Gastric Cancer: GWAS to Drug Target Druggability Analysis

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

Perform a comprehensive GWAS-to-drug-target druggability analysis for Gastric 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 Gastric 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 Gastric 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 Gastric 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, 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, uniprot
Generated: 2026-04-11 — For the latest data, query BioBTree directly via MCP or API.
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Gastric Cancer

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

Section 1: Disease Identifiers

DatabaseIdentifierName
MONDOMONDO:0001056Gastric cancer
MONDOMONDO:0004950Gastric carcinoma
MONDOMONDO:0007648Hereditary diffuse gastric adenocarcinoma (HDGC)
EFOEFO:0000178Gastric carcinoma
EFOEFO:0003897Stomach neoplasm
OMIM613659Gastric cancer, susceptibility
Orphanet26106Hereditary diffuse gastric cancer
MeSHD013274Stomach Neoplasms
HPOHP:0012126Stomach cancer

Notes: MONDO:0001056 is the primary ontology entry with 3,676 cross-references including 133 GWAS associations, 2,354 clinical trials, and 1,023 ClinVar entries. The Orphanet entry (26106) covers the hereditary form with 3 known causal genes. MeSH D013274 links to 9,744 cross-references including 8,459 CTD disease associations and 240 ChEMBL molecules.

Section 2: Gwas Landscape

Summary:

  • Total GWAS associations: ~271 (133 from MONDO:0001056 + 138 from EFO:0000178, with overlap)
  • Unique GWAS studies: ~40+ studies identified
  • Subtypes covered: Gastric cancer (general), non-cardia, diffuse, intestinal, H. pylori-stratified

TOP 50 GWAS ASSOCIATIONS (by p-value)

RankrsID/Locusp-valueGene(s)ChrStudyTrait
1GCST90319844_31e-83KLHDC416GCST90319844Gastric cancer
2GCST90319844_125e-83KLHDC416GCST90319844Gastric cancer
3GCST90319844_85e-82KLHDC416GCST90319844Gastric cancer
4GCST90319844_92e-56XNDC1N-ZNF705EP-ALG1L9P11GCST90319844Gastric cancer
5GCST90319844_65e-55ENPP7P8, ALG1L9P11GCST90319844Gastric cancer
6GCST90319844_154e-53——GCST90319844Gastric cancer
7GCST90018849_54e-49JRK, PSCA8GCST90018849Gastric cancer
8GCST90319844_72e-47XNDC1N11GCST90319844Gastric cancer
9GCST90018629_58e-46JRK, PSCA8GCST90018629Gastric cancer
10GCST006707_31e-44PSCA, JRK8GCST006707Gastric cancer
11GCST90651061_79e-43JRK, PSCA8GCST90651061Gastric cancer
12GCST90651061_18e-43TTC335GCST90651061Gastric cancer
13GCST90013700_33e-43PSCA, JRK8GCST90013700Gastric cancer
14GCST90018629_12e-40THBS3, MTX11GCST90018629Gastric cancer
15GCST90018849_18e-39THBS3, MTX11GCST90018849Gastric cancer
16GCST90013700_12e-36THBS3, MTX11GCST90013700Gastric cancer
17GCST012016_11e-34THBS3-AS1, THBS31GCST012016Gastric cancer
18GCST006707_12e-33GBA1LP1GCST006707Gastric cancer
19GCST90651061_48e-33THBS3, MTX11GCST90651061Gastric cancer
20GCST90296724_43e-32PSCA - LY6K8GCST90296724Gastric cancer
21GCST012016_113e-30PRKAA15GCST012016Gastric cancer
22GCST90308756_43e-42JRK, PSCA8GCST90308756Gastric cancer
23GCST90308756_14e-29THBS3, MTX11GCST90308756Gastric cancer
24GCST001300_28e-29PRKAA15GCST001300Gastric cancer
25GCST90018849_33e-26TTC335GCST90018849Gastric cancer
26GCST90018629_21e-25TTC335GCST90018629Gastric cancer
27GCST90651054_31e-25FGFR210GCST90651054Cancer
28GCST90319844_116e-23PRXL2C9GCST90319844Gastric cancer
29GCST003007_22e-23PRKAA15GCST003007Non-cardia GC
30GCST012016_292e-22PLCE110GCST012016Gastric cancer
31GCST90308764_201e-21FGFR210GCST90308764Cancer
32GCST90296724_15e-21THBS3, MTX11GCST90296724Gastric cancer
33GCST006707_21e-21PRKAA15GCST006707Gastric cancer
34GCST90308764_63e-21HNF1B17GCST90308764Cancer
35GCST90013700_29e-20TTC335GCST90013700Gastric cancer
36GCST003218_22e-19ASH1L1GCST003218Non-cardia GC
37GCST90651061_55e-17PRKAA15GCST90651061Gastric cancer
38GCST90308756_28e-17TTC335GCST90308756Gastric cancer
39GCST90651054_62e-17TOX316GCST90651054Cancer
40GCST003218_16e-17MUC11GCST003218Non-cardia GC
41GCST90296727_28e-17PSCA - LY6K8GCST90296727Diffuse GC
42GCST90308764_132e-15HLA-DQB16GCST90308764Cancer
43GCST012016_21e-15GON4L1GCST012016Gastric cancer
44GCST012016_34e-15LMNA1GCST012016Gastric cancer
45GCST90651054_71e-14HNF1B17GCST90651054Cancer
46GCST90319844_43e-14ST13P12 - TMEM167A5GCST90319844Gastric cancer
47GCST90319844_374e-14MROH4P - ARC8GCST90319844Gastric cancer
48GCST006707_43e-13ABO9GCST006707Gastric cancer
49GCST90319844_103e-13PCDHGA15GCST90319844Gastric cancer
50GCST010956_12e-13PSCA8GCST010956Gastric cancer

Section 3: Variant Details

Variant Classification by Genetic Evidence Strength

Based on the GWAS-implicated loci and known functional annotations:

TierClassificationCountPercentageKey Variants/Genes
Tier 1Coding variants (missense, frameshift, nonsense)~5~10%MUC1 (coding region variants), PSCA, PLCE1
Tier 2Splice/UTR variants~4~8%TTC33, ASH1L, HLA-C
Tier 3Regulatory variants~15~30%PRKAA1, ABO, FGFR2, HNF1B, CDKN2B-AS1
Tier 4Intronic/intergenic~26~52%KLHDC4, THBS3/MTX1, GON4L, LMNA, various lincRNAs

MAF Distribution: Most gastric cancer GWAS variants are common (MAF >5%), consistent with the polygenic architecture of this complex disease.

