Abstract
<jats:p>Purpose: Host germline genetic variation as a determinant of tumor drug response remains underexplored. We evaluated whether EPAS1 (HIF-2α) adaptive loss-of-function variants, enriched in high-altitude-adapted populations, predispose HCC to primary antiangiogenic TKI resistance through a HIF-2α/STC2 signaling axis, with implications for TKI selection and belzutifan combination strategies. Experimental Design: We integrated eight data sources: QHRCH-HCC cohort (n = 1,396), iPSC-EC transcriptomes (GSE160906), TCGA pan-cancer, GDSC2 pharmacogenomics (n = 951; 11 TKIs), DepMap, CPTAC proteomics, ICGC LIRI-JP, and HPA single-cell data. Bayesian integration employed the ENIPE method (δ = 0.504). Results: Altitude correlated with PIVKA-II (ρ = +0.244, p = 0.0003) and AESI_score (ρ = +0.517; AUC = 0.921 for high-altitude prediction). iPSC-EC EPAS1 expression ↓38.6% (p = 0.0006) with STC2 preservation (89.2%). TCGA-LIHC negative control (EPAS1→STC2 ρ = 0.092 vs. HIF1A→STC2 ρ = 0.379) was independently validated in ICGC LIRI-JP (ρ = −0.051). ccRCC positive control: ρ = 0.320 (p = 3.47x10⁻1⁴). GDSC2: 11/11 TKI directional consistency (sign test p = 0.0005; Q4 vs Q1 FC = 1.129). STC2-high predicted worse OS (HR = 1.711, p = 0.0028); EPAS1 (HR = 0.777) and STC2 (HR = 1.130) were independent prognostic factors. EPAS1 methylation correlated with silencing (ρ = −0.117, p = 0.025). Bayesian posterior: 0.994 (Log10BF = 2.23, Decisive). Conclusions: EPAS1 LoF represents a germline determinant of TKI response, independent of tumor-acquired alterations. The AESI_score and HIF-2α inhibitor belzutifan constitute a predictive biomarker-therapeutic pair for genotype-stratified clinical validation. Prospective EPAS1 genotype-stratified validation (2023-ZJ-786) is designed to test this hypothesis in high-altitude HCC.</jats:p>