Cholangiocarcinoma

Background

Cholangiocarcinoma (CCA) is a diverse group of malignancies originating from the biliary duct epithelium, and can be categorized anatomically as intrahepatic (iCCA), perihilar (pCCA) or distal (dCCA) [1]. Although considered a rare malignancy globally, its incidence and mortality has been rising, and only a small percentage of patients survive until 5 years after diagnosis [1]. PSC is a well-established risk factor for CCA, contributing to more than 30% of PSC-related deaths [2]. The lifetime risk of CCA development in PSC is considerable, reaching up to 20%, with an annual incidence of 1.5% (Vedeld et al JHEP Rep 2020) [3].

Early detection of CCA in PSC poses a significant challenge, as the inflammatory biliary strictures characteristic of PSC can mimic early malignant changes. Current diagnostic methods, including imaging, cytological evaluation, and assessment of serum tumor markers, face limitations in accuracy. Consequently, a substantial portion of CCAs in PSC are not diagnosed until liver transplantation or at autopsy [4], negatively impacting on prognosis. Surgery remains the only curative option, primarily for early-stage perihilar tumors. However, most patients are diagnosed at advanced stages which prevent the option of surgical intervention, leading to an overall survival of less than 12 months [4]. Since systemic chemotherapy offers only modest improvements in overall survival, earlier detection through novel biomarkers is crucial for enhancing outcomes.

Aims:

We have studied DNA methylation aberrations in CCA for more than 10 years, with the aim of identifying biomarkers for an earlier and more accurate diagnosis of CCA among high- risk PSC patients.

Research:

We have analyzed tissue samples (Andresen el al, Epigenetics 2012) [5], biliary brushes (Andresen et al, Hepatology 2015) [6] and bile samples (Vedeld, Grimsrud et al, Hepatology 2022) [7], and identified highly accurate DNA methylation biomarkers for differentiating between patients with CCA and PSC.

Relevant publications:

Reviews:

Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis - The promise of DNA methylation and molecular biomarkers. Vedeld HM, Folseraas T, Lind GE., JHEP Rep. 2020 Jul 11;2(5):100143.

Epigenetic biomarkers in gastrointestinal cancers: The current state and clinical perspectives. Vedeld HM, Goel A, Lind GE. Semin Cancer Biol. 2018 Aug;51:36-49.

Primary sclerosing cholangitis and malignancy. Boberg KM, Lind GE. Best Pract Res Clin Gastroenterol. 2011 Dec;25(6):753-64.

Scientific reports:

Early and accurate detection of cholangiocarcinoma in patients with primary sclerosing cholangitis by methylation markers in bile. Hepatology. 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. 2022 Jan;75(1):59-73.

Four DNA methylation biomarkers in biliary brush samples accurately identify the presence of cholangiocarcinoma. Andresen K, Boberg KM, Vedeld HM, Honne H, Jebsen P, Hektoen M, Wadsworth CA, Clausen OP, Lundin KE, Paulsen V, Foss A, Mathisen Ø, Aabakken L, Schrumpf E, Lothe RA, Lind GE. Hepatology. 2015 May;61(5):1651-9.

Novel target genes and a valid biomarker panel identified for cholangiocarcinoma. Andresen K, Boberg KM, Vedeld HM, Honne H, Hektoen M, Wadsworth CA, Clausen OP, Karlsen TH, Foss A, Mathisen O, Schrumpf E, Lothe RA, Lind GE. Epigenetics. 2012 Nov;7(11):1249-57.

References:

1. Banales, J.M., et al., Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nature Reviews Gastroenterology & Hepatology, 2020. 17(9): p. 557-588.
2. Boonstra, K., et al., Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis. Hepatology, 2013. 58(6): p. 2045-55.
3. Vedeld, H.M., T. Folseraas, and G.E. Lind, Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis - The promise of DNA methylation and molecular biomarkers. JHEP Rep, 2020. 2(5): p. 100143.
4. Boberg, K.M., et al., Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and clinical presentation. Scand J Gastroenterol, 2002. 37(10): p. 1205-11.
5. Andresen, K., et al., Novel target genes and a valid biomarker panel identified for cholangiocarcinoma. Epigenetics, 2012. 7(11): p. 1249-57.
6. Andresen, K., et al., Four DNA methylation biomarkers in biliary brush samples accurately identify the presence of cholangiocarcinoma. Hepatology, 2015. 61(5): p. 1651-9.
7. Vedeld, H. M. Grimsrud M. M., et al., Early and accurate detection of cholangiocarcinoma in patients with primary sclerosing cholangitis by methylation markers in bile, Hepatology, vol. 75, pp. 59-73, Jan 2022.