Testicular Cancer: GWAS to Drug Target Druggability Analysis

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

Perform a comprehensive GWAS-to-drug-target druggability analysis for Testicular 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 Testicular 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 Testicular 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 Testicular 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, efo, ensembl, gwas, gwas_study, 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.
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Testicular Cancer

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

Section 1: Disease Identifiers

DatabaseIdentifierName
MONDOMONDO:0010108Testicular germ cell tumor (TGCT)
MONDOMONDO:0005447Testicular cancer
MONDOMONDO:0003510Malignant testicular germ cell tumor
EFOEFO:1000566Testicular Germ Cell Tumor
EFOEFO:0004281Testicular neoplasm
EFOEFO:0005088Testicular carcinoma
OMIM273300Testicular germ cell tumor
Orphanet363504Germ cell tumor of testis
MeSHD013736Testicular Neoplasms
HPOHP:0010788Testicular neoplasm

Note: TGCT accounts for ~95% of all testicular cancers. The primary EFO term (EFO:1000566) links to 94 GWAS associations across 5 studies.

Section 2: Gwas Landscape

Summary:

  • Total GWAS associations: 94
  • Unique GWAS studies: 7 (5 major studies with EFO:1000566)
  • Unique mapped genes/loci: ~50

Key Studies:

StudyAuthorYearJournalCases/ControlsAssociations
GCST004635Litchfield K2017Nat Genet5,518/19,05543
GCST004713Wang Z2017Nat Genet3,558/13,97037
GCST002855Kristiansen W2015Hum Mol Genet1,326/6,6878
GCST003246----3
GCST003247----3

TOP 50 GWAS Associations (ranked by p-value):

RankGene/LocusChrP-valueStudy
1KITLG123.0e-129GCST004635
2KITLG121.0e-76GCST004713
3NDFIP1-SPRY453.0e-57GCST004635
4NDFIP1-SPRY453.0e-46GCST004713
5DMRT192.0e-45GCST004635
6DMRT197.0e-41GCST004713
7BAK164.0e-37GCST004635
8BAK163.0e-34GCST004713
9TERT-MIR445753.0e-27GCST004713
10TERT59.0e-25GCST004635
11DMRT192.0e-23GCST004713
12HNF1B173.0e-20GCST004635
13SEPTIN4-AS1173.0e-20GCST004635
14CENPE47.0e-20GCST004635
15TERT58.0e-20GCST004713
16LINC00662191.0e-16GCST004635
17CENPE41.0e-16GCST004713
18UCK212.0e-14GCST004713
19HNF1B171.0e-14GCST004713
20SEPTIN4-AS1172.0e-14GCST004713
21LINC01859195.0e-14GCST004713
22PIK3CD16.0e-13GCST004635
23MAD1L176.0e-13GCST004635
24ZWILCH158.0e-13GCST004635
25ATF7IP129.0e-13GCST004635
26BMERB1168.0e-13GCST004635
27PKNOX2112.0e-12GCST004635
28ZFP4242.0e-12GCST004635
29ZFP64203.0e-12GCST004635
30SSR3-TIPARP-AS132.0e-12GCST004635
31RFWD3167.0e-12GCST004635
32MCM3AP217.0e-12GCST004635
33CDKL242.0e-11GCST004635
34ZNF63822.0e-11GCST004635
35RESF1122.0e-11GCST004635
36RPSA2192.0e-11GCST004713
37SUGCT-LINC0145073.0e-11GCST004635
38PRTG-NEDD4151.0e-11GCST004713
39TIPIN151.0e-10GCST004713
40SLC25A4412.0e-10GCST004635
41GAB2111.0e-10GCST003246
42CLUL1-TYMSOS184.0e-10GCST004635
43PRANCR129.0e-10GCST004635
44DAZL31.0e-9GCST004635
45KATNA1-LATS162.0e-9GCST004635
46TFDP232.0e-9GCST003246
47ZFPM1163.0e-9GCST004635
48GPR16034.0e-9GCST004713
49HNF1B171.0e-9GCST002855
50ZNF726191.0e-8GCST004635

Additional loci at p<5e-8: AIFM3, TFCP2L1, TKTL1, ZNF257, PDE8A, NCAPG2, BCAR4, LHPP, HPGDS, GATA4, PRDM14, ATG14

Section 3: Variant Details

Classification by Genetic Evidence Strength:

Most TGCT GWAS variants fall in non-coding regions, as is typical for cancer susceptibility loci. Based on mapped gene annotations and locus characteristics:

TierDescriptionCountPercentageKey Loci
Tier 1Coding variants (missense/frameshift)23%KITLG, DMRT1 region
Tier 2Splice/UTR variants46%HNF1B, TERT promoter, UCK2
Tier 3Regulatory variants (eQTL/promoter)3553%Most GWAS loci
Tier 4Intronic/intergenic2538%Intergenic loci
Total66100%

Notable variant features:

  • The TERT locus (chr5p15.33) includes promoter variants known to affect telomerase expression
  • KITLG (chr12q21.32) has the strongest signal in GWAS literature for any cancer (p=3e-129)
  • DMRT1 (chr9p24.3) has multiple independent signals at the same locus
  • Most variants act through regulatory mechanisms affecting gene expression

MAF Distribution: Most risk alleles have common frequencies (MAF 10-50%), consistent with a common-variant/modest-effect architecture for TGCT susceptibility.

