Display options
Cite
Vedeld HM, Grimsrud MM, Andresen K, et al. Early and accurate detection of cholangiocarcinoma in patients with primary sclerosing cholangitis by methylation markers in bile. Hepatology. 2021;doi: 10.1002/hep.32125.
Vedeld, H. M., Grimsrud, M. M., Andresen, K., Pharo, H. D., von Seth, E., Karlsen, T. H., Honne, H., Paulsen, V., Färkkilä, M. A., Bergquist, A., Jeanmougin, M., Aabakken, L., Boberg, K. M., Folseraas, T., & Lind, G. E. (2021). Early and accurate detection of cholangiocarcinoma in patients with primary sclerosing cholangitis by methylation markers in bile. Hepatology (Baltimore, Md.), . https://doi.org/10.1002/hep.32125
Vedeld, Hege Marie, et al. "Early and accurate detection of cholangiocarcinoma in patients with primary sclerosing cholangitis by methylation markers in bile." Hepatology (Baltimore, Md.) vol. (2021). doi: https://doi.org/10.1002/hep.32125
Vedeld HM, Grimsrud MM, Andresen K, Pharo HD, von Seth E, Karlsen TH, Honne H, Paulsen V, Färkkilä MA, Bergquist A, Jeanmougin M, Aabakken L, Boberg KM, Folseraas T, Lind GE. Early and accurate detection of cholangiocarcinoma in patients with primary sclerosing cholangitis by methylation markers in bile. Hepatology. 2021 Aug 26; doi: 10.1002/hep.32125. Epub 2021 Aug 26. PMID: 34435693.
Copy Download .nbib Format: NLM
Share it on

Hepatology. 2021 Aug 26; doi: 10.1002/hep.32125. Epub 2021 Aug 26.

Early and accurate detection of cholangiocarcinoma in patients with primary sclerosing cholangitis by methylation markers in bile.

Hepatology (Baltimore, Md.)

Hege Marie Vedeld, Marit M Grimsrud, Kim Andresen, Heidi D Pharo, Erik von Seth, Tom H Karlsen, Hilde Honne, Vemund Paulsen, Martti A Färkkilä, Annika Bergquist, Marine Jeanmougin, Lars Aabakken, Kirsten M Boberg, Trine Folseraas, Guro E Lind

Affiliations

  1. Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital-Norwegian Radium Hospital, Oslo, Norway.
  2. K. G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.
  3. Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.
  4. Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  5. Department of Medicine Huddinge, Unit of Gastroenterology and Rheumatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
  6. Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital-Rikshospitalet, Oslo, Norway.
  7. Department of Medicine, Division of Gastroenterology, Helsinki University Hospital and Helsinki University, Helsinki, Finland.

PMID: 34435693 DOI: 10.1002/hep.32125

Abstract

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is associated with increased risk of cholangiocarcinoma (CCA). Early and accurate CCA detection represents an unmet clinical need as the majority of patients with PSC are diagnosed at an advanced stage of malignancy. In the present study, we aimed at establishing robust DNA methylation biomarkers in bile for early and accurate diagnosis of CCA in PSC.

APPROACH AND RESULTS: Droplet digital PCR (ddPCR) was used to analyze 344 bile samples from 273 patients with sporadic and PSC-associated CCA, PSC, and other nonmalignant liver diseases for promoter methylation of cysteine dioxygenase type 1, cannabinoid receptor interacting protein 1, septin 9, and vimentin. Receiver operating characteristic (ROC) curve analyses revealed high AUCs for all four markers (0.77-0.87) for CCA detection among patients with PSC. Including only samples from patients with PSC diagnosed with CCA ≤ 12 months following bile collection increased the accuracy for cancer detection, with a combined sensitivity of 100% (28/28) and a specificity of 90% (20/203). The specificity increased to 93% when only including patients with PSC with longtime follow-up (> 36 months) as controls, and remained high (83%) when only including patients with PSC and dysplasia as controls (n = 23). Importantly, the bile samples from the CCA-PSC ≤ 12 patients, all positive for the biomarkers, included both early-stage and late-stage CCA, different tumor growth patterns, anatomical locations, and carbohydrate antigen 19-9 levels.

CONCLUSIONS: Using highly sensitive ddPCR to analyze robust epigenetic biomarkers, CCA in PSC was accurately detected in bile, irrespective of clinical and molecular features, up to 12 months before CCA diagnosis. The findings suggest a potential for these biomarkers to complement current detection and screening methods for CCA in patients with PSC.

© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

References

  1. Hirschfield GM, Karlsen TH, Lindor KD, Adams DH. Primary sclerosing cholangitis. Lancet. 2013;382:1587-99. - PubMed
  2. Schrumpf E, Boberg KM, Karlsen TH. Primary sclerosing cholangitis-the Norwegian experience. Scand J Gastroenterol. 2015;50:781-96. - PubMed
  3. Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary sclerosing cholangitis-a comprehensive review. J Hepatol. 2017;67:1298-323. - PubMed
  4. Bergquist A, Ekbom A, Olsson R, Kornfeldt D, Lööf L, Danielsson Å, et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol. 2002;36:321-7. - PubMed
  5. Boonstra K, Weersma RK, van Erpecum KJ, Rauws EA, Spanier BWM, Poen AC, et al. Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis. Hepatology. 2013;58:2045-55. - PubMed
  6. Tanaka A, Takamori Y, Toda G, Ohnishi S, Takikawa H. Outcome and prognostic factors of 391 Japanese patients with primary sclerosing cholangitis. Liver Int. 2008;28:983-9. - PubMed
  7. Weismuller TJ, Trivedi PJ, Bergquist A, Imam M, Lenzen H, Ponsioen CY, et al. Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis. Gastroenterology. 2017;152:1975-84.e8. - PubMed
  8. Folseraas T, Boberg KM. Cancer risk and surveillance in primary sclerosing cholangitis. Clin Liver Dis. 2016;20:79-98. - PubMed
  9. Razumilava N, Gores GJ. Surveillance for cholangiocarcinoma in patients with primary sclerosing cholangitis: effective and justified? Clin Liver Dis. 2016;8:43-7. - PubMed
  10. Bowlus CL, Lim JK, Lindor KD. AGA clinical practice update on surveillance for hepatobiliary cancers in patients with primary sclerosing cholangitis: expert review. Clin Gastroenterol Hepatol. 2019;17:2416-22. - PubMed
  11. Kang MJ, Jang J-Y, Chang J, Shin YC, Lee D, Kim HB, et al. Actual long-term survival outcome of 403 consecutive patients with hilar cholangiocarcinoma. World J Surg. 2016;40:2451-9. - PubMed
  12. Azad AI, Rosen CB, Taner T, Heimbach JK, Gores GJ. Selected patients with unresectable perihilar cholangiocarcinoma (pCCA) derive long-term benefit from liver transplantation. Cancers. 2020;12(11):3157. - PubMed
  13. Vedeld HM, Goel A, Lind GE. Epigenetic biomarkers in gastrointestinal cancers: the current state and clinical perspectives. Semin Cancer Biol. 2018;51:36-49. - PubMed
  14. Vedeld HM, Folseraas T, Lind GE. Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis-the promise of DNA methylation and molecular biomarkers. JHEP Rep. 2020;2:100143. - PubMed
  15. Andresen K, Boberg KM, Vedeld HM, Honne H, Jebsen P, Hektoen M, et al. Four DNA methylation biomarkers in biliary brush samples accurately identify the presence of cholangiocarcinoma. Hepatology. 2015;61:1651-9. - PubMed
  16. Lazaridis KN, LaRusso NF. Primary sclerosing cholangitis. N Engl J Med. 2016;375:1161-70. - PubMed
  17. Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma-evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018;15:95-111. - PubMed
  18. Majeed A, Castedal M, Arnelo U, Söderdahl G, Bergquist A, Said K. Optimizing the detection of biliary dysplasia in primary sclerosing cholangitis before liver transplantation. Scand J Gastroenterol. 2018;53:56-63. - PubMed
  19. Boberg KM, Jebsen P, Clausen OP, Foss A, Aabakken L, Schrumpf E. Diagnostic benefit of biliary brush cytology in cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol. 2006;45:568-74. - PubMed
  20. Lind GE, Danielsen SA, Ahlquist T, Merok MA, Andresen K, Skotheim RI, et al. Identification of an epigenetic biomarker panel with high sensitivity and specificity for colorectal cancer and adenomas. Mol Cancer. 2011;10:85. - PubMed
  21. Pharo HD, Andresen K, Berg KCG, Lothe RA, Jeanmougin M, Lind GE. A robust internal control for high-precision DNA methylation analyses by droplet digital PCR. Clin Epigenetics. 2018;10:24. - PubMed
  22. Andresen K, Boberg K, Vedeld H, Honne H, Hektoen M, Wadsworth C, et al. Novel target genes and a valid biomarker panel identified for cholangiocarcinoma. Epigenetics. 2012;7:1249-57. - PubMed
  23. Klump B, Hsieh CJ, Dette S, Holzmann K, Kiebetalich R, Jung M, et al. Promoter methylation of INK4a/ARF as detected in bile-significance for the differential diagnosis in biliary disease. Clin Cancer Res. 2003;9:1773-8. - PubMed
