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

Nat Commun. 2018 Dec 7;9(1):5235. doi: 10.1038/s41467-018-07552-9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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

Supplementary concepts

  • Adeno-associated virus-2