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

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Bayard, Quentin | Meunier, Léa | Peneau, Camille | Renault, Victor | Shinde, Jayendra | Nault, Jean-Charles | Mami, Iadh | Couchy, Gabrielle | Amaddeo, Giuliana | Tubacher, Emmanuel | Bacq, Delphine | Meyer, Vincent | La Bella, Tiziana | Debaillon-Vesque, Audrey | Bioulac-Sage, Paulette | Seror, Olivier | Blanc, Jean-Frédéric | Calderaro, Julien | Deleuze, Jean-François | Imbeaud, Sandrine | Zucman-Rossi, Jessica | Letouze, Eric

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

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