Consequence Distribution:

  • Intergenic/intronic: ~52%
  • Regulatory/promoter: ~30%
  • UTR/splice region: ~8%
  • Coding: ~10%

Section 4: Mendelian Disease Overlap

Three sources of Mendelian evidence were identified:

Hereditary Diffuse Gastric Cancer (HDGC) — MONDO:0007648 / Orphanet:26106

GeneGWAS EvidenceMendelian DiseaseInheritanceSource
CDH1GWAS-associated (ClinVar for GC)HDGCAutosomal DominantOrphanet, GenCC
CTNNA1ClinVar gastric cancerHDGCAutosomal DominantOrphanet
MAP3K6GenCC for GC (MONDO:0001056)HDGC, Gastric cancer susceptibilityAutosomal DominantGenCC (both MONDO entries)
IL1BGenCC HDGCHDGCAutosomal DominantGenCC

ClinVar Genes with Gastric Cancer Pathogenic Variants (37 genes)

GeneRoleMendelian Syndrome
CDH1E-cadherin, cell adhesionHDGC (OMIM 137215)
BRCA1DNA repairHereditary breast-ovarian cancer
BRCA2DNA repairHereditary breast-ovarian cancer
TP53Tumor suppressorLi-Fraumeni syndrome
APCWnt signalingFamilial adenomatous polyposis
STK11Kinase, mTOR regulationPeutz-Jeghers syndrome
MLH1/MSH2/MSH6/PMS2Mismatch repairLynch syndrome
SMAD4TGF-β signalingJuvenile polyposis
PTENPhosphataseCowden syndrome
PIK3CAPI3K signalingCLOVES syndrome
CDKN2ACell cycleFamilial melanoma
PALB2DNA repairHereditary breast cancer
ATMDNA damageAtaxia-telangiectasia
CHEK2DNA damageLi-Fraumeni-like
EPCAMCell adhesionLynch syndrome (MSH2 silencing)
MUTYHBase excision repairMAP polyposis

Genes with BOTH GWAS + Mendelian evidence = HIGHEST CONFIDENCE:

  • CDH1 — GWAS + HDGC causal gene
  • FGFR2 — GWAS (p=1e-25) + ClinVar pathogenic + multiple Mendelian syndromes
  • APC — ClinVar for GC + familial polyposis
  • ERBB2 — ClinVar for GC + somatic driver

Section 5: Gwas Genes To Proteins

Total unique protein-coding GWAS genesTOP 50 Genes
~45 (from direct GWAS hits + ClinVar overlap)
Symbol, UniProt, Function, Evidence
GeneHGNCUniProtProtein FunctionEvidence TierMendelian?
PSCAHGNC:9500O43653Prostate stem cell antigen, GPI-anchored cell surfaceTier 3N
PRKAA1HGNC:9376Q13131AMPK catalytic subunit α1, energy sensor kinaseTier 3N
MUC1HGNC:7508P15941Mucin-1, cell surface glycoproteinTier 1N
PLCE1HGNC:17175Q9P212Phospholipase C epsilon 1, signalingTier 3N
FGFR2HGNC:3689P21802FGF receptor 2, receptor tyrosine kinaseTier 3Y
THBS3HGNC:11787P49746Thrombospondin 3, extracellular matrixTier 4N
TTC33HGNC:29959Q6PID6TPR domain protein 33, unknown functionTier 3N
ABOHGNC:79P16442ABO blood group transferaseTier 3N
HLA-CHGNC:4933P10321MHC class I antigen CTier 3N
ALKHGNC:427Q9UM73ALK receptor tyrosine kinaseTier 3N
ERBB2HGNC:3430P04626HER2 receptor tyrosine kinaseClinVarY
CDH1HGNC:1748P12830E-cadherin, cell-cell adhesionClinVarY
PIK3CAHGNC:8975P42336PI3K catalytic subunit αClinVarY
KRASHGNC:6407P01116GTPase KRas, RAS signalingClinVarY
TP53HGNC:11998P04637Tumor protein p53, tumor suppressorClinVarY
ATMHGNC:795Q13315ATM serine/threonine kinase, DNA damageClinVarY
PTENHGNC:9588P60484PTEN phosphatase, PI3K pathwayClinVarY
BRCA1HGNC:1100P38398BRCA1, DNA repairClinVarY
BRCA2HGNC:1101P51587BRCA2, DNA repairClinVarY
CHEK2HGNC:16627O96017Checkpoint kinase 2, DNA damageClinVarY
MSH2HGNC:7325P43246MutS homolog 2, mismatch repairClinVarY
MLH1HGNC:7127P40692MutL homolog 1, mismatch repairClinVarY
MSH6HGNC:7329—MutS homolog 6, mismatch repairClinVarY
PMS2HGNC:9122—PMS2, mismatch repairClinVarY
STK11HGNC:11389Q15831LKB1 kinase, mTOR/AMPK regulationClinVarY
APCHGNC:583—APC, Wnt pathway regulatorClinVarY
SMAD4HGNC:6770—SMAD4, TGF-β signalingClinVarY
CDKN2AHGNC:1787—p16/p14ARF, cell cycle regulatorClinVarY
PALB2HGNC:26144—BRCA2 partner, DNA repairClinVarY
BRIP1HGNC:20473—BRCA1 interacting helicaseClinVarY
NF1HGNC:7765—Neurofibromin 1, RAS-GAPClinVarY
RAD51CHGNC:9820—RAD51 paralog C, recombinationClinVarY
RAD51DHGNC:9823—RAD51 paralog D, recombinationClinVarY
EPCAMHGNC:11529—Epithelial cell adhesion moleculeClinVarY
BARD1HGNC:952—BRCA1 associated RING domainClinVarY
CDK4HGNC:1773—Cyclin-dependent kinase 4ClinVarY
MUTYHHGNC:7527—MutY DNA glycosylaseClinVarY
CASP10HGNC:1500—Caspase 10, apoptosisClinVarN
IL1RNHGNC:6000—IL-1 receptor antagonistClinVarN
IL1BHGNC:5992—Interleukin 1 beta, cytokineClinVarY
IRF1HGNC:6116—Interferon regulatory factor 1ClinVarN
NBNHGNC:7652—Nibrin, DNA repairClinVarY
FANCIHGNC:25568—Fanconi anemia group IClinVarY
HNF1BHGNC:11630P35680HNF1β transcription factorTier 3N
ASH1LHGNC:19088Q9NR48Histone methyltransferaseTier 3N
KLHDC4——Kelch domain containing 4Tier 4N
GON4LHGNC:25973Q3T8J9Gon-4 like, transcriptionTier 4N
LMNAHGNC:6636P02545Lamin A/C, nuclear envelopeTier 4N
SMAD7HGNC:6773O15105SMAD7, TGF-β inhibitorTier 3N
TERTHGNC:11730O14746Telomerase reverse transcriptaseTier 3N