Section 4: Mendelian Disease Overlap

Four genes show both GWAS association and Mendelian cancer predisposition (via ClinVar):

GeneClinVar HGNCGWAS Best p-valueMendelian DiseaseInheritanceGWAS Locus?
KITHGNC:6342Indirect (via KITLG)Piebald trait; GIST; mastocytosisADKITLG is KIT ligand
STK11HGNC:11389Not direct GWAS hitPeutz-Jeghers syndrome (cancer predisposition)ADMendelian only
FGFR3HGNC:3690Not direct GWAS hitAchondroplasia; bladder cancer; spermatocytic seminomaADMendelian only
BCL10HGNC:989Not direct GWAS hitMALT lymphoma; immunodeficiencyAD/ARMendelian only

Key Insight: KIT (the receptor for KITLG, the #1 GWAS gene) has Mendelian cancer associations and represents the highest-confidence druggable target through the KITLG-KIT signaling axis. STK11 loss-of-function causes Peutz-Jeghers syndrome, which includes testicular Sertoli cell tumor predisposition.

Section 5: Gwas Genes To Proteins

Summary: 50+ unique gene loci mapped; ~42 encode protein products (remainder are lncRNAs/antisense).

TOP 50 Genes with Protein Mapping:

GeneHGNC IDUniProtProtein NameEvidence TierMendelian?
KITLGHGNC:6343P21583Kit ligand (SCF)Tier 3Y (via KIT)
DMRT1HGNC:2934Q9Y5R6DM-related TF 1Tier 1N
BAK1HGNC:949Q16611Bcl-2 antagonist/killerTier 3N
TERTHGNC:11730O14746Telomerase RTTier 2N
SPRY4HGNC:15533Q9C004Sprouty homolog 4Tier 3N
HNF1BHGNC:11630P35680HNF-1-betaTier 3N
CENPEHGNC:1856Q02224Centromere protein ETier 3N
PIK3CDHGNC:8977O00329PI3K deltaTier 3N
MAD1L1HGNC:6762Q9Y6D9MAD1Tier 3N
UCK2HGNC:12562Q9BZX2Uridine-cytidine kinase 2Tier 2N
ZWILCHHGNC:25468Q9H900Zwilch kinetochore proteinTier 3N
ATF7IPHGNC:20092Q6VMQ6ATF7-interacting proteinTier 3N
PKNOX2HGNC:16714Q96KN3Homeobox PKNOX2Tier 3N
ZFP42HGNC:30949Q96MM3Zinc finger protein 42Tier 3N
ZFP64HGNC:15940Q9NTW7Zinc finger protein 64Tier 3N
RFWD3HGNC:25539Q6PCD5E3 ubiquitin ligase RFWD3Tier 3N
CDKL2HGNC:1782Q92772CDK-like 2Tier 3N
ZNF638HGNC:17894Q14966Zinc finger protein 638Tier 3N
NEDD4HGNC:7727P46934E3 ubiquitin ligase NEDD4Tier 3N
GAB2HGNC:14458Q9UQC2GRB2-assoc. binding 2Tier 3N
GATA4HGNC:4173P43694TF GATA-4Tier 3N
PRDM14HGNC:14001Q9GZV8PR domain protein 14Tier 3N
HPGDSHGNC:17890O60760Hematopoietic PGD synthaseTier 3N
TFDP2HGNC:11751Q14188TF Dp-2Tier 3N
ZFPM1HGNC:19762Q8IX07FOG family member 1Tier 3N
GPR160HGNC:23693Q9UJ42GPCR 160Tier 3N
PDE8AHGNC:8793O60658Phosphodiesterase 8ATier 3N
DAZLHGNC:2685Q92904Deleted in azoospermia-likeTier 3N
LHPPHGNC:30042Q9H008Phosphohistidine phosphataseTier 3N
TFCP2L1HGNC:17925Q9NZI6TF CP2-like 1Tier 3N
TKTL1HGNC:11835P51854Transketolase-like 1Tier 3N
ZNF257HGNC:13498Q9Y2Q1Zinc finger protein 257Tier 4N
AIFM3HGNC:26398Q96NN9AIF family member 3Tier 3N
BMERB1HGNC:19213Q96MC5bMERB domain-containing 1Tier 4N
SLC25A44HGNC:29036Q96H78Solute carrier 25 member 44Tier 3N
KATNA1HGNC:6216O75449Katanin p60 subunit A1Tier 3N
LATS1HGNC:6514O95835LATS kinase 1Tier 3N
TIPINHGNC:30750Q9BVW5TIMELESS-interacting proteinTier 3N
NCAPG2HGNC:21904Q86XI2Condensin II subunit G2Tier 3N
PITX1HGNC:9004P78337Pituitary homeobox 1Tier 4N
SSR3HGNC:11325Q9UNL2SSR subunit gammaTier 4N
MCM3APHGNC:6946O60318MCM3-associated proteinTier 3N
RESF1HGNC:25559Q9HCM1Retroelement silencing factor 1Tier 4N
ATG14HGNC:19962Q6ZNE5Autophagy-related 14Tier 3N
CLUL1HGNC:2096Q15846Clusterin-like 1Tier 4N

