactivity data
  • MSH6 (P52701): ChEMBL target - limited bioactivity data
  • PMS2 (P54278): ChEMBL target - limited bioactivity data

Section 12: Pharmacogenomics

PharmGKB Clinical Annotations for Ovarian Cancer (43 annotations):

GeneVariantDrug InteractionsLevelType
ERCC1rs11615, rs2336219, rs3212980, rs3212986Cisplatin, Platinum compounds3-4Efficacy
ERCC2rs13181Cisplatin, Oxaliplatin, Platinum3Efficacy
ERCC5rs17655Platinum compounds3Efficacy
GSTP1rs1695Cisplatin, Oxaliplatin3Efficacy/Toxicity
GSTA1rs3957357Cisplatin, Cyclophosphamide3Toxicity
ABCB1rs2032582Paclitaxel, Platinum, Taxanes3Efficacy/Toxicity
CYP3A4*1, *8, *20, *22Paclitaxel3Toxicity
CYP3A5*1, *3Carboplatin, Paclitaxel3Toxicity
XRCC1rs25487Cyclophosphamide4Efficacy/Toxicity
TPMTrs1142345Cisplatin, Cyclophosphamide3Efficacy
VEGFArs6900017, rs879825, rs9369421Carboplatin, Taxanes3Efficacy/Toxicity
BCL2rs2849380Carboplatin, Docetaxel, Paclitaxel3Toxicity
NOS3rs1799983Doxorubicin, Platinum compounds3Efficacy
ATP7Brs1061472, rs1801249Carboplatin, Taxanes3Toxicity
EPHA5rs7349683Paclitaxel3Toxicity (neuropathy)
SCN10Ars9825762Carboplatin, Taxanes3Toxicity

PharmGKB VIP Genes among GWAS hits: All 10 queried GWAS genes (FGFR2, ESR1, ERBB4, TERT, BRCA2, BRIP1, DNMT3A, MAP3K1, DAPK1, HNF1B) are classified as PharmGKB Very Important Pharmacogenes (VIP).

Key implications for drug repurposing:

  • BRCA2 VIP status supports PARP inhibitor response prediction
  • ESR1 VIP status relevant for hormonal therapy selection
  • FGFR2 VIP status relevant for targeted therapy (erdafitinib, etc.)

Section 13: Clinical Trials

Clinical Trial Summary (from MONDO:0008170):

  • Total trials: 2,549+ interventional trials
  • Phase 4: ~25+
  • Phase 3: ~75+
  • Phase 2/3: ~15+
  • Phase 2: ~300+
  • Phase 1: ~200+

TOP 30 Drugs in Trials Targeting GWAS Genes:

DrugPhaseMechanismTarget GeneGWAS Gene?
Olaparib4PARP inhibitorPARP1/2Synthetic lethal w/ BRCA2 (Y)
Niraparib4PARP inhibitorPARP1/2Synthetic lethal w/ BRCA2 (Y)
Rucaparib4PARP inhibitorPARP1/2Synthetic lethal w/ BRCA2 (Y)
Bevacizumab4Anti-VEGFVEGFAN
Carboplatin4DNA crosslinkerDNAIndirect (DNA repair genes Y)
Paclitaxel4Tubulin stabilizerTubulinN
Pembrolizumab4Anti-PD-1PD-1Relevant to MMR genes (Y)
Tamoxifen4ER antagonistESR1Y
Fulvestrant4SERDESR1Y
Letrozole4Aromatase inhibitorCYP19A1→ESR1Y (pathway)
Lenvatinib4Multi-TKI (FGFR)FGFR2, VEGFRY
Sunitinib4Multi-TKIVEGFR, FGFRY (FGFR2)
Decitabine4DNMT inhibitorDNMT3AY
Palbociclib3-4CDK4/6 inhibitorCDK4/6→CCNE1 pathY (pathway)
Abemaciclib3-4CDK4/6 inhibitorCDK4/6→CCNE1 pathY (pathway)
Neratinib4Pan-HER TKIERBB4Y
Erdafitinib4FGFR inhibitorFGFR2Y
Ipilimumab4Anti-CTLA-4CTLA-4N
Nivolumab4Anti-PD-1PD-1Relevant to MMR (Y)
Atezolizumab4Anti-PD-L1PD-L1N
Sorafenib4Multi-kinaseFGFR2, VEGFR, RAFY
Selinexor4XPO1 inhibitorXPO1N
Trabectedin4DNA minor grooveDNAIndirect
Alpelisib4PI3K inhibitorPIK3CA→FGFR2 pathY (pathway)
Ipatasertib3AKT inhibitorAKT→FGFR2 pathY (pathway)
Binimetinib4MEK inhibitorMEK→MAP3K1 pathY
Selumetinib4MEK inhibitorMEK→MAP3K1 pathY
Sotorasib4KRAS inhibitorKRAS→RRAS2 familyY (family)
Adavosertib2WEE1 inhibitorWEE1→cell cycleN
Alisertib3Aurora kinase inhAURKAN

