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

Quentin Bayard, Léa Meunier, Camille Peneau, Victor Renault, Jayendra Shinde, Jean-Charles Nault, Iadh Mami, Gabrielle Couchy, Giuliana Amaddeo, Emmanuel Tubacher, Delphine Bacq, Vincent Meyer, Tiziana Bella, Audrey Debaillon-Vesque, Paulette Bioulac-Sage, Olivier Seror, Jean-Frédéric Blanc, Julien Calderaro, Jean-François Deleuze, Sandrine Imbeaud, Jessica Zucman-Rossi () and Eric Letouzé ()
Additional contact information
Quentin Bayard: Institut Universitaire d’Hématologie
Léa Meunier: Institut Universitaire d’Hématologie
Camille Peneau: Institut Universitaire d’Hématologie
Victor Renault: Laboratory for Bioinformatics, Fondation Jean Dausset – CEPH
Jayendra Shinde: Institut Universitaire d’Hématologie
Jean-Charles Nault: Institut Universitaire d’Hématologie
Iadh Mami: Institut Universitaire d’Hématologie
Gabrielle Couchy: Institut Universitaire d’Hématologie
Giuliana Amaddeo: Inserm, U955, Team 18, Université Paris-Est Créteil, Faculté de Médecine
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
Audrey Debaillon-Vesque: Centre Hospitalier Universitaire de Bordeaux
Paulette Bioulac-Sage: Université Bordeaux, Bordeaux Research in Translational Oncology
Olivier Seror: Institut Universitaire d’Hématologie
Jean-Frédéric Blanc: Centre Hospitalier Universitaire de Bordeaux
Julien Calderaro: Inserm, U955, Team 18, Université Paris-Est Créteil, Faculté de Médecine
Jean-François Deleuze: Laboratory for Bioinformatics, Fondation Jean Dausset – CEPH
Sandrine Imbeaud: Institut Universitaire d’Hématologie
Jessica Zucman-Rossi: Institut Universitaire d’Hématologie
Eric Letouzé: Institut Universitaire d’Hématologie

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07552-9

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