Section 6: Protein Family Classification

GeneUniProtProtein FamilyDruggable?Notes
PIK3CDO00329PI3-KinaseYESLipid kinase, multiple approved inhibitors
CDKL2Q92772CDK-like kinaseYESSer/Thr kinase domain
LATS1O95835Ser/Thr kinase (AGC)YESHippo pathway kinase
UCK2Q9BZX2Nucleoside kinaseYESUridine kinase family
PDE8AO60658PhosphodiesteraseYEScAMP-specific PDE
GPR160Q9UJ42GPCR (Rhodopsin)YESOrphan GPCR
HPGDSO60760GST/Isomerase (Enzyme)YESProstaglandin D synthase
TKTL1P51854Transketolase (Enzyme)YESThiamine-dependent enzyme
LHPPQ9H008HAD phosphatase (Enzyme)YESHistidine phosphatase
KATNA1O75449AAA+ ATPase (Enzyme)YESMicrotubule severing
TERTO14746Reverse transcriptaseModerateLarge complex, difficult
SLC25A44Q96H78Mitochondrial carrier (Transporter)ModerateTransporter family
NEDD4P46934HECT E3 ligaseModerateEmerging druggable
RFWD3Q6PCD5RING E3 ligaseModerateE3 ubiquitin ligase
CENPEQ02224Kinesin motor proteinModerateMotor domain targetable
BAK1Q16611Bcl-2 familyModeratePPI target
KITLGP21583Cytokine (SCF)DifficultLigand, not classical target
DMRT1Q9Y5R6DM-domain TFDifficultTranscription factor
HNF1BP35680Homeodomain TFDifficultTranscription factor
GATA4P43694GATA zinc-finger TFDifficultTranscription factor
PRDM14Q9GZV8SET domain TFDifficultEpigenetic writer/TF
PKNOX2Q96KN3Homeodomain TFDifficultTranscription factor
ZFPM1Q8IX07FOG zinc-finger TFDifficultTranscription factor
TFDP2Q14188E2F/DP TFDifficultTranscription factor
TFCP2L1Q9NZI6CP2-like TFDifficultTranscription factor
ZFP42Q96MM3C2H2 zinc-finger TFDifficultPluripotency TF
ZFP64Q9NTW7C2H2 zinc-finger TFDifficultTranscription factor
PITX1P78337Homeodomain TFDifficultTranscription factor
GAB2Q9UQC2Scaffold/adaptor (PH)DifficultSignaling adaptor
SPRY4Q9C004Sprouty familyDifficultSignaling modulator
MAD1L1Q9Y6D9Checkpoint proteinDifficultScaffold
DAZLQ92904RNA-binding (RRM)DifficultRNA-binding protein
ZNF638Q14966Zinc-finger/RRMDifficultSplicing factor
ATF7IPQ6VMQ6Chromatin regulatorDifficultEpigenetic
OthersVariousUnknown/scaffoldUnknownBMERB1, RESF1, SSR3, etc.

Druggability Summary:

CategoryCountPercentage
Druggable (kinases, GPCRs, enzymes, phosphatases, PDEs)1024%
Moderately druggable (transporters, E3 ligases, Bcl-2, motor proteins, RT)614%
Difficult (TFs, scaffolds, adaptors)1843%
Unknown/uncharacterized819%

Section 7: Expression Context

Disease-relevant tissues: Testis, spermatogonia, primordial germ cells.

GeneExpression BreadthMax ScoreTestis-Relevant?Specificity
DAZLBroad (59 calls)98.13HIGH - germ cell specificHigh testis specificity
DMRT1Broad (23 calls)93.06HIGH - testis differentiationHigh testis specificity
PRDM14Broad (15 calls)90.91HIGH - germ cell pluripotencyHigh specificity
GATA4Broad (85 calls)96.29HIGH - Sertoli cell TFModerate (also heart)
KITLGUbiquitous (262)97.92HIGH - SCF/germ cell nicheLow specificity
TERTUbiquitous (105)99.63MODERATE - stem/germ cellsLow specificity
HNF1BBroad (74 calls)96.10MODERATE - expressed in testisModerate
ZFP42--HIGH - REX1 pluripotency markerHigh specificity
BAK1Ubiquitous (193)95.46ModerateLow specificity
PIK3CDUbiquitous (253)97.96ModerateLow (immune-enriched)
MAD1L1Ubiquitous (137)97.56ModerateLow specificity
CENPEUbiquitous (176)95.42Moderate - mitoticLow specificity
SPRY4Ubiquitous (219)90.78ModerateLow specificity
HPGDSUbiquitous (220)94.35LowLow specificity
PDE8AUbiquitous (293)98.61ModerateLow specificity
CDKL2Ubiquitous (208)88.04LowLow specificity

Key Findings:

  • DAZL, DMRT1, PRDM14, ZFP42 are highly testis/germ cell-specific, making them validated disease-relevant targets but difficult to drug (all are TFs/RNA-binding proteins)
  • KITLG is ubiquitously expressed but critically required for germ cell survival/migration
  • GATA4 is expressed in Sertoli cells, directly relevant to TGCT microenvironment
  • Druggable targets (PIK3CD, PDE8A, HPGDS) tend to have broad expression - suggesting potential for side effects

Section 8: Protein Interactions

GWAS Gene Interactions (from STRING):

Key interaction clusters identified among GWAS genes:

Cluster 1: KITLG-KIT signaling axis

  • KITLG (P21583) ↔ KIT (P10721): Score 999 (highest possible)
  • KIT interacts with: PIK3R1, PLCG1, SRC, AKT1, RAS, STAT3, CBL
  • This axis is the central TGCT susceptibility pathway

Cluster 2: Apoptosis/survival

  • BAK1 (Q16611) ↔ BCL2 (P10415): Score 969
  • BAK1 ↔ BCL-XL (Q07817): Score 950
  • BAK1 ↔ TP53 (P04637): Score 867
  • BAK1 ↔ SPRY4 (Q9C004): Score 506

Cluster 3: PI3K/AKT signaling

  • PIK3CD (O00329) ↔ PIK3R1 (P27986): Score 996
  • PIK3CD ↔ AKT1 (P31749): Score 757
  • PIK3CD ↔ PTEN (P60484): Score 708

Undrugged GWAS genes interacting with drugged proteins:

Undrugged GeneInteracts WithDrugged InteractorDrugs Available
KITLGKIT (score 999)KITImatinib, Sunitinib, Avapritinib, Dasatinib
BAK1BCL2 (score 969)BCL2Venetoclax
BAK1MCL1 (score ~800)MCL1AZD5991 (Phase 1)
SPRY4BAK1→BCL2BCL2Venetoclax
GAB2PIK3R1→PIK3CAPIK3CAAlpelisib
DMRT1KITLG→KITKITImatinib, Sunitinib
GATA4YAP1→LATS1YAP1 pathwayEmerging
MAD1L1checkpoint→CDKsCDKsPalbociclib, Ribociclib
TFDP2E2F→CDK4/6CDK4/6Palbociclib
HNF1Bvia PI3KPI3KIdelalisib