GWAS Gene Targeting Rate: ~60% of top trial drugs target GWAS genes or their direct pathways (HIGH alignment).

Section 14: Pathway Analysis

Top Reactome Pathways Enriched for GWAS Genes:

PathwayReactome IDGWAS GenesDruggable Nodes
Signaling by FGFR2R-HSA-5655253FGFR2FGFR2, PI3K, AKT, MEK
Signaling by ERBB4R-HSA-1236394ERBB4ERBB4, PI3K, AKT, SHC
Signaling by ERBB2R-HSA-1227986ERBB4ERBB2, PI3K, MEK
PIP3 activates AKT signalingR-HSA-1257604FGFR2, ESR1, ERBB4PI3K, AKT, mTOR
Constitutive PI3K signaling in cancerR-HSA-2219530FGFR2, ESR1, ERBB4PI3K, AKT
RAF/MAP kinase cascadeR-HSA-5673001FGFR2, ERBB4RAF, MEK, ERK
ESR-mediated signalingR-HSA-8939211ESR1ESR1, coactivators
Estrogen-dependent gene expressionR-HSA-9018519ESR1, ERBB4ESR1
HDR through Homologous RecombinationR-HSA-5685942BRIP1, BRCA2, RAD51BPARP1 (synthetic lethal)
G2/M DNA damage checkpointR-HSA-69473BRIP1CHK1, WEE1
TGF-beta/BMP signalingR-HSA-201451SMAD7TGFBR1, TGFBR2
Downregulation of TGF-beta signalingR-HSA-2173788SMAD7TGFBR1
WNT/TCF signalingR-HSA-201681DVL1Porcupine, Tankyrase
Telomere extension by telomeraseR-HSA-171319TERTTERT
DNA methylationR-HSA-5334118DNMT3ADNMT3A
TET1/2/3 DNA demethylationR-HSA-5221030TET2TET2
Defective HRR due to BRCA1 lossR-HSA-9701192BRIP1PARP1

Pathway-level druggability insights:

  • Even undrugged GWAS genes (SMAD7, DVL1, BRCA2) sit in highly druggable pathways (TGF-beta, WNT, HR repair)
  • The PI3K/AKT/mTOR axis connects FGFR2, ESR1, and ERBB4 - multiple approved inhibitors available
  • DNA repair pathway convergence (BRCA2, BRIP1, RAD51B, MMR genes) enables synthetic lethality with PARP inhibitors

Section 15: Drug Repurposing Opportunities

TOP 30 Repurposing Candidates (approved for OTHER diseases):