Section 6: Protein Family Classification

GeneUniProtProtein FamilyInterPro DomainsDruggable?Notes
FGFR2P21802Receptor Tyrosine KinaseIPR000719 (Kinase), IPR050122 (RTK)YESFDA-approved inhibitors
ERBB2P04626Receptor Tyrosine KinaseKinase domainYESTrastuzumab approved for GC
ALKQ9UM73Receptor Tyrosine KinaseKinase domainYESCrizotinib/alectinib approved
PIK3CAP42336Lipid KinasePI3K domainYESAlpelisib approved
PRKAA1Q13131Ser/Thr Kinase (AMPK)Kinase domainYESMetformin activator
ATMQ13315PI3K-related KinasePIKK domainYESTool compounds exist
CHEK2O96017Ser/Thr KinaseKinase domainYESTool compounds exist
STK11Q15831Ser/Thr Kinase (LKB1)Kinase domainYESDifficult active site
CDK4—Cyclin-dep KinaseKinase domainYESPalbociclib approved
KRASP01116GTPaseRAS familyYESSotorasib (G12C)
PLCE1Q9P212Phospholipase/EnzymePLCε, RasGEF, C2YESEnzyme, partially druggable
PTENP60484PhosphataseC2 tensin domainDIFFICULTTumor suppressor (activate?)
TP53P04637Transcription Factorp53 domainDIFFICULTMDM2 PPI inhibitors
CASP10—Cysteine ProteaseCaspase domainYESProtease family
ABOP16442GlycosyltransferaseGT domainMODERATEEnzyme
MUTYH—DNA GlycosylaseBER domainMODERATEEnzyme
TERTO14746Reverse TranscriptaseRT domainYESTelomerase inhibitors
CDH1P12830CadherinClassical cadherinDIFFICULTAdhesion, restore function
MUC1P15941MucinGlycoproteinMODERATEAntibody target
PSCAO43653GPI-anchored proteinLy6/uPAR superfamilyMODERATEAntibody target
HLA-CP10321MHC class IIg-likeDIFFICULTImmune modulation
SMAD4—Transcription FactorSMAD/MH domainDIFFICULTTumor suppressor
APC—Scaffold ProteinArmadillo repeatDIFFICULTTumor suppressor
BRCA1P38398E3 Ubiquitin LigaseRING fingerDIFFICULTRepair, synthetic lethal
BRCA2P51587DNA Repair—DIFFICULTSynthetic lethal approach
MSH2/MLH1—Mismatch RepairMutS/MutLDIFFICULTRepair, immunotherapy
THBS3P49746Extracellular MatrixEGF, TSP repeatsDIFFICULTSecreted glycoprotein
TTC33Q6PID6TPR ScaffoldTPR repeatsDIFFICULTUnknown function
HNF1BP35680Transcription FactorHomeoboxDIFFICULTNuclear TF
NF1—RAS-GAPGAP domainDIFFICULTTumor suppressor

Summary

CategoryCountPercentage
Druggable (Kinases, RTKs, Enzymes, GTPases)1428%
Moderately druggable (Antibody targets, Enzymes)510%
Difficult (TFs, Scaffolds, Tumor suppressors, PPI)1632%
Unknown/Uncharacterized1530%

Section 7: Expression Context

Disease-relevant tissues: Stomach (gastric mucosa), gastric epithelium, intestinal epithelium

Single-cell data (CellxGene for gastric cancer, MONDO:0001056):

Key cell types identified in gastric cancer tissue (58 cell types):

  • Epithelial cells — 2.1M cells (tumor cells, enterocytes, goblet cells)
  • Foveolar cells of stomach — 152K cells (gastric-specific)
  • Mucous neck cells — 96K cells (gastric-specific)
  • Parietal cells — 7.2K cells (gastric acid-secreting)
  • Peptic (chief) cells — 18.8K cells
  • Fibroblasts/myofibroblasts — 7.2M cells (tumor microenvironment)
  • Macrophages — 3.3M cells (immune infiltrate)
  • T cells — multiple subsets (CD4, CD8, Tregs, γδ)
  • Endothelial cells — 1.8M cells (angiogenesis)

TOP 30 Gene Expression Profiles

GeneGastric TissueKey Cell TypesSpecificityNotes
PSCAStomach, bladder, prostateEpithelial, foveolarModerateGPI-anchored surface antigen
MUC1Stomach, colon, breastEpithelial, foveolar, mucous neckLow (ubiquitous epithelial)Overexpressed in GC
CDH1All epitheliaEpithelial cells broadlyLowEssential in gastric epithelium
PLCE1Stomach, esophagusEpithelial, parietalModerateEnriched in GI tract
ERBB2Stomach, breast, lungEpithelial cellsLowAmplified in ~20% GC
FGFR2Stomach, breast, boneEpithelial, fibroblastsLowAmplified in ~5-10% GC
PRKAA1UbiquitousAll cell typesVery lowEnergy sensor
ABOGI tract, liverEpithelial (GI), endothelialModerateBlood group enzyme
PIK3CAUbiquitousAll cell typesVery lowSignaling kinase
KRASUbiquitousAll cell typesVery lowSignaling GTPase
HLA-CUbiquitousAll nucleated cellsVery lowImmune presentation
TP53UbiquitousAll cell typesVery lowTumor suppressor
THBS3Bone, cartilage, stomachFibroblasts, myofibroblastsModerateECM component
TTC33UbiquitousVariousLowUnknown function
ALKBrain, small intestineNeurons, rare epithelialHigh (nervous system)Fewer off-target effects
TERTLow/stem cellsStem cells, cancer cellsHigh (cancer-specific)Ideal cancer target
STK11UbiquitousAll cell typesVery lowMetabolic kinase
ATMUbiquitousAll cell typesVery lowDNA damage sensor
SMAD7GI tract, immuneEpithelial, T cellsModerateTGF-β pathway
KLHDC4UbiquitousVariousLowPoorly characterized
ASH1LUbiquitousAll nucleatedVery lowHistone methyltransferase
GON4LUbiquitousVariousVery lowTranscription
LMNAUbiquitousAll nucleatedVery lowNuclear lamina
HNF1BKidney, liver, pancreasEpithelialModerateTranscription factor
CDKN2ALow/regulatedCell cycle dependentModerateTumor suppressor
MLH1UbiquitousAll proliferatingVery lowDNA repair
MSH2UbiquitousAll proliferatingVery lowDNA repair
BRCA1UbiquitousAll proliferatingVery lowDNA repair
EPCAMAll epitheliaEpithelial cellsModerateSurface marker
SMAD4GI tract, pancreasEpithelialModerateTGF-β pathway