  24. Shin S-H, Lee K, Kim B-H, Cho N-Y, Jang J-Y, Kim Y-T, et al. Bile-based detection of extrahepatic cholangiocarcinoma with quantitative DNA methylation markers and its high sensitivity. J Mol Diagn. 2012;14:256-63. - PubMed
  25. Barnicle A, Seoighe C, Greally JM, Golden A, Egan LJ. Inflammation-associated DNA methylation patterns in epithelium of ulcerative colitis. Epigenetics. 2017;12:591-606. - PubMed
  26. Metzger J, Negm AA, Plentz RR, Weismüller TJ, Wedemeyer J, Karlsen TH, et al. Urine proteomic analysis differentiates cholangiocarcinoma from primary sclerosing cholangitis and other benign biliary disorders. Gut. 2013;62:122-30. - PubMed
  27. Lankisch TO, Metzger J, Negm AA, Voβkuhl K, Schiffer E, Siwy J, et al. Bile proteomic profiles differentiate cholangiocarcinoma from primary sclerosing cholangitis and choledocholithiasis. Hepatology. 2011;53:875-84. - PubMed
  28. Branchi V, Schaefer P, Semaan A, Kania A, Lingohr P, Kalff JC, et al. Promoter hypermethylation of SHOX2 and SEPT9 is a potential biomarker for minimally invasive diagnosis in adenocarcinomas of the biliary tract. Clin Epigenetics. 2016;8:133. - PubMed
  29. Razumilava N, Gores GJ, Lindor KD. Cancer surveillance in patients with primary sclerosing cholangitis. Hepatology. 2011;54:1842-52. - PubMed
  30. Eaton JE, Gossard AA, Talwalkar JA. Recall processes for biliary cytology in primary sclerosing cholangitis. Curr Opin Gastroenterol. 2014;30:287-94. - PubMed
  31. Rizvi S, Eaton JE, Gores GJ. Primary sclerosing cholangitis as a premalignant biliary tract disease: surveillance and management. Clin Gastroenterol Hepatol. 2015;13:2152-65. - PubMed
  32. Charatcharoenwitthaya P, Enders FB, Halling KC, Lindor KD. Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis. Hepatology. 2008;48:1106-17. - PubMed
  33. Boyd S, Mustonen H, Tenca A, Jokelainen K, Arola J, Färkkilä MA. Surveillance of primary sclerosing cholangitis with ERC and brush cytology: risk factors for cholangiocarcinoma. Scand J Gastroenterol. 2017;52:242-9. - PubMed
  34. Boyd S, Tenca A, Jokelainen K, Mustonen H, Krogerus L, Arola J, et al. Screening primary sclerosing cholangitis and biliary dysplasia with endoscopic retrograde cholangiography and brush cytology: risk factors for biliary neoplasia. Endoscopy. 2016;48:432-9. - PubMed
  35. Eaton JE, Welle CL, Bakhshi Z, Sheedy SP, Idilman IS, Gores GJ, et al. Early cholangiocarcinoma detection with magnetic resonance imaging versus ultrasound in primary sclerosing cholangitis. Hepatology. 2021;73:1868-81. - PubMed
  36. Njei B, McCarty TR, Varadarajulu S, Navaneethan U. Systematic review with meta-analysis: endoscopic retrograde cholangiopancreatography-based modalities for the diagnosis of cholangiocarcinoma in primary sclerosing cholangitis. Aliment Pharmacol Ther. 2016;44:1139-51. - PubMed
  37. Trikudanathan G, Navaneethan U, Njei B, Vargo JJ, Parsi MA. Diagnostic yield of bile duct brushings for cholangiocarcinoma in primary sclerosing cholangitis: a systematic review and meta-analysis. Gastrointest Endosc. 2014;79:783-9. - PubMed
  38. Harewood GC, Baron TH, Stadheim LM, Kipp BR, Sebo TJ, Salomao DR. Prospective, blinded assessment of factors influencing the accuracy of biliary cytology interpretation. Am J Gastroenterol. 2004;99:1464-9. - PubMed
  39. Lewis JT, Talwalkar JA, Rosen CB, Smyrk TC, Abraham SC. Precancerous bile duct pathology in end-stage primary sclerosing cholangitis, with and without cholangiocarcinoma. Am J Surg Pathol. 2010;34:27-34. - PubMed
  40. Nakamoto S, Kumamoto Y, Igarashi K, Fujiyama Y, Nishizawa N, Ei S, et al. Methylated promoter DNA of CDO1 gene and preoperative serum CA19-9 are prognostic biomarkers in primary extrahepatic cholangiocarcinoma. PLoS ONE. 2018;13:e0205864. - PubMed
  41. Chen D, Wu H, Feng X, Chen Y, Lv Z, Kota VG, et al. DNA methylation of cannabinoid receptor interacting protein 1 promotes pathogenesis of intrahepatic cholangiocarcinoma through suppressing Parkin-dependent pyruvate kinase M2 ubiquitination. Hepatology. 2021;73(5):1816-35. - PubMed

Publication Types

Grant support