Genomic Characterization of Cholangiocarcinoma in Primary Sclerosing Cholangitis Reveals Therapeutic Opportunities

被引：51

作者：

Goeppert, Benjamin ^{[1
]}

Folseraas, Trine ^{[2
,3
,4
,5
,6
]}

Roessler, Stephanie ^{[1
]}

Kloor, Matthias ^{[7
]}

Volckmar, Anna-Lena ^{[1
]}

Endris, Volker ^{[1
]}

Buchhalter, Ivo ^{[1
,8
]}

Stenzinger, Albrecht ^{[1
]}

Grzyb, Krzysztof ^{[9
]}

Grimsrud, Marit M. ^{[2
,3
,4
]}

Gornicka, Barbara ^{[10
]}

von Seth, Erik ^{[11
]}

Reynolds, Gary M. ^{[12
]}

Franke, Andre ^{[13
]}

Gotthardt, Daniel N. ^{[14
]}

Mehrabi, Arianeb ^{[15
]}

Cheung, Angela ^{[16
]}

Verheij, Joanne ^{[17
]}

Arola, Johanna ^{[18
]}

Makisalo, Heikki ^{[19
]}

Eide, Tor J. ^{[9
]}

Weidemann, Soren ^{[20
]}

Cheville, John C. ^{[21
]}

Mazza, Giuseppe ^{[22
]}

Hirschfield, Gideon M. ^{[12
,23
]}

Ponsioen, Cyriel Y. ^{[24
]}

Bergquist, Annika ^{[11
]}

Milkiewicz, Piotr ^{[25
,26
]}

Lazaridis, Konstantinos N. ^{[16
]}

Schramm, Christoph ^{[27
,28
]}

Manns, Michael P. ^{[29
]}

Farkkila, Martti ^{[30
]}

Vogel, Arndt ^{[29
]}

Boberg, Kirsten M. ^{[2
,3
,4
,5
,6
]}

Schirmacher, Peter ^{[1
]}

Karlsen, Tom H. ^{[2
,3
,4
,5
,6
]}

机构：

[1] Univ Hosp Heidelberg, Inst Pathol, Dept Gen Pathol, Heidelberg, Germany

[2] Oslo Univ Hosp, Norwegian PSC Res Ctr, Div Surg Inflammatory Med & Transplantat, Dept Transplantat Med,Rikshosp, Oslo, Norway

[3] Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway

[4] Oslo Univ Hosp, Res Inst Internal Med, Div Surg Inflammatory Med & Transplantat, Rikshosp, Oslo, Norway

[5] Univ Oslo, Fac Med, KG Jebsen Inflammat Res Ctr, Inst Clin Med, Oslo, Norway

[6] Oslo Univ Hosp, Dept Transplantat Med, Div Surg Inflammatory Med & Transplantat, Sect Gastroenterol,Rikshosp, Oslo, Norway

[7] Heidelberg Univ, Inst Pathol, Dept Appl Tumor Biol, Heidelberg, Germany

[8] German Canc Res Ctr, Inst Pathol, Omics IT & Data Management Core Facil, Heidelberg, Germany

[9] Oslo Univ Hosp, Dept Pathol, Oslo, Norway

[10] Med Univ Warsaw, Dept Pathol, Warsaw, Poland

[11] Karolinska Univ Hosp, Karolinska Inst, Dept Gastroenterol & Hepatol, Stockholm, Sweden

[12] Univ Birmingham, Ctr Liver Res, NIHR Birmingham Liver Biomed Res Unit, Birmingham, W Midlands, England

[13] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[14] Univ Hosp Heidelberg, Dept Internal Med 4, Heidelberg, Germany

[15] Heidelberg Univ, Dept Gen Visceral & Transplantat Surg, Heidelberg, Germany

[16] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA

[17] Acad Med Ctr, Dept Pathol, Amsterdam, Netherlands

[18] Helsinki Univ Hosp, Haartman Inst, Dept Pathol, Helsinki, Finland

[19] Helsinki Univ Hosp, Dept Transplantat & Liver Surg, Helsinki, Finland

[20] Univ Med Ctr Hamburg Eppendorf, Inst Pathol, Hamburg, Germany

[21] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA

[22] UCL, Inst Liver & Digest Hlth, Div Med, Royal Free Hosp, London, England

[23] Univ Hosp Birmingham, NHS Fdn Trust, Birmingham, W Midlands, England

[24] Acad Med Ctr, Dept Gastroenterol & Hepatol, Amsterdam, Netherlands

[25] Med Univ Warsaw, Liver & Internal Med Unit, Warsaw, Poland

[26] Pomeranian Med Univ, Translat Med Grp, Szczecin, Poland

[27] Univ Med Ctr Hamburg Eppendorf, Dept Med, Hamburg, Germany

[28] Univ Med Ctr Hamburg Eppendorf, Martin Zeitz Ctr Rare Dis, Hamburg, Germany

[29] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany

[30] Helsinki Univ Hosp, Dept Gastroenterol & Hepatol, Helsinki, Finland

来源：

HEPATOLOGY | 2020年 / 72卷 / 04期

基金：

欧盟地平线“2020”;

关键词：

MUTATIONS; PATTERNS; RECEPTOR; RISK;

D O I：

10.1002/hep.31110

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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 asTP53(35.5%),KRAS(28.0%),CDKN2A(14.5%), andSMAD4(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.

引用

页码：1253 / 1266

页数：14

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