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Genomic Characterization of Cholangiocarcinoma in Primary Sclerosing Cholangitis Reveals Therapeutic Opportunities
Author(s) -
Goeppert Benjamin,
Folseraas Trine,
Roessler Stephanie,
Kloor Matthias,
Volckmar AnnaLena,
Endris Volker,
Buchhalter Ivo,
Stenzinger Albrecht,
Grzyb Krzysztof,
Grimsrud Marit M.,
Gornicka Barbara,
Seth Erik,
Reynolds Gary M.,
Franke Andre,
Gotthardt Daniel N.,
Mehrabi Arianeb,
Cheung Angela,
Verheij Joanne,
Arola Johanna,
Mäkisalo Heikki,
Eide Tor J.,
Weidemann Sören,
Cheville John C.,
Mazza Giuseppe,
Hirschfield Gideon M.,
Ponsioen Cyriel Y.,
Bergquist Annika,
Milkiewicz Piotr,
Lazaridis Konstantinos N.,
Schramm Christoph,
Manns Michael P.,
Färkkilä Martti,
Vogel Arndt,
Boberg Kirsten M.,
Schirmacher Peter,
Karlsen Tom H.
Publication year - 2020
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31110
Subject(s) - primary sclerosing cholangitis , kras , cdkn2a , klatskin tumor , pathology , cancer , biology , colorectal cancer , medicine , disease , surgery , resection
Background and Aims Lifetime risk of biliary tract cancer (BTC) in primary sclerosing cholangitis (PSC) may exceed 20%, and BTC is currently the leading cause of death in patients with PSC. To open new avenues for management, we aimed to delineate clinically relevant genomic and pathological features of a large panel of PSC‐associated BTC (PSC‐BTC). Approach and Results We analyzed formalin‐fixed, paraffin‐embedded tumor tissue from 186 patients with PSC‐BTC 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. Regardless 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, such as 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 nontypical/nonductal histomorphological subtypes (55.2%) and of the usually rare BTC precursor lesion, intraductal papillary neoplasia (18.3%). Conclusions Genomic alterations in PSC‐BTC include a significant number of putative actionable therapeutic targets. Notably, PSC‐BTC shows 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.