Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-018-07552-9
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Funding
- Reseau national CRB Foie [BB-00330085]
- tumor banks of CHU Bordeaux [BB-0033-00036]
- INCa within the ICGC project
- MUTHEC project (INCa translationnel PRTK2014)
- France Genomique
- Canceropole Ile de France (ExhauTrans project)
- ITMO Cancer AVIESAN (Alliance Nationale pour les Sciences de la Vie et de la Sante, National Alliance for Life Sciences Health)
- BPI France (ICE project)
- ANRS
- French Liver Biobanks network - INCa [BB-0033-00085]
- Ligue Nationale Contre le Cancer (Equipe Labellise'e)
- Labex OncoImmunology (investissement d'avenir)
- Coup d'Elan de la Fondation Bettencourt-Shueller
- SIRIC CARPEM
- Fondation Me'rieux
- HOB doctoral school
- ministry of Education and Research
- Attractivite IDEX fellowship from IUH
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Cyclins A2 and El 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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