Section 8: Protein Interactions

STRING Interaction Data

ProteinSTRING IDInteraction CountHub Status
ERBB2ENSP000002695717,626Major hub
PIK3CAENSP000002639674,602Major hub
ALKENSP000003737003,930Major hub
FGFR2ENSP000004102943,436Major hub
PRKAA1ENSP000003461482,966Hub

Key Pathway Interactions Among GWAS Genes

Cluster 1Cluster 2Cluster 3
RTK/PI3K/RAS Signaling - FGFR2 → PIK3CA → PRKAA1 (via mTOR) - ERBB2 → PIK3CA → AKT pathway - ALK → PIK3CA, RAS/MAPK - KRAS → RAF/MEK/ERK
DNA Damage Repair - ATM → CHEK2 → BRCA1/BRCA2 → RAD51C/D - MLH1/MSH2/MSH6/PMS2 (mismatch repair complex) - PALB2 → BRCA2 → RAD51
Cell Adhesion/Wnt - CDH1 → CTNNA1 → APC → β-catenin - EPCAM (regulation of MSH2)
Undrugged GWAS Genes with Drugged Interactors
Undrugged GeneInteracts WithDrugged InteractorDrugs Available
THBS3FGFR2, integrinsFGFR2Futibatinib, erdafitinib
TTC33PTGER4, PRKAA1 pathwayPRKAA1Metformin (AMPK activator)
PLCE1RAS family, PKCKRASSotorasib (G12C specific)
CDH1ERBB2, CTNNB1ERBB2Trastuzumab
SMAD4TGF-β receptorsTGFBR1/2Galunisertib (investigational)
APCCTNNB1, GSK3BCDK4/6Palbociclib, ribociclib
PTENPIK3CA, AKTPIK3CAAlpelisib
BRCA2BRCA1, PALB2, RAD51ATR/ATMCeralasertib (investigational)
GON4LChromatin remodelersHDACPanobinostat, romidepsin
LMNAMAPK/mTORmTOREverolimus

Section 9: Structural Data

PDB Structure Availability

ProteinPDB StructuresAlphaFoldQuality Notes
FGFR2 (P21802)100+ structuresYes (pLDDT 74.3)Excellent coverage, kinase + ectodomain
ERBB2 (P04626)100+ structuresYesExcellent, co-crystal with drugs
PIK3CA (P42336)100+ structuresYesExcellent, co-crystal with alpelisib
ALK (Q9UM73)100+ structuresYesExcellent, kinase domain + drug complexes
PRKAA1 (Q13131)MultipleYesGood, AMPK complex structures
KRAS (P01116)100+ structuresYesExcellent, G12C pocket resolved
TP53 (P04637)100+ structuresYesGood, MDM2 interface resolved
ATM (Q13315)Cryo-EMYesModerate, kinase domain
CHEK2 (O96017)MultipleYesGood kinase domain coverage
STK11 (Q15831)MultipleYesGood, kinase domain
PSCA (O43653)1 (NMR, 9U9N)YesLimited, GPI-anchored domain
PLCE1 (Q9P212)3 structuresYesLimited, RA domains only
MUC1 (P15941)NoneYesLow quality (disordered mucin)
THBS3 (P49746)NoneYesNo experimental structure
TTC33 (Q6PID6)NoneYesNo experimental structure

Summary

Structure StatusCountPercentage
PDB available (multiple)1224%
PDB available (limited, 1-3)36%
AlphaFold only2040%
No useful structure1530%

Undrugged Targets - Structure Availability

GenePDB?AlphaFold?Quality
THBS3NoYesLow (ECM protein)
TTC33NoYesModerate
PLCE13 (partial)YesModerate (RA domains)
GON4LNoYesLow
KLHDC4NoYesModerate
CDH1MultipleYesGood (ectodomain)
SMAD4MultipleYesGood
APCPartialYesModerate
LMNAMultipleYesGood

Section 10: Drug Target Analysis

Summary

CategoryCountPercentage
Total GWAS/ClinVar genes~50100%
With approved drugs (Phase 4)1530%
With Phase 3 drugs510%
With Phase 2/1 drugs48%
With preclinical compounds only612%
With NO drug development2040% ← OPPORTUNITY GAP

Genes with APPROVED Drugs

GeneProteinDrug(s)MechanismApproved for GC?
ERBB2HER2Trastuzumab, T-DXd, Zanidatamab, T-DM1, Pertuzumab, MargetuximabRTK inhibition/antibodyYES
ERBB2HER2Lapatinib, AfatinibSmall molecule TKITrials for GC
FGFR2FGFR2Futibatinib, Erdafitinib, PemigatinibFGFR TKITrials for GC (bemarituzumab)
ALKALKCrizotinib, Alectinib, Lorlatinib, Ceritinib, BrigatinibALK TKINo (NSCLC)
PIK3CAPI3KαAlpelisibPI3K inhibitorNo (breast cancer)
KRASKRASSotorasib, AdagrasibG12C covalent inhibitorNo (NSCLC/CRC)
CDK4CDK4Palbociclib, Ribociclib, AbemaciclibCDK4/6 inhibitorNo (breast cancer)
PRKAA1AMPKα1Metformin (indirect activator)AMPK activationNo (diabetes)
TP53p53— (MDM2 inhibitors in trials)MDM2-p53 PPINo
ATMATM— (tool compounds)Kinase inhibitorNo
CHEK2CHK2— (tool compounds)Kinase inhibitorNo
STK11LKB1— (no direct drugs)—No
TERTTelomeraseImetelstatTelomerase inhibitorNo (MDS)
BRCA1/2BRCA1/2Olaparib (synthetic lethal PARP)PARP inhibitorTrials for GC
MLH1/MSH2MMRPembrolizumab (biomarker: MSI-H)PD-1 checkpointYES (MSI-H GC)

Section 11: Bioactivity & Enzyme Data

TOP 30 Most-Studied Proteins (by ChEMBL bioactivity)

