title: Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma.
abstract: Intrahepatic cholangiocarcinoma (iCCA) is a fatal bile duct cancer with dismal prognosis and limited therapeutic options. By performing RNA- and exome-sequencing analyses, we report a novel fusion event, FGFR2-PPHLN1 (16%), and damaging mutations in the ARAF oncogene (11%). Here we demonstrate that the chromosomal translocation t(10;12)(q26;q12) leading to FGFR2-PPHLN1 fusion possesses transforming and oncogenic activity, which is successfully inhibited by a selective FGFR2 inhibitor in vitro. Among the ARAF mutations, N217I and G322S lead to activation of the pathway and N217I shows oncogenic potential in vitro. Screening of a cohort of 107 iCCA patients reveals that FGFR2 fusions represent the most recurrent targetable alteration (45%, 17/107), while they are rarely present in other primary liver tumours (0/100 of hepatocellular carcinoma (HCC); 1/21 of mixed iCCA-HCC). Taken together, around 70% of iCCA patients harbour at least one actionable molecular alteration (FGFR2 fusions, IDH1/2, ARAF, KRAS, BRAF and FGF19) that is amenable for therapeutic targeting.
authors.affiliation: 1] Barcelona-Clínic Liver Cancer Group (HCC Translational Research Laboratory, Liver Unit, Hepato-biliary Surgery), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona 08036, Spain [2] Gastrointestinal Surgery and Liver Transplantation Unit, Department of Surgery, National Cancer Institute, Milan 20133, Italy [3] Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Sia
authors.affiliation: 1] Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York 10029, USA [2] Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Bojan
authors.initials: B
authors.lastname: Losic
authors.affiliation: Barcelona-Clínic Liver Cancer Group (HCC Translational Research Laboratory, Liver Unit, Hepato-biliary Surgery), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona 08036, Spain.
authors.forename: Agrin
authors.initials: A
authors.lastname: Moeini
authors.affiliation: Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Laia
authors.initials: L
authors.lastname: Cabellos
authors.affiliation: 1] Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York 10029, USA [2] Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Hao
authors.affiliation: Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Revill
authors.affiliation: Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Bonal
authors.affiliation: Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Oriana
authors.initials: O
authors.lastname: Miltiadous
authors.affiliation: 1] Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York 10029, USA [2] Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Zhongyang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hoshida
authors.affiliation: Barcelona-Clínic Liver Cancer Group (HCC Translational Research Laboratory, Liver Unit, Hepato-biliary Surgery), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona 08036, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Cornella
authors.affiliation: Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Mireia
authors.initials: M
authors.lastname: Castillo-Martin
authors.affiliation: Barcelona-Clínic Liver Cancer Group (HCC Translational Research Laboratory, Liver Unit, Hepato-biliary Surgery), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona 08036, Spain.
authors.forename: Roser
authors.initials: R
authors.lastname: Pinyol
authors.affiliation: Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kasai
authors.affiliation: Liver Cancer Program, Hofstra-North Shore LIJ School of Medicine, Lenox Hill Hospital, New York, New York 11042, USA.
authors.forename: Sasan
authors.initials: S
authors.lastname: Roayaie
authors.affiliation: Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Swan N
authors.initials: SN
authors.lastname: Thung
authors.affiliation: Barcelona-Clínic Liver Cancer Group (HCC Translational Research Laboratory, Liver Unit, Hepato-biliary Surgery), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona 08036, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Fuster
authors.affiliation: Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Myron E
authors.initials: ME
authors.lastname: Schwartz
authors.affiliation: Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Waxman
authors.affiliation: Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.affiliation: Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Schadt
authors.affiliation: Gastrointestinal Surgery and Liver Transplantation Unit, Department of Surgery, National Cancer Institute, Milan 20133, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mazzaferro
authors.affiliation: 1] Barcelona-Clínic Liver Cancer Group (HCC Translational Research Laboratory, Liver Unit, Hepato-biliary Surgery), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona 08036, Spain [2] Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York 10029, USA [3] Institució Catalana de Recerca i Estudis Avançats, Barcelona 08010, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
mesh_terms: D016475:3T3 Cells; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics*; D001483:Base Sequence; D001650:Bile Duct Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000235:genetics*; D015331:Cohort Studies; D059472:Exome; D005091:Exons; D005260:Female; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D048491:Proto-Oncogene Proteins A-raf / Q000235:genetics*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D017423:Sequence Analysis, RNA; D017386:Sequence Homology, Amino Acid; D014178:Translocation, Genetic
chemical_list: D000951:Antigens, Neoplasm; D009687:Nuclear Proteins; C478775:PPHLN1 protein, human; D011993:Recombinant Fusion Proteins; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D048491:Proto-Oncogene Proteins A-raf