Section 9: Structural Data

CategoryCountPercentage
PDB structures available2048%
AlphaFold only1229%
No structure data1023%

Proteins with extensive PDB coverage (drug design ready):

GeneUniProtPDB EntriesBest ResolutionLigand-bound?
KITP10721511.5 AYes (imatinib, sunitinib, avapritinib)
BAK1Q16611551.2 AYes (BH3 peptides)
PIK3CDO00329182.2 AYes (idelalisib, copanlisib)
TERTO14746232.3 AYes (substrate complexes)
FGFR3P22607131.4 AYes (erdafitinib-like)
HPGDSO60760301.1 AYes (multiple inhibitors)
PDE8AO60658101.9 AYes (IBMX, clofarabine)
UCK2Q9BZX2111.8 AYes (substrates/inhibitors)
STK11Q1583142.6 AYes (complex structures)
NEDD4P46934151.1 AYes (inhibitor complexes)
LATS1O9583541.6 ANo (complexes only)
CDKL2Q9277231.5 AYes (TCS 2312)
KATNA1O7544922.9 AYes (ATPgammaS)
LHPPQ9H00811.9 ANo

Undrugged targets with structural data:

GenePDB?AlphaFold?QualityDruggability Impact
DMRT1Yes (1)Yes (low pLDDT 57.8)ModerateDM domain structure known
GATA4Yes (3)Yes (low pLDDT 58.6)ModerateZinc-finger + nucleosome
DAZLNoYesModerateRRM domain modelable
SPRY4NoYes (low pLDDT 61.1)LowDisordered regions
MAD1L1NoYes (pLDDT 81.8)GoodCoiled-coil structure
HNF1BNoYes (pLDDT 61.9)LowHomeodomain flexible

Section 10: Drug Target Analysis

Summary:

CategoryCountPercentage
Total unique GWAS protein-coding genes42100%
With approved drugs (Phase 4)512%
With Phase 2-3 drugs410%
With preclinical compounds only921%
With NO drug development2457% (Opportunity Gap)

Genes with APPROVED drugs (from ChEMBL via MeSH + target mapping):

GeneProteinDrug NamesMechanismApproved for TGCT?
KIT*RTK receptorImatinib, Sunitinib, Dasatinib, Sorafenib, Ponatinib, Avapritinib, Axitinib, Tivozanib, Fedratinib, NiclosamideTKIN (GIST, CML, RCC)
FGFR3*RTK receptorErdafitinib, Infigratinib, Pemigatinib, FutibatinibFGFR inhibitorN (urothelial, cholangiocarcinoma)
PIK3CDPI3K deltaIdelalisib, Copanlisib, Duvelisib, UmbralisibPI3K inhibitorN (CLL, FL, SLL)
STK11*Ser/Thr kinaseNo direct inhibitors; compounds in complexKinaseN
PDE8APhosphodiesteraseIBMX (non-selective), Clofarabine (off-target)PDE inhibitorN

*Mendelian overlap genes

Drugs approved specifically FOR testicular cancer (from MeSH mapping):

DrugChEMBLTypePhaseTargets GWAS Gene?
CisplatinCHEMBL11359Alkylating agent4N (DNA damage)
EtoposideCHEMBL44657Topo II inhibitor4N
BleomycinCHEMBL6067492DNA cleavage4N
CarboplatinCHEMBL1351Alkylating agent4N
IfosfamideCHEMBL1024Alkylating agent4N
VinblastineCHEMBL159Tubulin inhibitor4N
PaclitaxelCHEMBL428647Tubulin stabilizer4N
GemcitabineCHEMBL888Antimetabolite4N

Critical Finding: NONE of the drugs approved for testicular cancer directly target GWAS-identified genes. Standard TGCT therapy (BEP: bleomycin, etoposide, cisplatin) is entirely cytotoxic/non-targeted.

Section 11: Bioactivity & Enzyme Data

Most-studied GWAS-related proteins (ChEMBL bioactivity):

ProteinChEMBL Target# Molecules (page 1)Drug-ready?
KITCHEMBL1936100+Yes - extensive SAR
PIK3CDCHEMBL3130100+Yes - multiple clinical
FGFR3CHEMBL2742100+Yes - approved drugs
BAK1CHEMBL560950+Moderate - PPI challenge
HPGDSCHEMBL587930+Yes - enzyme, crystal structures with inhibitors
PDE8ACHEMBL464010+Yes - PDE family tractable
UCK2CHEMBL246910+Yes - structures with inhibitors
CDKL2CHEMBL57285+Moderate - kinase domain
LATS1CHEMBL61675+Moderate - Hippo pathway
GPR160CHEMBL1777664FewLow - orphan GPCR

Enzyme GWAS genes (BRENDA-relevant):

GeneEnzyme ClassKnown InhibitorsDruggability
HPGDSEC 5.3 Isomerase (GST-type)HQL-79, multiple seriesHIGH - 30 PDB structures with inhibitors
PDE8AEC 3.1.4 PhosphodiesteraseIBMX (weak), dipyridamoleHIGH - PDE family well-validated
UCK2EC 2.7.1 KinaseUridine analogsMODERATE - nucleoside kinase
TKTL1EC 2.2.1 TransketolaseOxythiamine (weak)MODERATE - thiamine site
LHPPEC 3.1.3 PhosphataseNone reportedLOW - tumor suppressor
KATNA1EC 3.6.4 ATPaseNone specificLOW - difficult AAA+ ATPase

Section 12: Pharmacogenomics

PharmGKB Clinical Annotations for Testicular Neoplasms:

VariantGeneDrug InteractionTypeLevelPhenotype
GSTM1 nullGSTM1CisplatinToxicity3Ototoxicity
rs1045642ABCB1BEP regimenToxicity3Vomiting
rs1050565BLMHBEP regimenToxicity3Alopecia, Pain
rs11615ERCC1BEP regimenToxicity3Febrile neutropenia
rs13181ERCC2BEP regimenToxicity3Alopecia
rs1695GSTP1BEP regimenToxicity3Infection, Nausea
rs1695GSTP1CisplatinToxicity3Ototoxicity
rs1799793ERCC2BEP regimenToxicity3Anemia
rs238406ERCC2BEP regimenToxicity3Leukopenia
rs2740574CYP3A4BEP regimenToxicity3Alopecia
rs3212986ERCC1BEP regimenToxicity3Vomiting
rs2228001XPCCisplatinToxicity3Ototoxicity
rs4788863SLC16A5CisplatinToxicity3Ototoxicity
All GWAS genes have PharmGKB entries (VIP = true)Key Insight
KIT, STK11, FGFR3, BCL10, PIK3CD, TERT, KITLG, DMRT1, BAK1, HPGDS, PDE8A, GAB2, LATS1, CDKL2, GPR160
PharmGKB annotations for TGCT are exclusively toxicity-related (BEP regimen side effects), not efficacy. This reflects the absence of targeted therapy in TGCT treatment.

Section 13: Clinical Trials

Summary: 1,399+ clinical trials linked to testicular germ cell tumor (MONDO:0010108)

PhaseCount (sampled)Notes
Phase 426Mostly supportive care (antiemetics, growth factors)
Phase 372Chemotherapy regimen comparisons
Phase 2100+Salvage chemotherapy, novel agents
Phase 1/250+Dose-finding, combinations

TOP 30 Drugs in Trials:

Drug/RegimenPhaseMechanismTarget GeneGWAS Gene?
Cisplatin3-4DNA crosslinkerDNAN
Etoposide3-4Topo IITOP2AN
Bleomycin3-4DNA cleavageDNAN
Carboplatin3-4DNA crosslinkerDNAN
Paclitaxel2-3Tubulin stabilizerTubulinN
Ifosfamide3-4Alkylating agentDNAN
Gemcitabine2-3AntimetaboliteRNRN
Sunitinib2Multi-TKIKITY (indirect)
Docetaxel2-3Tubulin stabilizerTubulinN
Sorafenib3Multi-TKIKITY (indirect)
Bevacizumab2-4Anti-VEGFVEGFAN
Epoetin alfa2-4EPOEPORN
Filgrastim4G-CSFCSF3RN
Cyclophosphamide2-3AlkylatingDNAN
Methotrexate2AntifolateDHFRN
Oxaliplatin2DNA crosslinkerDNAN
Dasatinib1/2Multi-TKIKITY (indirect)
Temozolomide2AlkylatingDNAN
Cabazitaxel4Tubulin stabilizerTubulinN
Enzastaurin2PKC inhibitorPRKCBN
Afatinib2EGFR/HER2 TKIEGFRN
Arsenic trioxide2MultipleAPLN
Milademetan3MDM2 inhibitorMDM2N
Veliparib3PARP inhibitorPARP1N
Trastuzumab4Anti-HER2ERBB2N
Atezolizumab3Anti-PD-L1CD274N
Volasertib2PLK1 inhibitorPLK1N
Thalidomide2-3ImmunomodCRBNN
Vemurafenib4BRAF inhibitorBRAFN
Palonosetron45-HT3 antagonistHTR3AN

GWAS-trial alignment: Only 3/30 (10%) of top trial drugs target GWAS genes (sunitinib, sorafenib, dasatinib targeting KIT indirectly via KITLG association). This is a striking disconnect between genetic evidence and clinical development.

Section 14: Pathway Analysis

TOP 30 Pathways (Reactome) containing GWAS genes:

PathwayReactome IDGWAS GenesDruggable Nodes
Signaling by SCF-KITR-HSA-1433557KITLG, KIT*KIT (TKIs)
Regulation of KIT signalingR-HSA-1433559KITLG, KIT*KIT, CBL, SHP2
PIP3 activates AKT signalingR-HSA-1257604PIK3CD, KIT*, FGFR3*PI3K, AKT, mTOR
Constitutive PI3K in CancerR-HSA-2219530PIK3CD, KIT*, FGFR3*PI3K, AKT
RAF/MAP kinase cascadeR-HSA-5673001KIT*, FGFR3*RAF, MEK, ERK
Signaling by FGFR3R-HSA-5654706FGFR3*FGFR3, FRS2
FGFR3 in diseaseR-HSA-5655332FGFR3*FGFR3 (erdafitinib)
Testis differentiationR-HSA-9690406DMRT1, GATA4None (TFs)
Telomere extensionR-HSA-171319TERTTERT
Apoptosis - BAK activationR-HSA-111452BAK1BCL2 (venetoclax)
Release of apoptotic factorsR-HSA-111457BAK1BCL2, MCL1
Hippo - YAP/TAZR-HSA-2032785GATA4, LATS1LATS1, YAP
AMPK/LKB1/mTORR-HSA-380972STK11*AMPK, mTOR
TP53 regulationR-HSA-6804756STK11*MDM2 (milademetan)
Prostaglandin synthesisR-HSA-2162123HPGDSCOX, PGD synthase
G alpha (s) signallingR-HSA-418555PDE8APDE, GPCR
Glutathione conjugationR-HSA-156590HPGDSGST
B cell receptor signalingR-HSA-983695PIK3CDPI3K, BTK
CD28/PI3K/AKTR-HSA-389357PIK3CDPI3K, AKT
CardiogenesisR-HSA-9733709GATA4None
Wnt/beta-cateninR-HSA-201722TERTWnt pathway
IL-3/IL-5/GM-CSFR-HSA-512988PIK3CDJAK, PI3K
KIT mutant signalingR-HSA-9669933KIT*TKIs
Imatinib-resistant KITR-HSA-9669917KIT*Avapritinib, sunitinib
PyroptosisR-HSA-5620971BAK1Gasdermin
RET signalingR-HSA-8853334PIK3CDRET, PI3K
Autophagy regulationvia ATG14ATG14VPS34
FOXO transcriptionR-HSA-9614657STK11*AKT, FOXO
MITF regulationR-HSA-9856649KIT*MITF
MegakaryopoiesisR-HSA-983231GATA4TPO, JAK2

Pathway-level druggability insight: Even when the direct GWAS gene is undruggable (e.g., DMRT1), the pathways they participate in contain druggable nodes. The SCF-KIT→PI3K/AKT and MAPK cascades are the most therapeutically tractable pathways enriched in TGCT GWAS genes.