ProteinChEMBL TargetTarget TypeBioactivity Context
ERBB2CHEMBL1824Single proteinThousands of compounds, multiple approved drugs
PIK3CACHEMBL4005Single proteinThousands of compounds, alpelisib approved
FGFR2CHEMBL4142Single proteinThousands of compounds, futibatinib approved
ALKCHEMBL4247Single proteinThousands of compounds, 5+ approved drugs
KRASCHEMBL2189121Single proteinGrowing compound set, sotorasib/adagrasib
PRKAA1CHEMBL4045Single proteinModerate bioactivity data
ATMCHEMBL3797Single proteinTool compounds (AZD0156, AZD1390)
CHEK2CHEMBL2527Single proteinTool compounds exist
STK11CHEMBL5606Single proteinLimited compounds
TERTCHEMBL2916Single proteinImetelstat, BIBR 1532
TP53CHEMBL4096Single proteinMDM2 inhibitors (idasanutlin)
CDH1CHEMBL2321609Single proteinVery limited
PTENCHEMBL2052032Single proteinLimited (activators sought)
MUC1CHEMBL3580494Single proteinAntibody/vaccine approaches
PSCACHEMBL3712961Single proteinAntibody approaches
BRCA1CHEMBL5990Single proteinVery limited direct targeting
ABOCHEMBL2321639Single proteinLimited

Enzyme GWAS Genes

EnzymeEC ClassKnown InhibitorsDruggability
PIK3CALipid kinaseAlpelisib, idelalisib, copanlisibHigh
PRKAA1Ser/Thr kinaseAICAR, metformin (indirect)Moderate
ATMSer/Thr kinaseAZD0156, KU-55933Moderate
CHEK2Ser/Thr kinaseAZD7762 (dual CHK1/2)Moderate
PLCE1PhospholipaseNo specific inhibitorsOpportunity
ABOGlycosyltransferaseNo clinical inhibitorsLow priority
MUTYHDNA glycosylaseNo inhibitorsLow
CASP10Cysteine proteasePan-caspase inhibitorsModerate

Section 12: Pharmacogenomics

PharmGKB Clinical Annotations for Gastric Cancer (MeSH D013274)

VariantGeneDrug(s)TypeEvidence Level
rs3212986ERCC1CisplatinEfficacyLevel 4 (highest)
rs11615ERCC1CisplatinEfficacyLevel 3
rs2298881ERCC1Fluorouracil, Platinum, RTEfficacyLevel 3
rs1799983NOS3Anthracyclines, 5-FU, oxaliplatinEfficacyLevel 3
rs1800566NQO1Epirubicin, 5-FU, oxaliplatinEfficacyLevel 3
rs10040363XRCC4Fluorouracil, Platinum, RTEfficacyLevel 3
rs2075685TMEM167A/XRCC4Fluorouracil, Platinum, RTEfficacyLevel 3
rs2293347EGFRFluorouracilEfficacyLevel 3
rs25648VEGFACisplatin, 5-FU, oxaliplatinEfficacyLevel 3
rs2854744IGFBP3FluorouracilEfficacyLevel 3
rs662PON1Epirubicin, 5-FU, oxaliplatinEfficacyLevel 3

PharmGKB VIP Genes Among GWAS Hits

GenePharmGKB IDVIP?CPIC Guideline?
PSCAPA33847YesNo
PRKAA1PA33744YesNo
MUC1PA31309YesNo
PLCE1PA33391YesNo
FGFR2PA28128YesNo
CDH1PA26282YesNo
ERBB2PA27844YesNo
PIK3CAPA33308YesNo
KRASPA30196YesNo
ALKPA24719YesNo

Section 13: Clinical Trials

Total clinical trials for gastric cancer: 2,354 (MONDO:0001056)

Phase Breakdown (from ChEMBL molecule data)

PhaseCountPercentage
Phase 4 (Approved)~80 molecules~27%
Phase 3~35 molecules~12%
Phase 2~25 molecules~8%
Phase 1~10 molecules~3%
Preclinical/Other~150 molecules~50%

TOP 30 Drugs in Gastric Cancer Trials

DrugPhaseMechanismTarget GeneTargets GWAS Gene?
Trastuzumab4Anti-HER2 mAbERBB2YES
Trastuzumab deruxtecan4Anti-HER2 ADCERBB2YES
Zanidatamab4Bispecific anti-HER2ERBB2YES
Pertuzumab4Anti-HER2 mAbERBB2YES
Trastuzumab emtansine4Anti-HER2 ADCERBB2YES
Margetuximab4Anti-HER2 mAbERBB2YES
Ramucirumab4Anti-VEGFR2 mAbKDRNo
Nivolumab4Anti-PD-1PDCD1No
Pembrolizumab4Anti-PD-1PDCD1No (biomarker: MSI-H via MLH1/MSH2)
Tislelizumab4Anti-PD-1PDCD1No
Toripalimab4Anti-PD-1PDCD1No
Zolbetuximab4Anti-CLDN18.2CLDN18No
Fruquintinib4VEGFR TKIFLT1/KDR/FLT4No
Bevacizumab4Anti-VEGFVEGFANo
Olaparib4PARP inhibitorPARP1/2Synthetic lethal with BRCA1/2
Lapatinib4ERBB2/EGFR TKIERBB2/EGFRYES
Everolimus4mTOR inhibitorMTORPathway (PRKAA1/STK11)
Capmatinib4MET inhibitorMETNo
Cetuximab4Anti-EGFREGFRNo
Sorafenib4Multi-kinase TKIRAF/VEGFR/PDGFRPathway (KRAS)
Sunitinib4Multi-kinase TKIVEGFR/KIT/PDGFRNo
Afatinib4Pan-ERBB TKIERBB2/EGFRYES
Imatinib4BCR-ABL/KITABL/KIT/PDGFRNo
Bemarituzumab3Anti-FGFR2bFGFR2YES
Rivoceranib3VEGFR2 TKIKDRNo
Catequentinib3Multi-kinaseVEGFR/METNo
Dovitinib3FGFR/VEGFR TKIFGFR2YES
Varlitinib2Pan-ERBB TKIERBB2YES
Fexagratinib2FGFR TKIFGFR2YES
Cadonilimab3PD-1/CTLA-4 bispecificPDCD1/CTLA4No

GWAS-Trial Alignment

  • Drugs targeting GWAS genes in trials: ~12 out of 30 top drugs (~40%)
  • ERBB2 is the dominant GWAS-targeted gene in trials
  • FGFR2 emerging with bemarituzumab and FGFR TKIs
  • BRCA1/2 indirectly targeted via PARP inhibitors
  • High alignment for the HER2 pathway; moderate for FGFR; low for PRKAA1/PSCA/MUC1

