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Massive parallel sequencing uncovers actionable FGFR2–PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma

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  • Daniela Sia

    (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
    Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute
    Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Bojan Losic

    (Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
    Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai)

  • Agrin Moeini

    (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)

  • Laia Cabellos

    (Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Ke Hao

    (Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
    Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai)

  • Kate Revill

    (Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Dennis Bonal

    (Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Oriana Miltiadous

    (Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Zhongyang Zhang

    (Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
    Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai)

  • Yujin Hoshida

    (Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Helena Cornella

    (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)

  • Mireia Castillo-Martin

    (Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Roser Pinyol

    (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)

  • Yumi Kasai

    (Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai)

  • Sasan Roayaie

    (Liver Cancer Program, Hofstra-North Shore LIJ School of Medicine, Lenox Hill Hospital)

  • Swan N. Thung

    (Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Josep Fuster

    (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)

  • Myron E. Schwartz

    (Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Samuel Waxman

    (Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Carlos Cordon-Cardo

    (Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Eric Schadt

    (Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai)

  • Vincenzo Mazzaferro

    (Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute)

  • Josep M. Llovet

    (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
    Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
    Institució Catalana de Recerca i Estudis Avançats)

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.

Suggested Citation

  • Daniela Sia & Bojan Losic & Agrin Moeini & Laia Cabellos & Ke Hao & Kate Revill & Dennis Bonal & Oriana Miltiadous & Zhongyang Zhang & Yujin Hoshida & Helena Cornella & Mireia Castillo-Martin & Roser , 2015. "Massive parallel sequencing uncovers actionable FGFR2–PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma," Nature Communications, Nature, vol. 6(1), pages 1-11, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7087
    DOI: 10.1038/ncomms7087
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    Cited by:

    1. Stephan Spahn & Fabian Kleinhenz & Ekaterina Shevchenko & Aaron Stahl & Yvonne Rasen & Christine Geisler & Kristina Ruhm & Marion Klaumuenzer & Thales Kronenberger & Stefan A. Laufer & Holly Sundberg-, 2024. "The molecular interaction pattern of lenvatinib enables inhibition of wild-type or kinase-mutated FGFR2-driven cholangiocarcinoma," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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