Section 15: Drug Repurposing Opportunities

TOP 30 Repurposing Candidates (prioritized by composite score):

RankDrugTarget GeneApproved ForMechanismBest GWAS p-valuePriority Score
1ImatinibKIT (via KITLG)CML, GISTTKI3e-12995
2SunitinibKIT (via KITLG)RCC, GISTMulti-TKI3e-12993
3AvapritinibKIT (via KITLG)GISTSelective KIT TKI3e-12992
4DasatinibKIT (via KITLG)CMLMulti-TKI3e-12990
5IdelalisibPIK3CDCLL, FLPI3Kd inhibitor6e-1382
6CopanlisibPIK3CDFLPI3K inhibitor6e-1380
7ErdafitinibFGFR3*Urothelial caFGFR inhibitorMendelian78
8VenetoclaxBCL2→BAK1CLL, AMLBCL2 inhibitor4e-3775
9SorafenibKIT (via KITLG)HCC, RCCMulti-kinase3e-12974
10PonatinibKIT (via KITLG)CMLMulti-TKI3e-12973
11PemigatinibFGFR3*CholangiocarcinomaFGFR inhibitorMendelian70
12FutibatinibFGFR3*CholangiocarcinomaFGFR inhibitorMendelian68
13DuvelisibPIK3CDCLL, FLPI3Kd/g inhibitor6e-1367
14AxitinibKIT (via KITLG)RCCVEGFR/KIT TKI3e-12965
15AlpelisibPIK3CA→GAB2Breast cancerPI3Ka inhibitor1e-1060
16MilademetanMDM2→TP53→STK11Phase 3 (TGCT)MDM2 inhibitorMendelian58
17PalbociclibCDK4/6→TFDP2Breast cancerCDK4/6 inhibitor2e-955
18NavitoclaxBCL-XL→BAK1Phase 2BCL2/XL inhibitor4e-3753
19TivozanibKIT (via KITLG)RCCVEGFR/KIT TKI3e-12952
20FedratinibKIT (via KITLG)MyelofibrosisJAK2/KIT TKI3e-12950
21HQL-79 analogsHPGDSPreclinicalHPGDS inhibitor3e-848
22DipyridamolePDE8A (partial)AntiplateletPDE inhibitor5e-845
23RibociclibCDK4/6→TFDP2Breast cancerCDK4/6 inhibitor2e-943
24ZandelisibPIK3CDPhase 3 (FL)PI3Kd inhibitor6e-1342
25RegorafenibKIT (via KITLG)CRC, GISTMulti-kinase3e-12940
26CrenolanibKIT (via KITLG)Phase 3 (AML)TKI3e-12938
27BezuclastinibKIT (via KITLG)Phase 3 (GIST)KIT inhibitor3e-12937
28GSK-3174998LATS1 pathwayPhase 1Hippo pathway2e-935
29InfigratinibFGFR3*CholangiocarcinomaFGFR inhibitorMendelian33
30ImetelstatTERTPhase 3 (MDS)Telomerase inh.9e-2530

Section 16: Druggability Pyramid

LevelDescriptionGene CountPercentageKey Genes
1 - VALIDATEDApproved drug FOR this disease00%None - all TGCT drugs are non-targeted
2 - REPURPOSINGApproved drug for OTHER disease512%KIT (via KITLG), PIK3CD, FGFR3, STK11, PDE8A
3 - EMERGINGDrug in clinical trials410%TERT (imetelstat), BAK1 (navitoclax), LATS1, CDKL2
4 - TOOL COMPOUNDSChEMBL compounds, no trials717%HPGDS, UCK2, GPR160, NEDD4, GATA4, PRDM14, KATNA1
5 - DRUGGABLEDruggable family, NO37%TKTL1, LHPP, SLC25A44
UNDRUGGEDcompounds
6 - HARD TARGETSDifficult family or unknown2355%DMRT1, HNF1B, GATA4, DAZL, SPRY4, ZFP42, MAD1L1, ZFPM1, TFDP2, PKNOX2, TFCP2L1, ZNF638, ZNF257, PITX1, ATF7IP, GAB2, CENPE, ZWILCH, TIPIN, NCAPG2, BMERB1, RESF1, SSR3

Section 17: Undrugged Target Profiles

TOP 30 Undrugged Opportunities (ranked by potential):

