{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T12:12:44Z","timestamp":1788351164430,"version":"build-2803163510"},"reference-count":39,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"unspecified","delay-in-days":28,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"DFG","award":["DFG LU2185\/2-1"],"award-info":[{"award-number":["DFG LU2185\/2-1"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["egastro"],"accepted":{"date-parts":[[2026,4,15]]},"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cholangiocarcinoma (CCA) is a rare cancer, with limited understanding of genetic and prognostic determinants. We aimed to explore genetic risk factors, assess their prognostic implications and evaluate associated systemic and intratumoral features.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We screened the UK Biobank to identify single-nucleotide polymorphisms (SNPs) potentially associated with intrahepatic CCA (International Classification of Diseases, 10th Revision (ICD-10) code: C22.1). Candidate SNPs were genotyped in a real-life cohort of 221 patients undergoing liver resection for intrahepatic or perihilar CCA at Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin. Intratumoral gene expression and pathway co-expression were examined. Serum proteomic profiles were evaluated in patients with intrahepatic CCA and the overall population.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In exploratory analyses, the telomerase reverse transcriptase\n                      <jats:italic>(TERT)<\/jats:italic>\n                      rs10069690 T allele was associated with a reduced risk of intrahepatic CCA (T allele vs C\/C homozygotes: adjusted OR 0.824 (95% CI 0.713 to 0.951), p=0.008). However, T allele carriers undergoing liver resection for CCA had independently shorter overall survival (OS) compared with C\/C homozygotes (median OS 21 (17\u201325) months vs 31 (24\u201338) months, p=0.034, HR 1.427 (1.023\u20131.991)). In serum proteomic analyses of the general population, presence of the T allele was associated with differences in immune-related pathways, including signatures consistent with increased lymphocyte differentiation and reduced NK-cell-mediated cytotoxicity. In intrahepatic CCA tumours, higher\n                      <jats:italic>TERT<\/jats:italic>\n                      mRNA expression was positively correlated with gene expression patterns consistent with increased cell cycle activity and regulatory T cell signatures, and negatively associated with pathways of cell differentiation, adhesion and immune effector function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These exploratory, hypothesis-generating findings suggest that the\n                      <jats:italic>TERT<\/jats:italic>\n                      rs10069690 variant may be associated with intrahepatic CCA risk and clinical outcomes, as well as with immune-related and proliferative pathways. The observed context-dependent associations warrant independent validation and further functional investigation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/egastro-2025-100320","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T16:05:15Z","timestamp":1780070715000},"page":"e100320","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["<i>TERT<\/i>\n                    rs10069690 variant is linked to reduced cholangiocarcinoma incidence but adverse prognosis in patients undergoing resection"],"prefix":"10.1136","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4006-7707","authenticated-orcid":false,"given":"Isabella","family":"Lurje","sequence":"first","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Charit\u00e9 - Universit\u00e4tsmedizin Berlin, Berlin, Germany"},{"name":"Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justus","family":"Pein","sequence":"additional","affiliation":[{"name":"Department of Surgery, Charit\u00e9 - Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8755-7703","authenticated-orcid":false,"given":"Paul","family":"Horn","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Charit\u00e9 - Universit\u00e4tsmedizin Berlin, Berlin, Germany"},{"name":"Berlin Institute of Health at Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charit\u00e9 Digital Clinician Scientist Program, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deniz","family":"Uluk","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlene","family":"Kohlhepp","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Charit\u00e9 - Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minh Duc","family":"Phan","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Charit\u00e9 - Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia","family":"Niklisch","sequence":"additional","affiliation":[{"name":"Department of Surgery, Charit\u00e9 - Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"Schliephake","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany"},{"name":"Department of Surgery, Charit\u00e9 - Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niharika","family":"Jakhar","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai Markus","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany"},{"name":"Department of Medicine I, University Hospital Carl-Gustav-Carus