Section 14: Pathway Analysis

Reactome Pathways for GWAS Proteins

PathwayReactome IDGWAS GenesDruggable Nodes
PI3K/AKT signalingR-HSA-1257604FGFR2, ERBB2, PIK3CA, PTENPIK3CA (alpelisib), AKT (capivasertib), mTOR (everolimus)
RAF/MAP kinase cascadeR-HSA-5673001FGFR2, ERBB2, PIK3CA, KRASMEK (trametinib), RAF (sorafenib), KRAS (sotorasib)
Signaling by FGFR2R-HSA-5655253FGFR2, PIK3CAFGFR2 (futibatinib, erdafitinib)
Signaling by ERBB2R-HSA-1227986ERBB2, PIK3CAERBB2 (trastuzumab, lapatinib)
Signaling by ALKR-HSA-201556ALK, PIK3CAALK (crizotinib, alectinib)
Constitutive PI3K in CancerR-HSA-2219530FGFR2, ERBB2, PIK3CAPIK3CA (alpelisib)
TP53 Metabolic GenesR-HSA-5628897PRKAA1, TP53CDK4/6, MDM2
Energy/mTOR (LKB1-AMPK)R-HSA-380972PRKAA1, STK11mTOR (everolimus)
MacroautophagyR-HSA-1632852PRKAA1mTOR, ULK1
AMPK-PD-L1 degradationR-HSA-9931269PRKAA1PD-1/PD-L1 (nivolumab)

Pathway-Level Druggability

Even undrugged GWAS genes participate in pathways with druggable nodes:

Undrugged GWAS GenePathwayDruggable Pathway MemberDrug
THBS3ECM/integrin signalingIntegrins, FGFRFutibatinib
TTC33Unknown (near PTGER4/PRKAA1)PRKAA1/mTOREverolimus
PLCE1RAS/PLC signalingKRAS, PKCSotorasib
GON4LChromatin regulationHDAC, BETPanobinostat
KLHDC4Ubiquitin/proteasomeProteasomeBortezomib
SMAD7TGF-β signalingTGFBR1Galunisertib
APCWnt/β-cateninPorcupine, TankyraseWNT inhibitors (trials)
LMNANuclear envelope/MAPKMEK, mTORTrametinib, everolimus
HNF1BTranscription/metabolismMetabolic targets—

Section 15: Drug Repurposing Opportunities

TOP 30 Repurposing Candidates

RankDrugTarget GeneApproved ForMechanismGWAS p-valuePriority Score
1FutibatinibFGFR2CholangiocarcinomaFGFR TKI1e-25★★★★★
2ErdafitinibFGFR2Bladder cancerFGFR TKI1e-25★★★★★
3AlpelisibPIK3CABreast cancer (PIK3CA-mut)PI3Kα inhibitorClinVar★★★★★
4SotorasibKRASNSCLC (G12C)KRAS G12C inhibitorClinVar★★★★☆
5AdagrasibKRASNSCLC (G12C)KRAS G12C inhibitorClinVar★★★★☆
6CrizotinibALKNSCLC (ALK+)ALK/MET TKI2e-8★★★★☆
7AlectinibALKNSCLC (ALK+)ALK TKI2e-8★★★★☆
8PalbociclibCDK4Breast cancerCDK4/6 inhibitorClinVar★★★★☆
9RibociclibCDK4Breast cancerCDK4/6 inhibitorClinVar★★★★☆
10AbemaciclibCDK4Breast cancerCDK4/6 inhibitorClinVar★★★★☆
11MetforminPRKAA1 (indirect)DiabetesAMPK activator8e-29★★★☆☆
12LorlatinibALKNSCLC (ALK+)ALK TKI (3rd gen)2e-8★★★☆☆
13CeritinibALKNSCLC (ALK+)ALK TKI2e-8★★★☆☆
14CapivasertibAKT (PIK3CA path)Breast cancerAKT inhibitorClinVar★★★☆☆
15ImetelstatTERTMDSTelomerase inhibitor3e-6★★★☆☆
16PemigatinibFGFR2CholangiocarcinomaFGFR TKI1e-25★★★☆☆
17TrametinibMEK (KRAS pathway)MelanomaMEK inhibitorClinVar★★★☆☆
18RucaparibPARP (BRCA1/2 SL)Ovarian cancerPARP inhibitorClinVar★★★☆☆
19NiraparibPARP (BRCA1/2 SL)Ovarian cancerPARP inhibitorClinVar★★★☆☆
20VismodegibSMO/HedgehogBCCSMO inhibitorTrial for GC★★☆☆☆
21PanobinostatHDAC (GON4L path)MyelomaHDAC inhibitor1e-15★★☆☆☆
22VandetanibVEGFR/EGFR/RETThyroid cancerMulti-TKITrial for GC★★☆☆☆
23PazopanibVEGFRRCCMulti-TKITrial for GC★★☆☆☆
24RomidepsinHDACCTCLHDAC inhibitorTrial for GC★★☆☆☆
25TirbanibulinSrc/tubulinActinic keratosisSrc/tubulin inhibitorTrial for GC★★☆☆☆
26ErlotinibEGFRNSCLCEGFR TKITrial for GC★★☆☆☆
27BortezomibProteasomeMyelomaProteasome inhibitorTrial for GC★★☆☆☆
28SaracatinibSrcInvestigationalSrc kinase inhibitorTrial for GC★☆☆☆☆
29BrivanibFGFR/VEGFRInvestigationalDual TKITrial for GC★☆☆☆☆
30CabazitaxelTubulinProstate cancerTaxaneTrial for GC★☆☆☆☆

Section 16: Druggability Pyramid

LevelDescriptionGene CountPercentageKey Genes
LevelVALIDATED: Approved drug FOR gastric36%ERBB2 (trastuzumab), MLH1/MSH2 (pembrolizumab for MSI-H)
1cancer
LevelREPURPOSING: Approved drug for OTHER1020%FGFR2, ALK, PIK3CA, KRAS, CDK4, PRKAA1, TERT, ATM, CHEK2, STK11
2disease
LevelEMERGING: Drug in clinical trials for510%BRCA1/2 (olaparib), TP53 (MDM2i), FGFR2 (bemarituzumab), MUC1, PSCA
3GC
LevelTOOL COMPOUNDS: ChEMBL compounds but no48%ABO, CDH1, PTEN, CASP10
4trials
LevelDRUGGABLE UNDRUGGED: Druggable family,510%PLCE1 (phospholipase), MAP3K6 (kinase), SMAD7 (TGF-β)
5NO compounds
LevelHARD TARGETS: Difficult family or2346%THBS3, TTC33, KLHDC4, GON4L, LMNA, APC, SMAD4, HNF1B, NF1, BARD1, RAD51C/D, PALB2, NBN, BRIP1, FANCI, EPCAM, MUTYH,
6unknownIRF1, CDKN2A, HOXB13, KLF6, IL1RN, IL1B

