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

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; Letouzé, Eric.
Nat Commun; 9(1): 5235, 2018 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-30531861
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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