Dresden, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Ro\u00dfner","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Charit\u00e9 - Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Horst","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Charit\u00e9 - Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johann","family":"Pratschke","sequence":"additional","affiliation":[{"name":"Department of Surgery, Charit\u00e9 - Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6206-0226","authenticated-orcid":false,"given":"Frank","family":"Tacke","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Charit\u00e9 - Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6728-9246","authenticated-orcid":false,"given":"Carolin Victoria","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Lurje","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Charit\u00e9 - Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"2026090204151091000_4.2.e100320.1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1111\/liv.14095","article-title":"Cholangiocarcinoma: Epidemiology and risk factors","volume":"39 Suppl 1","author":"Khan","year":"2019","journal-title":"Liver Int"},{"key":"2026090204151091000_4.2.e100320.2","doi-asserted-by":"crossref","DOI":"10.1136\/egastro-2023-100045","article-title":"Treatment of cholangiocarcinoma in patients with primary sclerosing cholangitis: a comprehensive review","volume":"2","author":"Villard","year":"2024","journal-title":"eGastroenterology"},{"key":"2026090204151091000_4.2.e100320.3","doi-asserted-by":"crossref","DOI":"10.1016\/j.lanepe.2024.101171","article-title":"Mapping the landscape of biliary tract cancer in Europe: challenges and controversies","volume":"50","author":"Rimassa","year":"2025","journal-title":"Lancet Reg Health Eur"},{"key":"2026090204151091000_4.2.e100320.4","doi-asserted-by":"crossref","first-page":"3954","DOI":"10.1097\/JS9.0000000000000711","article-title":"Outcomes of elective liver surgery worldwide: a global, prospective, multicenter, cross-sectional study","volume":"109","author":"TLo","year":"2023","journal-title":"Int J Surg"},{"key":"2026090204151091000_4.2.e100320.5","doi-asserted-by":"publisher","DOI":"10.1097\/SLA.0000000000005103"},{"key":"2026090204151091000_4.2.e100320.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2023.03.010"},{"key":"2026090204151091000_4.2.e100320.7","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2022-327099"},{"key":"2026090204151091000_4.2.e100320.8","doi-asserted-by":"crossref","DOI":"10.1111\/liv.16106","article-title":"PNPLA3 I148M Interacts With Environmental Triggers to Cause Human Disease","volume":"45","author":"Speliotes","year":"2025","journal-title":"Liver Int"},{"key":"2026090204151091000_4.2.e100320.9","doi-asserted-by":"crossref","DOI":"10.3390\/cancers12123826","article-title":"Impact of Angiogenesis- and Hypoxia-Associated Polymorphisms on Tumor Recurrence in Patients with Hepatocellular Carcinoma Undergoing Surgical Resection","volume":"12","author":"Miller","year":"2020","journal-title":"Cancers (Basel)"},{"key":"2026090204151091000_4.2.e100320.10","doi-asserted-by":"crossref","DOI":"10.3390\/cancers14041026","article-title":"Prognostic and Predictive Molecular Markers in Cholangiocarcinoma","volume":"14","author":"Pavicevic","year":"2022","journal-title":"Cancers (Basel)"},{"key":"2026090204151091000_4.2.e100320.11","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/s41419-024-06454-7","article-title":"The regulations of telomerase reverse transcriptase (TERT) in cancer","volume":"15","author":"Liu","year":"2024","journal-title":"Cell Death Dis"},{"key":"2026090204151091000_4.2.e100320.12","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-025-56947-y","article-title":"Genetic regulation of TERT splicing affects cancer risk by altering cellular longevity and replicative potential","volume":"16","author":"Florez-Vargas","year":"2025","journal-title":"Nat Commun"},{"key":"2026090204151091000_4.2.e100320.13","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2566"},{"key":"2026090204151091000_4.2.e100320.14","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1005286","article-title":"A Common Cancer Risk-Associated Allele in the hTERT Locus Encodes a Dominant Negative Inhibitor of Telomerase","volume":"11","author":"Killedar","year":"2015","journal-title":"PLoS Genet"},{"key":"2026090204151091000_4.2.e100320.15","doi-asserted-by":"crossref","first-page":"17569","DOI":"10.1002\/cam4.6374","article-title":"Body composition is associated with disease aetiology and prognosis in patients undergoing resection of intrahepatic cholangiocarcinoma","volume":"12","author":"Lurje","year":"2023","journal-title":"Cancer Med"},{"key":"2026090204151091000_4.2.e100320.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.12.006"},{"key":"2026090204151091000_4.2.e100320.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-024-01020-z"},{"key":"2026090204151091000_4.2.e100320.18","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0013984","article-title":"Enrichment map: a network-based method for gene-set enrichment visualization and interpretation","volume":"5","author":"Merico","year":"2010","journal-title":"PLoS One"},{"key":"2026090204151091000_4.2.e100320.19","doi-asserted-by":"crossref","DOI":"10.12688\/f1000research.9090.1","article-title":"AutoAnnotate: A Cytoscape app for summarizing networks with semantic annotations [version 1; peer review: 2 approved]","volume":"5","author":"Kucera","year":"2016","journal-title":"F1000Res"},{"key":"2026090204151091000_4.2.e100320.20","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v098.i14"},{"key":"2026090204151091000_4.2.e100320.21","doi-asserted-by":"crossref","DOI":"10.1002\/cpz1.90","article-title":"Gene Set Knowledge Discovery with Enrichr","volume":"1","author":"Xie","year":"2021","journal-title":"Curr Protoc"},{"key":"2026090204151091000_4.2.e100320.