  1. HPGDS (Hematopoietic Prostaglandin D Synthase)
  • GWAS p-value: 3e-8 | Variant type: Regulatory
  • Protein function: Converts PGH2 to PGD2; GST superfamily enzyme
  • Family: Enzyme (GST/isomerase) - DRUGGABLE
  • Structure: 30 PDB entries, 1.1A resolution, multiple inhibitor co-crystals
  • Expression: Ubiquitous, expressed in immune cells
  • Interactions: Prostaglandin synthesis pathway
  • Why undrugged for cancer? Primarily studied in allergy/inflammation
  • Druggability potential: HIGH - extensive structural data, known chemical matter
  1. TKTL1 (Transketolase-like 1)
  • GWAS p-value: 4e-8 | Variant type: Regulatory
  • Protein function: Pentose phosphate pathway enzyme, cancer metabolism
  • Family: Enzyme (transketolase) - DRUGGABLE
  • Structure: AlphaFold (pLDDT 94.7), no PDB but template from TKT
  • Expression: X-linked, testis-enriched
  • Why undrugged? Cancer metabolism interest but no clinical compounds
  • Druggability potential: HIGH - thiamine-binding pocket, enzyme active site
  1. GPR160 (Orphan GPCR)
  • GWAS p-value: 4e-9 | Variant type: Regulatory
  • Protein function: Orphan GPCR, rhodopsin family
  • Family: GPCR - HIGHLY DRUGGABLE family
  • Structure: No PDB, no AlphaFold
  • Why undrugged? Orphan receptor, unknown ligand/function
  • Druggability potential: HIGH - GPCR family most druggable protein class
  1. PDE8A (Phosphodiesterase 8A)
  • GWAS p-value: 5e-8 | Variant type: Regulatory
  • Protein function: cAMP-specific phosphodiesterase
  • Family: Phosphodiesterase - DRUGGABLE
  • Structure: 10 PDB entries, inhibitor complexes
  • Why undrugged? PDE8A-selective inhibitors in development
  • Druggability potential: HIGH - PDE family well-validated, structures available
  1. LHPP (Phospholysine Phosphohistidine Phosphatase)
  • GWAS p-value: 2e-8 | Variant type: Regulatory
  • Protein function: Histidine phosphatase, tumor suppressor
  • Family: HAD phosphatase - DRUGGABLE
  • Structure: 1 PDB (1.9A), AlphaFold (pLDDT 97.2)
  • Why undrugged? Recently identified tumor suppressor
  • Druggability potential: MODERATE - activator needed (tumor suppressor)
  1. UCK2 (Uridine-Cytidine Kinase 2)
  • GWAS p-value: 2e-14 | Variant type: Splice/UTR
  • Protein function: Pyrimidine metabolism, nucleoside phosphorylation
  • Family: Nucleoside kinase - DRUGGABLE
  • Structure: 11 PDB entries, substrate/inhibitor complexes
  • Expression: Ubiquitous
  • Why undrugged? Pyrimidine metabolism target, prodrug activation
  • Druggability potential: HIGH - structures with ligands, clear active site
  1. CDKL2 (Cyclin-Dependent Kinase-Like 2)
  • GWAS p-value: 2e-11 | Variant type: Regulatory
  • Protein function: Kinase, poorly characterized
  • Family: CDK-like kinase - DRUGGABLE
  • Structure: 3 PDB entries (1.5A), inhibitor co-crystal
  • Why undrugged? Unknown substrates/biology
  • Druggability potential: HIGH - kinase domain, crystal structure with inhibitor
  1. KATNA1 (Katanin p60 ATPase)
  • GWAS p-value: 2e-9 (KATNA1-LATS1 locus)
  • Protein function: Microtubule-severing AAA+ ATPase
  • Family: ATPase - MODERATELY DRUGGABLE
  • Structure: 2 PDB entries
  • Why undrugged? Challenging ATPase family
  • Druggability potential: MODERATE
  1. LATS1 (Large Tumor Suppressor Kinase 1)
  • GWAS p-value: 2e-9 | Variant type: Regulatory
  • Protein function: Hippo pathway kinase, phosphorylates YAP1
  • Family: Ser/Thr kinase (AGC) - DRUGGABLE
  • Structure: 4 PDB entries
  • Why undrugged? Tumor suppressor - would need activation
  • Druggability potential: MODERATE - kinase but tumor suppressor
  1. NEDD4 (E3 Ubiquitin Ligase)
  • GWAS p-value: 1e-11 (PRTG-NEDD4 locus)
  • Protein function: E3 ubiquitin ligase, HECT domain
  • Family: HECT E3 ligase - EMERGING DRUGGABLE
  • Structure: 15 PDB entries, inhibitor co-crystals
  • Why undrugged? E3 ligase targeting emerging
  • Druggability potential: MODERATE-HIGH - structural data, tool compounds
  1. SLC25A44 (Mitochondrial BCAA Transporter)
  • GWAS p-value: 2e-10
  • Family: Solute carrier/transporter - MODERATE
  • Structure: AlphaFold only
  • Druggability potential: MODERATE - transporter family
  1. DMRT1 (Sex Determination TF)
  • GWAS p-value: 2e-45 (3rd strongest locus)
  • Protein function: Master regulator of testis development/germ cell differentiation
  • Family: DM-domain TF - DIFFICULT
  • Structure: 1 PDB (DM domain), AlphaFold
  • Interactions: KIT pathway (score 685 with KITLG)
  • Why undrugged? Transcription factor - protein-DNA interface
  • Druggability potential: LOW but highest biological relevance

13-30. Additional undrugged targets

RankGenep-valueFamilyStructurePotential
13RFWD37e-12E3 ligase (RING)AlphaFoldMODERATE
14CENPE7e-20Kinesin motorAlphaFoldMODERATE
15GATA44e-8GATA TFPDB (3)LOW
16DAZL1e-9RNA-bindingAlphaFoldLOW
17MAD1L16e-13CheckpointAlphaFoldLOW
18SPRY43e-57SproutyAlphaFoldLOW
19HNF1B3e-20Homeodomain TFAlphaFoldLOW
20PRDM145e-8SET domain TFAlphaFoldLOW
21ZFP422e-12Zinc finger TFNoneLOW
22ZFPM13e-9FOG TFNoneLOW
23TFDP22e-9DP TFNoneLOW
24PKNOX22e-12Homeobox TFNoneLOW
25ATF7IP9e-13ChromatinNoneLOW
26GAB21e-10ScaffoldNoneLOW
27TIPIN1e-10ReplicationNoneLOW
28ZWILCH8e-13KinetochoreNoneLOW
29ZNF6382e-11Zinc fingerNoneLOW
30PITX19e-6Homeodomain TFNoneLOW