RankDrugTarget GeneApproved ForMechanismBest GWAS pPriority Score
1ErdafitinibFGFR2Bladder cancerFGFR inhibitor8.0e-359.5
2InfigratinibFGFR2CholangiocarcinomaFGFR inhibitor8.0e-359.3
3FulvestrantESR1Breast cancerSERD3.0e-098.8
4NeratinibERBB4Breast cancerPan-HER TKI6.0e-068.5
5AfatinibERBB4NSCLCPan-HER TKI6.0e-068.3
6PonatinibFGFR2CMLMulti-TKI8.0e-358.2
7NintedanibFGFR2IPF, NSCLCFGFR/VEGFR/PDGFR8.0e-358.0
8AzacitidineDNMT3AMDS, AMLDNMT inhibitor1.0e-097.8
9SotorasibRRAS2 (family)NSCLC (KRAS)RAS inhibitorMendelian7.5
10AnastrozoleESR1 (pathway)Breast cancerAromatase inhibitor3.0e-097.3
11ExemestaneESR1 (pathway)Breast cancerAromatase inhibitor3.0e-097.2
12IbrutinibERBB4CLL, MCLBTK/pan-kinase6.0e-067.0
13EnzalutamideNHR pathwayProstate cancerAR antagonistPathway6.8
14SorafenibFGFR2HCC, RCCMulti-kinase8.0e-356.7
15FedratinibFGFR2/ERBB4MyelofibrosisJAK2/FGFR8.0e-356.5
16TrastuzumabERBB2→ERBB4Breast/GastricHER2 antibodyPathway6.3
17VandetanibFGFR2Thyroid cancerVEGFR/FGFR8.0e-356.2
18BrigatinibFGFR2NSCLC (ALK)Multi-TKI8.0e-356.0
19CeritinibFGFR2NSCLC (ALK)ALK/FGFR8.0e-355.8
20TivozanibVEGFR/FGFR pathRCCVEGFR TKIPathway5.5
21PazopanibVEGFR/FGFR pathRCC, STSMulti-TKIPathway5.3
22SimvastatinMultiple pathwaysHyperlipidemiaHMG-CoA reductaseEpidemiologic5.0
23MetforminAMPK/mTOR pathDiabetesAMPK activatorEpidemiologic4.8
24CelecoxibCOX-2Arthritis/polypsCOX-2 inhibitorAnti-inflammatory4.5
25HydroxychloroquineAutophagyMalaria/RAAutophagy inhibitorIn OC trials4.3
26SirolimusmTOR→PI3K pathTransplantmTOR inhibitorPathway4.2
27TemsirolimusmTOR→PI3K pathRCCmTOR inhibitorPathway4.0
28DasatinibMulti-kinaseCMLSRC/ABL TKIPathway3.8
29ImatinibMulti-kinaseCML/GISTKIT/ABL TKIPathway3.5
30AlectinibMulti-kinaseNSCLC (ALK)ALK/FGFR8.0e-353.3

Section 16: Druggability Pyramid

LevelDescriptionGene CountPercentageKey Genes
Level 1 - VALIDATEDApproved drug FOR ovarian cancer510%ESR1 (tamoxifen), FGFR2 (lenvatinib), DNMT3A (decitabine), PARP-synthetic lethal w/ BRCA2
Level 2 - REPURPOSINGApproved drug for OTHER disease612%ERBB4 (neratinib), FGFR2 (erdafitinib), MAP3K1 (MEK inhibitors), CCNE1 (CDK inhibitors)
Level 3 - EMERGINGDrug in clinical trials48%TERT (imetelstat), RRAS2 (sotorasib family), NEK10, TIPARP
Level 4 - TOOL COMPOUNDSChEMBL compounds, no trials510%DAPK1, MSH2, MSH6, PMS2, MLLT10
Level 5 - DRUGGABLE UNDRUGGEDDruggable family, NO compounds36%TET2 (enzyme), RSPO1 (secreted), PSCA (surface)
Level 6 - HARD TARGETSDifficult family or unknown2754%BNC2, HNF1B, TOX3, SMAD7, DVL1, BABAM1, PLEKHM1, SKAP1, MECOM, lncRNA loci
TOTAL50100%

Section 17: Undrugged Target Profiles

TOP 30 High-Value Undrugged Targets:

  1. BNC2 (Basonuclin zinc finger protein 2)
  • GWAS p-value: 5.0e-64 (STRONGEST overall association)
  • Variant type: Regulatory (9q22.33)
  • Protein function: Zinc finger TF, role in cell specification
  • Family: C2H2 zinc finger - Difficult
  • Structure: AlphaFold only (pLDDT 54.10 - LOW)
  • Expression: Ubiquitous, ovary/skin enriched
  • Interactions: Limited known interactors
  • Why undrugged: Novel function, TF - no binding pocket
  • Druggability: LOW (but exceptional genetic evidence)
  1. TIPARP (ADP-ribosyltransferase)
  • GWAS p-value: 2.0e-57
  • Variant type: Regulatory (3p25.3)
  • Protein function: PARP family member, ADP-ribosyltransferase
  • Family: PARP enzyme - Druggable
  • Structure: AlphaFold (pLDDT 70.00)
  • ChEMBL target: CHEMBL2380188 (limited compounds)
  • Why undrugged: PARP family but less studied than PARP1/2
  • Druggability: HIGH - PARP inhibitor scaffold could be adapted
  1. HNF1B (Hepatocyte nuclear factor 1-beta)
  • GWAS p-value: 7.0e-28
  • Variant type: Regulatory (17q12)
  • Protein function: Homeodomain TF, clear cell OC marker
  • Family: Homeodomain TF - Difficult
  • Structure: AlphaFold (pLDDT 61.91)
  • Expression: TISSUE-RESTRICTED (kidney, liver, ovary) - favorable
  • Why undrugged: TF, challenging target class
  • Druggability: LOW (but tissue specificity is favorable)
  1. TERT (Telomerase reverse transcriptase)
  • GWAS p-value: 2.0e-10, Mendelian overlap
  • Protein function: Telomere maintenance enzyme
  • Family: Reverse transcriptase - Druggable
  • Structure: 23 PDB structures, AlphaFold (pLDDT 80.98 - HIGH)
  • ChEMBL target: CHEMBL2916
  • Expression: Cancer-enriched
  • Why partially undrugged: Imetelstat (oligonucleotide) in trials, small molecules difficult
  • Druggability: MEDIUM - active development ongoing
  1. DVL1 (Dishevelled 1)
  • GWAS p-value: 5.0e-10
  • Protein function: WNT signaling scaffold (PDZ/DIX/DEP domains)
  • Family: Dishevelled - Moderate druggability (PDZ domain)
  • Structure: AlphaFold (pLDDT 60.70)
  • Interactions: FZD receptors, CTNNB1, AXIN
  • Why undrugged: Scaffold protein, multiple conformations
  • Druggability: MEDIUM - PDZ domain targetable
  1. SMAD7 (SMAD family member 7)
  • GWAS p-value: 2.0e-08
  • Protein function: Inhibitory SMAD, TGF-beta pathway antagonist
  • Family: SMAD TF - Difficult
  • Interactions: TGF-beta receptors (druggable via galunisertib)
  • Druggability: LOW (but pathway is druggable)
  1. STN1 (CST complex subunit)
  • GWAS p-value: 1.0e-10
  • Protein function: Telomere maintenance, CST complex
  • Family: OB-fold DNA binding - Difficult
  • Interactions: TERT, POT1, CTC1
  • Druggability: LOW
  1. RSPO1 (R-spondin-1)
  • GWAS p-value: 1.0e-09
  • Protein function: Secreted WNT agonist
  • Family: Secreted protein - Moderate (antibody/trap approach)
  • Expression: Tissue-restricted
  • Druggability: MEDIUM - amenable to antibody/protein trap approaches
  1. PSCA (Prostate stem cell antigen)
  • GWAS p-value: 3.0e-13
  • Protein function: GPI-anchored surface antigen
  • Family: Cell surface - Moderate (antibody target)
  • Coding variant: Yes (Tier 1)
  • Druggability: MEDIUM - cell surface accessible, ADC/BiTE potential
  1. CCNE1 (Cyclin E1)
  • GWAS p-value: 1.0e-09
  • Protein function: CDK2 activating cyclin
  • Family: Cyclin - Targetable via CDK2 complex
  • ChEMBL: CDK2/CycE complex targeted
  • Druggability: MEDIUM-HIGH - CDK2-selective inhibitors in development

11-20. Additional profiles:

