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Hepatology. 2020 Jan 10. doi: 10.1002/hep.31110. [Epub ahead of print]

Genomic characterization of cholangiocarcinoma in primary sclerosing cholangitis reveals novel therapeutic opportunities.

Author information

1
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
2
Norwegian PSC Research Center Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
3
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
4
Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
5
K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
6
Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
7
Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
8
Department of Pathology, Oslo University Hospital, Oslo, Norway.
9
Department of Pathology, Medical University of Warsaw, Poland.
10
Department of Gastroenterology and Hepatology, Karolinska University Hospital, Huddinge, Karolinska Institutet, Stockholm, Sweden.
11
Centre for Liver Research, NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK.
12
Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
13
Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany.
14
Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
15
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
16
Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands.
17
Department of Pathology, Haartman Institute and Huslab, Helsinki University Hospital, Helsinki, Finland.
18
Departments of Transplantation and Liver Surgery, Helsinki University Hospital, Helsinki, Finland.
19
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
20
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
21
University College London, Division of Medicine, Institute for Liver and Digestive Health Royal Free Hospital, London, UK.
22
University Hospital Birmingham, NHS Foundation Trust, Birmingham, UK.
23
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands.
24
Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland.
25
Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland.
26
Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
27
Martin Zeitz Center for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
28
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
29
Department of Gastroenterology & Hepatology, Helsinki University Hospital, Helsinki, Finland.

Abstract

BACKGROUND & AIMS:

Lifetime risk of biliary tract cancer (BTC) in primary sclerosing cholangitis (PSC) exceeds 20% and BTC is currently the leading cause of death in PSC patients. To open new avenues for management, we aimed to delineate novel and clinically relevant genomic and pathological features of a large panel of PSC-associated BTC (PSC-BTC).

APPROACH & RESULTS:

We analysed formalin fixed, paraffin embedded tumor tissue from 186 PSC-BTC patients from 11 centers in eight countries with all anatomical locations included. We performed tumor DNA sequencing at 42 clinically relevant genetic loci to detect mutations, translocations and copy number variations, along with histomorphological and immunohistochemical characterization. Irrespective of the anatomical localization, PSC-BTC exhibited a uniform molecular and histological characteristic similar to extrahepatic cholangiocarcinoma. We detected a high frequency of genomic alterations typical of extrahepatic cholangiocarcinoma, e.g. TP53 (35.5%), KRAS (28.0%), CDKN2A (14.5%), and SMAD4 (11.3%), as well as potentially druggable mutations (e.g. HER2/ERBB2). We found a high frequency of non-typical/non-ductal histomorphological subtypes (55.2%) and of the usually rare BTC precursor lesion, intraductal papillary neoplasia (18.3%) CONCLUSION: Genomic alterations in PSC-BTC include a significant number of putative actionable therapeutic targets. Notably, PSC-BTC show a distinct extrahepatic morpho-molecular phenotype, independent of the anatomical location of the tumor. These findings advance our understanding of PSC-associated cholangiocarcinogenesis and provide strong incentives for clinical trials to test genome-based personalized treatment strategies in PSC-BTC.

KEYWORDS:

Biliary tract cancer; druggable mutations; intraductal papillary neoplasia; personalized treatment; tumor DNA sequencing

PMID:
31925805
DOI:
10.1002/hep.31110

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