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

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 5235 (12 07 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 30531861 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCNE1 protein, human
• Cyclin A2
• Cyclin E
• Oncogene Proteins

Topics

• Adult
• Aged
• Aged, 80 and over
• Carcinoma, Hepatocellular (genetics, metabolism, pathology)
• Cyclin A2 (genetics, metabolism)
• Cyclin E (genetics, metabolism)
• Dependovirus
• Female
• Gene Expression Regulation, Neoplastic
• Gene Rearrangement
• Hepatitis B virus (genetics)
• Humans
• Liver Neoplasms (genetics, metabolism)
• Male
• Middle Aged
• Mutagenesis, Insertional
• Oncogene Proteins (genetics, metabolism)
• Parvovirinae (genetics)
• Promoter Regions, Genetic (genetics)
• Survival Analysis