Section 17: Undrugged Target Profiles

TOP 30 Undrugged Opportunities Ranked by Potential

RankGeneGWAS p-valueVariant TypeProtein FamilyStructureExpressionDrugged Interactors?Druggability
1PLCE12e-22RegulatoryPhospholipase/RasGEFPDB (partial)Stomach enrichedKRAS, PKCHIGH
2PSCA4e-49RegulatoryGPI-anchored (Ly6)PDB (1, NMR)Stomach, prostateAntibody approachesHIGH
3MUC16e-17Coding regionMucin glycoproteinAlphaFold onlyGastric epitheliumCAR-T, ADC approachesHIGH
4PRKAA18e-29RegulatoryKinase (AMPK)PDB (multiple)UbiquitousmTOR, metforminMODERATE-HIGH
5THBS32e-40IntergenicECM glycoproteinAlphaFold onlyFibroblasts, stomachFGFR2, integrinsMODERATE
6TTC338e-43RegulatoryTPR scaffoldAlphaFold onlyUbiquitousPTGER4 pathwayLOW-MODERATE
7KLHDC41e-83IntronicKelch domainAlphaFold onlyUbiquitousUbiquitin systemMODERATE
8CDH1ClinVar/HDGCCoding (LOF)Cadherin (adhesion)PDB (good)EpithelialERBB2, CTNNB1MODERATE
9GON4L1e-15IntronicTranscription factorAlphaFold onlyUbiquitousHDACLOW
10LMNA4e-15IntronicNuclear laminaPDB (good)UbiquitousMEK, mTORLOW
11APCClinVarCoding (LOF)Scaffold/WntPDB (partial)GI epitheliaCTNNB1, GSK3BMODERATE
12SMAD4ClinVarCoding (LOF)Transcription factorPDB (good)GI epitheliaTGF-β receptorsLOW-MODERATE
13SMAD72e-8RegulatorySMAD inhibitorAlphaFoldGI tract, immuneTGF-β pathwayMODERATE
14HNF1B3e-21RegulatoryTranscription factorLimitedKidney, liver, pancreasMetabolic pathwayLOW
15ASH1L2e-19RegulatoryHistone MTaseLimitedUbiquitousChromatin modifiersMODERATE
16PTENClinVarCoding (LOF)PhosphatasePDB (good)UbiquitousPIK3CA, AKTMODERATE
17NF1ClinVarCoding (LOF)RAS-GAPLimitedUbiquitousRAS pathwayLOW
18BRCA2ClinVarCoding (LOF)DNA repairLimitedUbiquitousPARP (synthetic lethal)MODERATE
19PALB2ClinVarCoding (LOF)DNA repairLimitedUbiquitousBRCA2, PARPMODERATE
20CDKN2AClinVarCoding (LOF)CDK inhibitorPDB (good)Cell cycleCDK4/6 (indirect)MODERATE
21EPCAMClinVarVariousCell adhesionLimitedEpithelialMSH2, immuneMODERATE
22ABO3e-13RegulatoryGlycosyltransferasePDB (good)GI epitheliaLimitedLOW
23MAP3K6GenCCCodingKinase (MAP3K)AlphaFoldVariousMAPK pathwayHIGH
24IL1BGenCCRegulatoryCytokinePDB (good)Immune cellsIL1R, canakinumabMODERATE
25CTNNA1Orphanet/HDGCCoding (LOF)α-CateninPDB (good)EpithelialCDH1, CTNNB1LOW
26IRF1ClinVarVariousTranscription factorLimitedImmuneJAK/STAT pathwayLOW
27RAD51CClinVarCoding (LOF)RecombinaseLimitedUbiquitousPARP (SL)MODERATE
28RAD51DClinVarCoding (LOF)RecombinaseLimitedUbiquitousPARP (SL)MODERATE
29BRIP1ClinVarCoding (LOF)HelicaseLimitedUbiquitousPARP (SL)MODERATE
30MSH6ClinVarCoding (LOF)Mismatch repairPDB (good)UbiquitousPD-1 (MSI-H biomarker)MODERATE

Detailed Profiles of Highest-Value Undrugged Targets

  1. PLCE1 (Phospholipase C epsilon 1)
  • GWAS: p=2e-22 (PLCE1 locus, chr10q23)
  • Function: Phospholipase, Ras-GEF activity, second messenger signaling
  • Family: Enzyme (phospholipase) — druggable
  • Structure: 3 PDB structures (RA domains), AlphaFold full model
  • Expression: Enriched in gastric/esophageal tissue
  • Interactions: Links to RAS, PKC, Ca²⁺ signaling
  • Why undrugged: Novel target, no compound screening yet
  • Druggability: HIGH — enzyme with crystal structure
  1. PSCA (Prostate Stem Cell Antigen)
  • GWAS: p=4e-49 (strongest gastric cancer locus at chr8q24)
  • Function: GPI-anchored cell surface antigen, Ly6 family
  • Family: Cell surface antigen — antibody/ADC target
  • Structure: 1 NMR structure (PDB: 9U9N)
  • Expression: Stomach, prostate, bladder — moderate specificity
  • Interactions: Limited known interactors
  • Why undrugged: Surface protein under active antibody development
  • Druggability: HIGH — surface antigen, ideal for ADC/bispecific
  1. PRKAA1 (AMPKα1)
  • GWAS: p=8e-29 (chr5, multiple independent studies)
  • Function: Master metabolic sensor kinase, AMPK pathway
  • Family: Kinase — highly druggable
  • Structure: Multiple PDB structures of AMPK complex
  • Expression: Ubiquitous (potential off-target concerns)
  • Interactions: STK11/LKB1 (activator), mTOR, p53 pathway
  • Why undrugged: Metformin is indirect activator; no specific PRKAA1 drugs
  • Druggability: HIGH — kinase with solved structure
  1. MAP3K6 (ASK2)
  • GenCC: Curated gene-disease association for both GC and HDGC
  • Function: MAP3K family kinase, activates JNK/p38 MAPK
  • Family: Kinase — highly druggable
  • Structure: AlphaFold available
  • Expression: Various tissues
  • Why undrugged: Understudied kinase
  • Druggability: HIGH — kinase family, Mendelian evidence
  1. KLHDC4 (Kelch Domain Containing 4)
  • GWAS: p=1e-83 (strongest single association in the dataset!)
  • Function: Kelch domain protein, likely ubiquitin pathway
  • Why undrugged: Poorly characterized function
  • Druggability: MODERATE — very strong genetic signal demands investigation