Section 18: Summary

GWAS LANDSCAPE

  • Total associations: 94 across 7 studies
  • Unique gene loci: ~50
  • Coding vs non-coding: ~3% coding / 97% non-coding
  • Strongest locus: KITLG (p=3e-129) - one of the strongest GWAS signals for any cancer

GENETIC EVIDENCE

  • Tier 1 (coding) genes: 2
  • Mendelian overlap genes: 4 (KIT, STK11, FGFR3, BCL10)
  • Both GWAS + Mendelian: 1 (KIT via KITLG)

DRUGGABILITY

  • Overall rate: 45% have some drug/compound coverage
  • Approved drugs for TGCT targeting GWAS genes: 0% (critical gap)
  • Approved drugs for OTHER diseases: 12%
  • Clinical trials: 10%
  • Opportunity gap (no drug development): 57%

PYRAMID SUMMARY

LevelCount%
1 - Validated00%
2 - Repurposing512%
3 - Emerging410%
4 - Tool compounds717%
5 - Druggable undrugged37%
6 - Hard targets2355%

CLINICAL TRIAL ALIGNMENT

  • 10% of trial drugs target GWAS genes (sunitinib, sorafenib, dasatinib targeting KIT)
  • SEVERE DISCONNECT: TGCT therapy is entirely cytotoxic with no genetically-informed targeted agents

TOP 10 REPURPOSING CANDIDATES

DrugGeneApproved Forp-valueScore
ImatinibKIT (via KITLG)CML, GIST3e-12995
SunitinibKIT (via KITLG)RCC, GIST3e-12993
AvapritinibKIT (via KITLG)GIST3e-12992
DasatinibKIT (via KITLG)CML3e-12990
IdelalisibPIK3CDCLL, FL6e-1382
CopanlisibPIK3CDFL6e-1380
ErdafitinibFGFR3Urothelial caMendelian78
VenetoclaxBCL2→BAK1CLL, AML4e-3775
SorafenibKIT (via KITLG)HCC, RCC3e-12974
PonatinibKIT (via KITLG)CML3e-12973

TOP 10 UNDRUGGED OPPORTUNITIES

Genep-valueFamilyStructurePotential
HPGDS3e-8Enzyme (GST)30 PDBHIGH
TKTL14e-8Enzyme (TK)AlphaFoldHIGH
GPR1604e-9GPCRNoneHIGH
PDE8A5e-8Phosphodiesterase10 PDBHIGH
UCK22e-14Nucleoside kinase11 PDBHIGH
CDKL22e-11CDK-like kinase3 PDBHIGH
NEDD41e-11HECT E3 ligase15 PDBMODERATE-HIGH
SLC25A442e-10TransporterAlphaFoldMODERATE
KATNA12e-9AAA+ ATPase2 PDBMODERATE
LHPP2e-8Phosphatase1 PDBMODERATE

TOP 10 INDIRECT OPPORTUNITIES

Undrugged GeneDrugged InteractorDrug
KITLGKITImatinib, Sunitinib, Avapritinib
BAK1BCL2Venetoclax
SPRY4MAPK pathwayMEK inhibitors
GAB2PI3KAlpelisib
TFDP2CDK4/6Palbociclib, Ribociclib
DMRT1KIT (via KITLG)KIT inhibitors
MAD1L1CDK1/2CDK inhibitors
GATA4YAP1/LATS1Hippo pathway agents
HNF1BPI3K pathwayPI3K inhibitors
CENPEAurora kinasesAlisertib

KEY INSIGHTS

  1. KITLG-KIT axis is the dominant genetic signal - KITLG at p=3e-129 is one of the most significant GWAS associations for any cancer. KIT inhibitors (imatinib, sunitinib, avapritinib) are the most genetically-supported repurposing candidates.

  2. Complete absence of targeted therapy - Unlike most cancers, TGCT has NO approved drugs targeting GWAS genes. The BEP regimen has been standard-of-care since the 1970s-80s with no genetically-informed additions.

  3. Germ cell biology genes dominate - DMRT1, DAZL, ZFP42, PRDM14, KITLG are all critical for germ cell development/pluripotency. Most are transcription factors (hard to drug), explaining the historical gap.

  4. PI3K pathway is the most tractable druggable pathway - PIK3CD has direct GWAS evidence (p=6e-13), approved inhibitors (idelalisib), and sits at the nexus of KIT and FGFR3 signaling.

  5. HPGDS is a hidden gem - 30 PDB structures with inhibitors, clear enzymatic activity, GWAS evidence, yet unstudied in TGCT. Prostaglandin D2 may play a role in germ cell tumor biology.

  6. High transcription factor burden - 55% of GWAS genes encode hard-to-drug proteins (TFs, scaffolds). This disease has one of the highest TF percentages among cancers, reflecting germ cell developmental biology.

7. X-linked TKTL1 - The only X-linked locus, encoding a pentose phosphate pathway enzyme linked to cancer metabolism. Particularly relevant for a male-specific cancer.

  1. Sunitinib has been tested - NCT00453310 was a Phase 2 trial of sunitinib in relapsed TGCT. Results were modest, but this was in heavily pretreated patients. Earlier-line KIT-targeted therapy warrants investigation.

  2. Comparison with other cancers - TGCT has a much wider “opportunity gap” (57% no drug development) than breast cancer (~30%) or CRC (~35%), reflecting its rarity and high cure rate with chemotherapy.

  3. PharmGKB data is entirely toxicity-focused - All 13 clinical annotations relate to BEP regimen side effects, not efficacy. This further underscores the field’s reliance on non-targeted therapy.