Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress
2018
Cyclins A2and E1 regulate the cell cycle by promoting S phase entry and progression. Here, we identify a hepatocellular carcinoma (HCC) subgroup exhibiting
cyclinactivation through various mechanisms including hepatitis B virus (HBV) and
adeno-associated virustype 2 (AAV2) insertions, enhancer hijacking and recurrent CCNA2 fusions.
Cyclin A2or E1 alterations define a homogenous entity of aggressive HCC, mostly developed in non-cirrhotic patients, characterized by a transcriptional activation of
E2Fand 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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