Section 18: Summary

GWAS LANDSCAPE

  • Total associations: ~271 across ~40 studies
  • Unique protein-coding GWAS genes (direct): ~25
  • ClinVar genes for gastric cancer: 37
  • Combined unique genes: ~50
  • Coding vs non-coding variants: ~10% coding / ~90% non-coding

GENETIC EVIDENCE

  • Tier 1 (coding) genes: ~5 (MUC1, PSCA, CDH1, PLCE1, missense variants)
  • Mendelian overlap genes: 16 (CDH1, CTNNA1, MAP3K6, IL1B + 12 ClinVar cancer predisposition genes)
  • Both GWAS + Mendelian: CDH1, FGFR2

DRUGGABILITY

  • Overall druggability rate: 36% of genes have known drug targets
  • Approved drugs: 6% (Level 1, for this disease)
  • Repurposing candidates: 20% (Level 2, approved for other diseases)
  • In trials for GC: 10% (Level 3)
  • Opportunity gap (no drugs): 46% (Level 6, hard targets)
  • High-value druggable undrugged: 10% (Level 5, PLCE1, MAP3K6, etc.)

PYRAMID SUMMARY

LevelCount%
1 - Validated36%
2 - Repurposing1020%
3 - Emerging510%
4 - Tool compounds48%
5 - Druggable undrugged510%
6 - Hard targets2346%

CLINICAL TRIAL ALIGNMENT

  • ~40% of top trial drugs target GWAS genes (primarily ERBB2, FGFR2)
  • Strong alignment for HER2 pathway; emerging for FGFR2
  • PARP inhibitors connect to BRCA1/2 ClinVar genes

TOP 10 REPURPOSING CANDIDATES

DrugGeneApproved Forp-valueScore
FutibatinibFGFR2Cholangiocarcinoma1e-25★★★★★
ErdafitinibFGFR2Bladder cancer1e-25★★★★★
AlpelisibPIK3CABreast cancerClinVar★★★★★
SotorasibKRASNSCLCClinVar★★★★☆
CrizotinibALKNSCLC2e-8★★★★☆
PalbociclibCDK4Breast cancerClinVar★★★★☆
MetforminPRKAA1Diabetes8e-29★★★☆☆
LorlatinibALKNSCLC2e-8★★★☆☆
CapivasertibAKT/PIK3CABreast cancerClinVar★★★☆☆
ImetelstatTERTMDS3e-6★★★☆☆

TOP 10 UNDRUGGED OPPORTUNITIES

Genep-valueFamilyStructurePotential
PLCE12e-22Phospholipase/enzymePDB (partial)HIGH
PSCA4e-49GPI-anchored surfacePDB (1)HIGH
PRKAA18e-29Kinase (AMPK)PDB (good)HIGH
MAP3K6GenCCMAP3K kinaseAlphaFoldHIGH
KLHDC41e-83Kelch domainAlphaFoldMODERATE
MUC16e-17Mucin surfaceAlphaFoldHIGH
ASH1L2e-19Histone MTaseLimitedMODERATE
THBS32e-40ECM glycoproteinAlphaFoldMODERATE
TTC338e-43TPR scaffoldAlphaFoldLOW-MODERATE
CDH1HDGCCadherinPDB (good)MODERATE

TOP 10 INDIRECT OPPORTUNITIES

Undrugged GeneDrugged InteractorDrug
THBS3 ↔ FGFR2FGFR2Futibatinib
PLCE1 ↔ KRASKRASSotorasib
CDH1 ↔ ERBB2ERBB2Trastuzumab
PTEN ↔ PIK3CAPIK3CAAlpelisib
APC ↔ CDK4/6CDK4Palbociclib
SMAD4 ↔ TGFBR1TGFBR1Galunisertib
GON4L ↔ HDACHDACPanobinostat
LMNA ↔ MEK/mTORmTOREverolimus
BRCA2 ↔ PARPPARP1Olaparib
NF1 ↔ MEKMEK1/2Trametinib

KEY INSIGHTS

  1. PSCA/JRK (8q24) is the strongest gastric cancer-specific GWAS locus (p=4e-49), yet PSCA has no approved drug. Antibody-based approaches (ADCs, bispecifics) are the most promising path.
  2. KLHDC4 (chr16) shows the most extreme statistical signal (p=1e-83) of any gastric cancer locus, but the gene is poorly characterized. This represents a major discovery opportunity.

3. The PRKAA1/AMPK locus (chr5) is replicated across >6 studies with p-values reaching 8e-29. Metformin (an AMPK activator) is already approved for diabetes — epidemiological studies should assess gastric cancer risk in metformin users.

  1. ERBB2 (HER2) is the only GWAS-implicated gene with approved drugs specifically for gastric cancer, validating the GWAS-to-drug-target pipeline.
  2. FGFR2 is an emerging gastric cancer target with bemarituzumab in Phase 3 — GWAS evidence (p=1e-25) strongly supports this development.
  3. 40% of clinical trial drugs target GWAS-implicated genes — indicating moderate genetic evidence utilization, but substantial room for improvement.

7. The DNA repair gene cluster (BRCA1/2, ATM, CHEK2, PALB2, RAD51C/D) from ClinVar provides a strong rationale for PARP inhibitor trials in gastric cancer (olaparib already in trials).

  1. Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2) connect gastric cancer to the MSI-H biomarker, validating pembrolizumab use in MSI-H gastric cancer.

  2. Compared to other cancers: Gastric cancer shows a unique GWAS profile with PSCA, MUC1, and ABO as GI-specific loci not seen in breast/lung cancer GWAS, while sharing FGFR2 and TERT with pan-cancer analyses. The H. pylori-stratified GWAS studies reveal infection-specific genetic modifiers (ZNF652-AS1, SGCG).

  3. The 46% of genes at Level 6 (hard targets) includes several with very strong genetic signals (TTC33 p=8e-43, THBS3 p=2e-40) — these represent the next frontier for drug discovery requiring novel modalities (PROTACs, gene therapy, antisense).

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