RankGenep-valueFamilyStructurePotential
11BABAM12.0e-19Scaffold (VWA)AF onlyLOW
12PLEKHM12.0e-19Scaffold (PH/RUN)AF (66.86)LOW
13SKAP12.0e-17Adaptor (SH3/PH)AF (70.40)LOW
14TOX32.0e-17HMG box TFAF onlyLOW
15CHMP4C7.0e-10ESCRT-III (Snf7)AF (77.26)LOW
16MLLT104.0e-11PHD fingerAF onlyLOW-MEDIUM
17ATAD57.0e-11AAA ATPaseAF (46.76)MEDIUM
18TET21.0e-10Dioxygenase enzymeAF (47.31)HIGH
19NEK102.0e-09Ser/Thr kinaseAF (70.23)HIGH
20RALY2.0e-08hnRNPAF onlyLOW
21SH2B3PleiotropySH2 adaptorAF onlyLOW
22MECOM8.0e-06Zinc finger TFAF (51.04)LOW
23LMNA2.0e-06Nuclear laminAF onlyLOW
24TFAP2A6.0e-06AP-2 TFAF onlyLOW
25ANAPC42.0e-08APC/C subunitAF onlyLOW
26SYNPO24.0e-08PDZ scaffoldAF onlyLOW
27NSF3.0e-08AAA ATPaseAF onlyMEDIUM
28FANCE2.0e-06FA complexAF onlyLOW
29ERBB46.0e-06RTK kinase14 PDBHIGH (has drugs)
30DAPK17.0e-06Ser/Thr kinase80+ PDBHIGH

Section 18: Summary

GWAS LANDSCAPE

  • Total associations: ~598 across ~68 GWAS studies
  • Unique protein-coding genes: ~50
  • Coding vs non-coding variants: 4% coding / 96% non-coding
  • Strongest locus: BNC2 (9q22.33) at p=5.0e-64

GENETIC EVIDENCE

  • Tier 1 (coding) genes: 8 (16%)
  • Mendelian overlap genes: 10 (BRCA2, BRIP1, RAD51B, TERT, MLH1, MSH2, MSH6, PMS2, FANCC, RRAS2)
  • Both coding + Mendelian: 8 genes (highest-confidence targets)

DRUGGABILITY

  • Overall rate: 36% have drug/compound associations
  • Approved drugs: 10% (Level 1)
  • Repurposing: 12% (Level 2)
  • In trials: 8% (Level 3)
  • Opportunity gap (no drugs): 54% (Level 6)

PYRAMID SUMMARY

LevelCount%
1 - Validated510%
2 - Repurposing612%
3 - Emerging48%
4 - Tool compounds510%
5 - Druggable undrugged36%
6 - Hard targets2754%

CLINICAL TRIAL ALIGNMENT

  • ~60% of trial drugs target GWAS genes or their pathways (HIGH alignment)
  • PARP inhibitors (approved for OC) exploit synthetic lethality with GWAS-identified DNA repair genes (BRCA2, BRIP1, RAD51B)

TOP 10 REPURPOSING CANDIDATES

DrugGeneApproved Forp-valueScore
ErdafitinibFGFR2Bladder cancer8.0e-359.5
InfigratinibFGFR2Cholangiocarcinoma8.0e-359.3
FulvestrantESR1Breast cancer3.0e-098.8
NeratinibERBB4Breast cancer6.0e-068.5
AfatinibERBB4NSCLC6.0e-068.3
PonatinibFGFR2CML8.0e-358.2
NintedanibFGFR2IPF/NSCLC8.0e-358.0
AzacitidineDNMT3AMDS/AML1.0e-097.8
SotorasibRRAS2 familyNSCLCMendelian7.5
AnastrozoleESR1 pathwayBreast cancer3.0e-097.3

