EPAS1 Adaptive Loss-of-Function Variants as Germline Determinants of Primary Antiangiogenic TKI Resistance in High-Altitude Hepatocellular Carcinoma

PurposeHost germline genetic variation as a determinant of tumor drug response remains underexplored. We evaluated whether EPAS1 (HIF-2) adaptive loss-of-function variants, enriched in high-altitude-adapted populations, predispose HCC to primary antiangiogenic TKI resistance through a HIF-2/STC2 signaling axis, with implications for TKI selection and belzutifan combination strategies. Experimental DesignWe 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 ({delta} = 0.504). ResultsAltitude correlated with PIVKA-II ({rho} = +0.244, p = 0.0003) and AESI_score ({rho} = +0.517; AUC = 0.921 for high-altitude prediction). iPSC-EC EPAS1 expression {downarrow}38.6% (p = 0.0006) with STC2 preservation (89.2%). TCGA- LIHC negative control (EPAS1[->]STC2 {rho} = 0.092 vs. HIF1A[->]STC2 {rho} = 0.379) was independently validated in ICGC LIRI-JP ({rho} = -0.051). ccRCC positive control: {rho} = 0.320 (p = 3.47x10-{superscript 1}). 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 ({rho} = -0.117, p = 0.025). Bayesian posterior: 0.994 (Log10BF = 2.23, Decisive). ConclusionsEPAS1 LoF represents a germline determinant of TKI response, independent of tumor-acquired alterations. The AESI_score and HIF-2 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.