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 integrates five independent data sources, including the QHRCH-HCC retrospective cohort (n=1,396) and multi-ancestry iPSC-derived endothelial cell transcriptome data (GSE1609...). It proposes that host germline EPAS1 variants—adaptive in high-altitude populations—act as pharmacogenomic determinants of antiangiogenic TKI resistance in HCC. The mechanistic hypothesis implicates reduced HIF-2 function leading to altered STC2 signaling, which may impair tumor vascular response to TKIs. If validated, these findings could inform personalized treatment strategies for HCC patients of high-altitude ancestry and highlight the role of host genetics in tumor drug response.