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Clinical relevance of biomarkers in cholangiocarcinoma: critical revision and future directions
  1. Rocio I R Macias1,2,
  2. Vincenzo Cardinale3,
  3. Timothy J Kendall4,
  4. Matias A Avila2,5,
  5. Maria Guido6,
  6. Cedric Coulouarn7,
  7. Chiara Braconi8,
  8. Adam E Frampton9,
  9. John Bridgewater10,
  10. Diletta Overi11,
  11. Stephen P Pereira12,
  12. Marco Rengo13,
  13. Jakob N Kather14,
  14. Angela Lamarca15,
  15. Federica Pedica16,
  16. Alejandro Forner2,17,
  17. Juan W Valle15,
  18. Eugenio Gaudio11,
  19. Domenico Alvaro18,
  20. Jesus M Banales2,19,20,
  21. Guido Carpino21
  1. 1 Experimental Hepatology and Drug Targeting (HEVEPHARM) group, University of Salamanca, IBSAL, Salamanca, Spain
  2. 2 Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
  3. 3 Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
  4. 4 Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
  5. 5 Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
  6. 6 Department of Medicine - DIMED, University of Padua, Padua, Italy
  7. 7 UMR_S 1242, COSS, Centre de Lutte contre le Cancer Eugène Marquis, INSERM University of Rennes 1, Rennes, France
  8. 8 Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
  9. 9 Department of Clinical and Experimental Medicine, University of Surrey, Guildford, Surrey, UK
  10. 10 Department of Medical Oncology, UCL Cancer Institute, London, UK
  11. 11 Department of Anatomical, Histological, Forensic Medicine and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy
  12. 12 Institute for Liver & Digestive Health, University College London, London, UK
  13. 13 Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Rome, Italy
  14. 14 Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
  15. 15 Medical Oncology/Institute of Cancer Sciences, The Christie NHS Foundation Trust/University of Manchester, Manchester, UK
  16. 16 Department of Pathology, San Raffaele Scientific Institute, Milan, Italy
  17. 17 BCLC group, Liver Unit, Hospital Clínic Barcelona. IDIBAPS, University of Barcelona, Barcelona, Spain
  18. 18 Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
  19. 19 Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, San Sebastian, Spain
  20. 20 Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
  21. 21 Department of Movement, Human and Health Sciences, University of Rome 'Foro Italico', Rome, Italy
  1. Correspondence to Prof Guido Carpino, Department of Movement, Human and Health Sciences, University of Rome 'Foro Italico', Rome 00135, Italy; guido.carpino{at}


Cholangiocarcinoma (CCA) is a malignant tumour arising from the biliary system. In Europe, this tumour frequently presents as a sporadic cancer in patients without defined risk factors and is usually diagnosed at advanced stages with a consequent poor prognosis. Therefore, the identification of biomarkers represents an utmost need for patients with CCA. Numerous studies proposed a wide spectrum of biomarkers at tissue and molecular levels. With the present paper, a multidisciplinary group of experts within the European Network for the Study of Cholangiocarcinoma discusses the clinical role of tissue biomarkers and provides a selection based on their current relevance and potential applications in the framework of CCA. Recent advances are proposed by dividing biomarkers based on their potential role in diagnosis, prognosis and therapy response. Limitations of current biomarkers are also identified, together with specific promising areas (ie, artificial intelligence, patient-derived organoids, targeted therapy) where research should be focused to develop future biomarkers.


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  • Contributors RIRM, VC, GC: concept and design, drafting of the manuscript, figure preparation/design, and critical revisions of the manuscript, and study supervision. TK, MG, MA, CC, CB, AF, JB, SPP, JNK, AL, FP, AF, JMB: drafting of the manuscript, and critical revisions of the manuscript. DO, MR: drafting of the manuscript, and figure preparation. JWV, DA: critical revision of the manuscript for clinical significance.

  • Funding Dr Angela Lamarca received funding from The Christie Charity and the European Union’s Horizon 2020 Research and Innovation Programme [grant number 825510, ESCALON]. Dr Alejandro Forner received grant support from Instituto de Salud Carlos III (PI13/01229 and PI18/00542). Prof Stephen Pereira was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Prof Matias Avila was supported by FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación grant (PID2019-104878RB-100), Spain; Grant 2018/117 from AMMF The Cholangiocarcinoma Charity, UK; Grants 58/2017 from Gobierno de Navarra Salud, Spain; Grant 0011-1411-2020-000010 AGATA Strategic Project from Gobierno de Navarra, Spain. Prof Rocio IR Macias received grant support from Instituto de Salud Carlos III, Spain (PI20/00189, co-funded by European Regional Development Fund/European Social Fund, ‘Investing in your future’). Prof Eugenio Gaudio was supported by grants from Sapienza University. This article/publication is based upon work from COST Action European Cholangiocarcinoma Network CA18122, supported by COST (European Cooperation in Science and Technology;, a funding agency for research and innovation networks.

  • Competing interests Dr Angela Lamarca reports travel and educational support from Ipsen, Pfizer, Bayer, AAA, Sirtex, Novartis, Mylan and Delcath; Speaker honoraria from Merck, Pfizer, Ipsen, Incyte, AAA, QED, Servier, Astra Zeneca and EISAI; Advisory and consultancy honoraria from EISAI, Nutricia Ipsen, QED, Roche, Servier, Boston Scientific and Albireo Pharma; Member of the Knowledge Network and NETConnect Initiatives funded by Ipsen.Alejandro Forner: Lecture fees from Bayer, Gilead, Roche, Boston Scientific and MSD; consultancy fees from Bayer, AstraZeneca, Roche, Boston Scientific, SIRTEX, Exact Science and Guerbert.Chiara Braconi (or family members) received honoraria from Incyte, Merck-Serono, EliLilly, Pfizer, Roche.Jakob N Kather has provided consulting services for Owkin, France and Panakeia, UK and has received honoraria by MSD, Eisai and Falk Pharma.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.