Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas

Nat Genet. 2015 Oct;47(10):1187-93. doi: 10.1038/ng.3389. Epub 2015 Aug 24.


Hepatocellular carcinomas (HCCs) are liver tumors related to various etiologies, including alcohol intake and infection with hepatitis B (HBV) or C (HCV) virus. Additional risk factors remain to be identified, particularly in patients who develop HCC without cirrhosis. We found clonal integration of adeno-associated virus type 2 (AAV2) in 11 of 193 HCCs. These AAV2 integrations occurred in known cancer driver genes, namely CCNA2 (cyclin A2; four cases), TERT (telomerase reverse transcriptase; one case), CCNE1 (cyclin E1; three cases), TNFSF10 (tumor necrosis factor superfamily member 10; two cases) and KMT2B (lysine-specific methyltransferase 2B; one case), leading to overexpression of the target genes. Tumors with viral integration mainly developed in non-cirrhotic liver (9 of 11 cases) and without known risk factors (6 of 11 cases), suggesting a pathogenic role for AAV2 in these patients. In conclusion, AAV2 is a DNA virus associated with oncogenic insertional mutagenesis in human HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular / genetics*
  • Cyclin A2 / genetics
  • Cyclin E / genetics
  • Dependovirus / genetics*
  • Humans
  • Liver Neoplasms / genetics*
  • Molecular Sequence Data
  • Mutagenesis, Insertional*
  • Oncogene Proteins / genetics
  • TNF-Related Apoptosis-Inducing Ligand / genetics
  • Telomerase / genetics
  • Virus Integration


  • CCNE1 protein, human
  • Cyclin A2
  • Cyclin E
  • Oncogene Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Telomerase

Associated data

  • GENBANK/KT258720
  • GENBANK/KT258721
  • GENBANK/KT258722
  • GENBANK/KT258723
  • GENBANK/KT258724
  • GENBANK/KT258725
  • GENBANK/KT258726
  • GENBANK/KT258727
  • GENBANK/KT258728
  • GENBANK/KT258729
  • GENBANK/KT258730