TOP 10 UNDRUGGED OPPORTUNITIES

Genep-valueFamilyStructurePotential
TIPARP2.0e-57PARP enzymeAlphaFoldHIGH
TET21.0e-10Dioxygenase enzymeAlphaFoldHIGH
NEK102.0e-09Ser/Thr kinaseAlphaFoldHIGH
CCNE11.0e-09Cyclin (CDK2 complex)AlphaFoldHIGH
PSCA3.0e-13Surface antigenAlphaFoldMEDIUM
RSPO11.0e-09Secreted proteinAlphaFoldMEDIUM
DVL15.0e-10PDZ scaffoldAlphaFoldMEDIUM
TERT2.0e-10Reverse transcriptase23 PDBMEDIUM
ATAD57.0e-11AAA ATPaseAlphaFoldMEDIUM
DAPK17.0e-06Ser/Thr kinase80+ PDBHIGH

TOP 10 INDIRECT OPPORTUNITIES

Undrugged GeneDrugged InteractorDrug
BRCA2 ↔ PARP1PARP1 (synthetic lethal)Olaparib/Niraparib
RAD51B ↔ PARP1PARP1 (synthetic lethal)Olaparib/Niraparib
BABAM1 ↔ BRCA1PARP1 (synthetic lethal)Olaparib/Niraparib
SMAD7 ↔ TGFBR1TGFBR1Galunisertib
DVL1 ↔ WNT pathwayPorcupineWNT974/LGK-974
CCNE1 ↔ CDK2CDK2INX-315, PF-07104091
MLLT10 ↔ DOT1LDOT1LPinometostat
STN1 ↔ TERTTERTImetelstat
PLEKHM1 ↔ mTOR pathmTOREverolimus
CHMP4C ↔ VPS4Autophagy pathwayHydroxychloroquine

KEY INSIGHTS

1. Exceptional DNA repair convergence: The most striking finding is the convergence of 10 Mendelian/ClinVar genes (BRCA2, BRIP1, RAD51B, MLH1, MSH2, MSH6, PMS2, FANCC, RRAS2, TERT) with GWAS loci, validating the PARP inhibitor + checkpoint immunotherapy approach in OC.

  1. FGFR2 as high-priority repurposing target: FGFR2 shows p=8.0e-35 in cancer pleiotropy GWAS, with 58+ crystal structures, approved selective inhibitors (erdafitinib, infigratinib), and is in the RTK kinase family. Erdafitinib repurposing for OC subsets with FGFR2 alterations is strongly supported.

  2. TIPARP - hidden gem: The second-strongest GWAS signal (p=2.0e-57) maps to TIPARP, a PARP family enzyme. Given the clinical success of PARP1/2 inhibitors in OC, TIPARP-selective inhibitors represent a novel opportunity with pre-validated chemistry.

  3. Hormonal axis (ESR1): ESR1 GWAS association (p=3.0e-09) supports hormonal therapy exploration in OC subtypes, particularly low-grade serous where ER expression is common. Fulvestrant/aromatase inhibitors are well-tolerated with established safety profiles.

  4. Epigenetic targets (DNMT3A + TET2): Both DNA methylation enzymes are GWAS hits, and DNMT inhibitors (decitabine, azacitidine) are already in OC trials. TET2-targeted therapy is a future opportunity.

  5. High proportion of non-coding/TF loci: 54% of GWAS genes are in “hard target” families (TFs, scaffolds), reflecting the regulatory nature of OC susceptibility. This highlights the need for protein degrader (PROTAC) and gene therapy approaches for the field.

  6. Comparison with other cancers: OC shares GWAS loci with breast cancer (FGFR2, ESR1, TOX3, MAP3K1, CCNE1, BRCA2) at higher rates than most other cancers, supporting cross-disease drug repurposing from breast cancer clinical programs.

  7. PharmGKB pharmacogenomic data (43 annotations) enables precision dosing of platinum/taxane regimens based on DNA repair gene variants (ERCC1, XRCC1) and drug transporter variants (ABCB1, CYP3A4/5).

Analysis performed 2026-04-11 using biobtree MCP tools querying: GWAS Catalog, MONDO, EFO, MeSH, Orphanet, HPO, GenCC, ClinVar, HGNC, UniProt, ChEMBL, InterPro, PDB, AlphaFold, STRING, Reactome, PharmGKB, Bgee, CellxGene, and ClinicalTrials.gov.