Z Gastroenterol 2020; 58(01): e37
DOI: 10.1055/s-0039-3402199
Lectures Session IV Tumors: Saturday, February 15, 2020, 9:15 am – 10:00 am, Lecture Hall P1
Georg Thieme Verlag KG Stuttgart · New York

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

B Goeppert
1   Pathologisches Institut, Heidelberg, Germany
,
T Folseraas
2   University of Oslo, Oslo, Norway
,
S Roessler
1   Pathologisches Institut, Heidelberg, Germany
,
M Kloor
1   Pathologisches Institut, Heidelberg, Germany
,
AL Volckmar
1   Pathologisches Institut, Heidelberg, Germany
,
V Endris
1   Pathologisches Institut, Heidelberg, Germany
,
I Buchhalter
1   Pathologisches Institut, Heidelberg, Germany
,
A Stenzinger
1   Pathologisches Institut, Heidelberg, Germany
,
K Grzyb
2   University of Oslo, Oslo, Norway
,
MM Grimsrud
2   University of Oslo, Oslo, Norway
,
B Gornicka
3   Medical University of Warsaw, Warsaw, Poland
,
E von Seth
2   University of Oslo, Oslo, Norway
4   Karolinska Institutet, Stockholm, Sweden
,
GM Reynolds
5   University of Birmingham, Birmingham, United Kingdom
,
A Franke
6   Christian-Albrechts-University, Kiel, Germany
,
DN Gotthardt
7   University Hospital Heidelberg, Heidelberg, Germany
,
A Mehrabi
7   University Hospital Heidelberg, Heidelberg, Germany
,
A Cheung
8   Mayo Clinic, Rochester, MN, United States
,
J Verheij
9   Department of Pathology, Amsterdam, Netherlands
,
J Arola
10   Helsinki University Hospital, Helsinki, Finland
,
H Mäkisalo
10   Helsinki University Hospital, Helsinki, Finland
,
TJ Eide
2   University of Oslo, Oslo, Norway
,
S Weidemann
11   University Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
JC Cheville
8   Mayo Clinic, Rochester, MN, United States
,
G Mazza
12   University College London, London, United Kingdom
,
GM Hirschfield
5   University of Birmingham, Birmingham, United Kingdom
,
CY Ponsioen
13   Academic Medical Center, Amsterdam, Netherlands
,
A Bergquist
4   Karolinska Institutet, Stockholm, Sweden
,
P Milkiewicz
3   Medical University of Warsaw, Warsaw, Poland
,
KN Lazaridis
8   Mayo Clinic, Rochester, MN, United States
,
MP Manns
14   Hannover Medical School, Hannover, Germany
,
C Schramm
11   University Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
M Färkkilä
10   Helsinki University Hospital, Helsinki, Finland
,
A Vogel
14   Hannover Medical School, Hannover, Germany
,
KM Boberg
2   University of Oslo, Oslo, Norway
,
P Schirmacher
1   Pathologisches Institut, Heidelberg, Germany
,
TH Karlsen
2   University of Oslo, Oslo, Norway
› Author Affiliations
Further Information

Publication History

Publication Date:
03 January 2020 (online)

Also available at
 

Background & Aims:

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

Approach & Results:

We analyzed 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 targets (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.