[HetColi] – Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress. - Published on 07 12 2018
2018 Dec 7, doi:  10.1038/s41467-018-07552-9
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 La Bella, Audrey Debaillon-Vesque, Paulette Bioulac-Sage, Olivier Seror, Jean-Frédéric Blanc, Julien Calderaro, Jean-François Deleuze, Sandrine Imbeaud, Jessica Zucman-Rossi & Eric Letouzé


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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