Genomic Characterization of Cholangiocarcinoma in Primary Sclerosing Cholangitis Reveals Therapeutic Opportunities
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Genomic Characterization of Cholangiocarcinoma in Primary Sclerosing Cholangitis Reveals Therapeutic Opportunities. / Goeppert, Benjamin; Folseraas, Trine; Roessler, Stephanie; Kloor, Matthias; Volckmar, Anna-Lena; Endris, Volker; Buchhalter, Ivo; Stenzinger, Albrecht; Grzyb, Krzysztof; Grimsrud, Marit M; Gornicka, Barbara; von 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; International PSC Study Group (IPSCSG).
in: HEPATOLOGY, Jahrgang 72, Nr. 4, 10.2020, S. 1253-1266.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Genomic Characterization of Cholangiocarcinoma in Primary Sclerosing Cholangitis Reveals Therapeutic Opportunities
AU - Goeppert, Benjamin
AU - Folseraas, Trine
AU - Roessler, Stephanie
AU - Kloor, Matthias
AU - Volckmar, Anna-Lena
AU - Endris, Volker
AU - Buchhalter, Ivo
AU - Stenzinger, Albrecht
AU - Grzyb, Krzysztof
AU - Grimsrud, Marit M
AU - Gornicka, Barbara
AU - von Seth, Erik
AU - Reynolds, Gary M
AU - Franke, Andre
AU - Gotthardt, Daniel N
AU - Mehrabi, Arianeb
AU - Cheung, Angela
AU - Verheij, Joanne
AU - Arola, Johanna
AU - Mäkisalo, Heikki
AU - Eide, Tor J
AU - Weidemann, Sören
AU - Cheville, John C
AU - Mazza, Giuseppe
AU - Hirschfield, Gideon M
AU - Ponsioen, Cyriel Y
AU - Bergquist, Annika
AU - Milkiewicz, Piotr
AU - Lazaridis, Konstantinos N
AU - Schramm, Christoph
AU - Manns, Michael P
AU - Färkkilä, Martti
AU - Vogel, Arndt
AU - Boberg, Kirsten M
AU - Schirmacher, Peter
AU - Karlsen, Tom H
AU - International PSC Study Group (IPSCSG)
N1 - © 2020 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.
PY - 2020/10
Y1 - 2020/10
N2 - 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.
AB - 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.
U2 - 10.1002/hep.31110
DO - 10.1002/hep.31110
M3 - SCORING: Journal article
C2 - 31925805
VL - 72
SP - 1253
EP - 1266
JO - HEPATOLOGY
JF - HEPATOLOGY
SN - 0270-9139
IS - 4
ER -
