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Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress

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  • Quentin Bayard

    (Institut Universitaire d’Hématologie
    Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine
    Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine
    Université Paris Diderot, Sorbonne Paris Cité)

  • Léa Meunier

    (Institut Universitaire d’Hématologie
    Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine
    Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine
    Université Paris Diderot, Sorbonne Paris Cité)

  • Camille Peneau

    (Institut Universitaire d’Hématologie
    Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine
    Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine
    Université Paris Diderot, Sorbonne Paris Cité)

  • Victor Renault

    (Laboratory for Bioinformatics, Fondation Jean Dausset – CEPH)

  • Jayendra Shinde

    (Institut Universitaire d’Hématologie
    Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine
    Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine
    Université Paris Diderot, Sorbonne Paris Cité)

  • Jean-Charles Nault

    (Institut Universitaire d’Hématologie
    Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine
    Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine
    Université Paris Diderot, Sorbonne Paris Cité)

  • Iadh Mami

    (Institut Universitaire d’Hématologie
    Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine
    Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine
    Université Paris Diderot, Sorbonne Paris Cité)

  • Gabrielle Couchy

    (Institut Universitaire d’Hématologie
    Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine
    Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine
    Université Paris Diderot, Sorbonne Paris Cité)

  • Giuliana Amaddeo

    (Inserm, U955, Team 18, Université Paris-Est Créteil, Faculté de Médecine
    Assistance Publique-Hôpitaux de Paris, Service d’Hépatologie, CHU Henri Mondor)

  • Emmanuel Tubacher

    (Laboratory for Bioinformatics, Fondation Jean Dausset – CEPH)

  • Delphine Bacq

    (Centre National de Recherche en Génomique Humaine, CEA)

  • Vincent Meyer

    (Centre National de Recherche en Génomique Humaine, CEA)

  • Tiziana Bella

    (Institut Universitaire d’Hématologie
    Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine
    Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine
    Université Paris Diderot, Sorbonne Paris Cité)

  • Audrey Debaillon-Vesque

    (Centre Hospitalier Universitaire de Bordeaux)

  • Paulette Bioulac-Sage

    (Université Bordeaux, Bordeaux Research in Translational Oncology
    Service de Pathologie, Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux)

  • Olivier Seror

    (Institut Universitaire d’Hématologie
    Hôpitaux Universitaires Paris-Seine-Saint-Denis, APHP)

  • Jean-Frédéric Blanc

    (Centre Hospitalier Universitaire de Bordeaux
    Université Bordeaux, Bordeaux Research in Translational Oncology)

  • Julien Calderaro

    (Inserm, U955, Team 18, Université Paris-Est Créteil, Faculté de Médecine
    Hôpital Henri Mondor)

  • Jean-François Deleuze

    (Laboratory for Bioinformatics, Fondation Jean Dausset – CEPH
    Centre National de Recherche en Génomique Humaine, CEA)

  • Sandrine Imbeaud

    (Institut Universitaire d’Hématologie
    Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine
    Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine
    Université Paris Diderot, Sorbonne Paris Cité)

  • Jessica Zucman-Rossi

    (Institut Universitaire d’Hématologie
    Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine
    Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine
    Université Paris Diderot, Sorbonne Paris Cité)

  • Eric Letouzé

    (Institut Universitaire d’Hématologie
    Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine
    Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine
    Université Paris Diderot, Sorbonne Paris Cité)

Abstract

Cyclins A2 and E1 regulate the cell cycle by promoting S phase entry and progression. Here, we identify a hepatocellular carcinoma (HCC) subgroup exhibiting cyclin activation through various mechanisms including hepatitis B virus (HBV) and adeno-associated virus type 2 (AAV2) insertions, enhancer hijacking and recurrent CCNA2 fusions. Cyclin A2 or E1 alterations define a homogenous entity of aggressive HCC, mostly developed in non-cirrhotic patients, characterized by a transcriptional activation of E2F and ATR pathways and a high frequency of RB1 and PTEN inactivation. Cyclin-driven HCC display a unique signature of structural rearrangements with hundreds of tandem duplications and templated insertions frequently activating TERT promoter. These rearrangements, strongly enriched in early-replicated active chromatin regions, are consistent with a break-induced replication mechanism. Pan-cancer analysis reveals a similar signature in BRCA1-mutated breast and ovarian cancers. Together, this analysis reveals a new poor prognosis HCC entity and a rearrangement signature related to replication stress.

Suggested Citation

  • Quentin Bayard & Léa Meunier & Camille Peneau & Victor Renault & Jayendra Shinde & Jean-Charles Nault & Iadh Mami & Gabrielle Couchy & Giuliana Amaddeo & Emmanuel Tubacher & Delphine Bacq & Vincent Me, 2018. "Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07552-9
    DOI: 10.1038/s41467-018-07552-9
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    Cited by:

    1. Emmanuel Benichou & Bolaji Seffou & Selin Topçu & Ophélie Renoult & Véronique Lenoir & Julien Planchais & Caroline Bonner & Catherine Postic & Carina Prip-Buus & Claire Pecqueur & Sandra Guilmeau & Ma, 2024. "The transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism," Nature Communications, Nature, vol. 15(1), pages 1-29, December.

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