{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T04:45:33Z","timestamp":1791780333541,"version":"4.3.4"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>\n                      To investigate the impact of\n                      <jats:italic toggle=\"yes\">VEGFA<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">EGF<\/jats:italic>\n                      genetic polymorphisms on postoperative survival, susceptibility, transcriptomics, and systemic proteomic regulation in cholangiocarcinoma (CCA).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Angiogenesis and growth factor signaling via vascular endothelial growth factor A (VEGFA) and epidermal growth factor (EGF) are key drivers of CCA biology, yet the clinical relevance of their genetic variants remains poorly defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      A cohort of 221 patients undergoing curative-intent CCA resection at Charit\u00e9-Berlin was analyzed. Patients were genotyped for 6 angiogenesis-related SNPs, including\n                      <jats:italic toggle=\"yes\">VEGFA<\/jats:italic>\n                      rs3025039 and\n                      <jats:italic toggle=\"yes\">EGF<\/jats:italic>\n                      rs4444903, and survival associations were assessed using Cox regression. The prognostic relevance of intratumoral\n                      <jats:italic toggle=\"yes\">VEGFA<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">EGF<\/jats:italic>\n                      mRNA expression and pathway co-expression was evaluated in an independent transcriptomic cohort. Population-level associations with CCA susceptibility and serum proteomics were analyzed in the UK Biobank (n&gt;500,000).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic toggle=\"yes\">VEGFA<\/jats:italic>\n                      rs3025039 T allele was associated with improved cancer-specific survival, particularly in intrahepatic CCA, while the\n                      <jats:italic toggle=\"yes\">EGF<\/jats:italic>\n                      rs4444903 G allele was linked to improved survival in perihilar CCA. High intratumoral\n                      <jats:italic toggle=\"yes\">VEGFA<\/jats:italic>\n                      or\n                      <jats:italic toggle=\"yes\">EGF<\/jats:italic>\n                      expression correlated with poorer survival in external validation, but this association was lost for\n                      <jats:italic toggle=\"yes\">EGF<\/jats:italic>\n                      after multivariable adjustment.\n                      <jats:italic toggle=\"yes\">VEGFA<\/jats:italic>\n                      -high tumors showed increased proliferative and suppressed immune transcriptional signatures, whereas\n                      <jats:italic toggle=\"yes\">EGF<\/jats:italic>\n                      -high tumors displayed limited changes. UK Biobank analysis revealed increased intrahepatic CCA susceptibility among\n                      <jats:italic toggle=\"yes\">VEGFA<\/jats:italic>\n                      T allele carriers, while the\n                      <jats:italic toggle=\"yes\">EGF<\/jats:italic>\n                      G allele was associated with elevated circulating EGF levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">VEGFA<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">EGF<\/jats:italic>\n                      polymorphisms exert distinct effects on CCA, influencing disease susceptibility, postoperative outcomes, and systemic signaling, supporting their potential as biomarkers for clinical stratification.\n                    <\/jats:p>\n                  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