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-019-0099-1"},{"key":"2026090204151091000_4.2.e100320.23","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07700-w"},{"key":"2026090204151091000_4.2.e100320.24","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-16-0062"},{"key":"2026090204151091000_4.2.e100320.25","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1038\/s43587-021-00146-z","article-title":"Telomerase Reverse Transcriptase Preserves Neuron Survival and Cognition in Alzheimer\u2019s Disease Models","volume":"1","author":"Shim","year":"2021","journal-title":"Nat Aging"},{"key":"2026090204151091000_4.2.e100320.26","doi-asserted-by":"publisher","DOI":"10.1172\/JCI79134"},{"key":"2026090204151091000_4.2.e100320.27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2020.07.003","article-title":"TERT promoter mutations and GABP transcription factors in carcinogenesis: More foes than friends","volume":"493","author":"Yuan","year":"2020","journal-title":"Cancer Lett"},{"key":"2026090204151091000_4.2.e100320.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmoldx.2020.11.003"},{"key":"2026090204151091000_4.2.e100320.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinre.2015.07.006"},{"key":"2026090204151091000_4.2.e100320.30","doi-asserted-by":"crossref","DOI":"10.1002\/mgg3.903","article-title":"TERT rs10069690 polymorphism and cancers risk: A meta-analysis","volume":"7","author":"He","year":"2019","journal-title":"Mol Genet Genomic Med"},{"key":"2026090204151091000_4.2.e100320.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0004-7"},{"key":"2026090204151091000_4.2.e100320.32","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.3390\/cancers15102673","article-title":"Short-Term TERT Inhibition Impairs Cellular Proliferation via a Telomere Length-Independent Mechanism and Can Be Exploited as a Potential Anticancer Approach","volume":"15","author":"Amin","year":"2023","journal-title":"Cancers (Basel)"},{"key":"2026090204151091000_4.2.e100320.33","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-020-20474-9","article-title":"Integrated analysis of telomerase enzymatic activity unravels an association with cancer stemness and proliferation","volume":"12","author":"Noureen","year":"2021","journal-title":"Nat Commun"},{"key":"2026090204151091000_4.2.e100320.34","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1055\/a-2334-8311","article-title":"Overcoming Resistance to Immune Checkpoint Blockade in Liver Cancer with Combination Therapy: Stronger Together?","volume":"44","author":"Werner","year":"2024","journal-title":"Semin Liver Dis"},{"key":"2026090204151091000_4.2.e100320.35","doi-asserted-by":"crossref","DOI":"10.1136\/egastro-2025-100257","article-title":"Regulatory T cells in liver metastases: emerging and divergent roles in tumour progression","volume":"3","author":"Wu","year":"2025","journal-title":"eGastroenterology"},{"key":"2026090204151091000_4.2.e100320.36","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1159\/000521613","article-title":"Genetic Variant of CXCR1 (rs2234671) Associates with Clinical Outcome in Perihilar Cholangiocarcinoma","volume":"11","author":"Lurje","year":"2022","journal-title":"Liver Cancer"},{"key":"2026090204151091000_4.2.e100320.37","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-023-39487-7","article-title":"Genetic polymorphisms in interleukin-1\u03b2 (rs1143634) and interleukin-8 (rs4073) are associated with survival after resection of intrahepatic cholangiocarcinoma","volume":"13","author":"Lurje","year":"2023","journal-title":"Sci Rep"},{"key":"2026090204151091000_4.2.e100320.38","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-00757-z"},{"key":"2026090204151091000_4.2.e100320.39","doi-asserted-by":"crossref","DOI":"10.1016\/j.jhepr.2025.101485","article-title":"Genome-wide meta-analysis identifies nine loci associated with higher risk of hepatocellular carcinoma development","volume":"7","author":"Ghouse","year":"2025","journal-title":"JHEP Rep"}],"container-title":["eGastroenterology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/egastro-2025-100320","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T11:15:22Z","timestamp":1788347722000},"score":1,"resource":{"primary":{"URL":"http:\/\/egastroenterology.bmj.com\/lookup\/doi\/10.1136\/egastro-2025-100320"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5]]},"references-count":39,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,5,29]]},"published-print":{"date-parts":[[2026,5]]}},"alternative-id":["10.1136\/egastro-2025-100320"],"URL":"https:\/\/doi.org\/10.1136\/egastro-2025-100320","relation":{},"ISSN":["2766-0125","2976-7296"],"issn-type":[{"value":"2766-0125","type":"print"},{"value":"2976-7296","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5]]}}}