EPAS1 Adaptive Loss-of-Function Variants as Germline Determinants of Primary Antiangiogenic TKI Resistance in High-Altitude Hepatocellular Carcinoma: A Translational Pharmacogenomic Study

The study investigated whether EPAS1 (HIF-2) gene variants enriched in high-altitude-adapted populations determine hepatocellular carcinoma resistance to antiangiogenic drugs. The research included 1,396 patients from the QHRCH-HCC cohort and data from multiple databases including TCGA and GDSC2. Results showed that altitude positively correlated with PIVKA-II levels (p = 0.0003) and with a high-altitude adaptation genetic score (p = 5.59×10⁻⁴⁹). Under hypoxia, EPAS1 expression in high-altitude-adapted cells was reduced to 61.4% compared to controls (p = 0.0006). In the GDSC2 database, EPAS1 positively correlated with resistance to all 11 tested antiangiogenic TKIs (p = 0.0005). Bayesian analysis showed a posterior probability of 0.970. The study suggests that EPAS1 variants represent a germline determinant of TKI resistance independent of tumor-acquired mutations.