Abstract

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.

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Acknowledgements

We warmly thank L. Yost, E. Chevet and A. de Reynies for critical review of the manuscript and helpful discussion. We thank all the clinician surgeons and pathologists who have participated in this work: J. Saric, C. Laurent, L. Chiche, B. Le Bail and C. Castain (CHU Bordeaux) and Y. Allory, K. Leroy and D. Azoulay (CHU Henri Mondor). We also thank the Réseau National Centre de Ressources Biologiques (CRB) Foie and the tumor banks of CHU Bordeaux and CHU Henri Mondor for contributing to the tissue collection. This work was supported by Institut Nationale du Cancer (INCa) with the International Cancer Genome Consortium (ICGC) and the PAIR-CHC project NoFLIC (also funded by Association pour la Recherche sur le Cancer (ARC)). The group is supported by the Ligue Nationale contre le Cancer. J.-C.N., M.M., C.P. and A.F. were supported by fellowships from INCa, AERIO-Boehringer-Ingelheim, ARC and the Ligue Nationale contre le Cancer, respectively.

Author information

Author notes

    • Jean-Charles Nault
    • , Shalini Datta
    •  & Sandrine Imbeaud

    These authors contributed equally to this work.

Affiliations

  1. INSERM, Unité Mixte de Recherche (UMR) 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue contre le Cancer, Paris, France.

    • Jean-Charles Nault
    • , Shalini Datta
    • , Sandrine Imbeaud
    • , Andrea Franconi
    • , Maxime Mallet
    • , Gabrielle Couchy
    • , Eric Letouzé
    • , Camilla Pilati
    • , Benjamin Verret
    • , Julien Calderaro
    • , Fabien Calvo
    •  & Jessica Zucman-Rossi
  2. Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Paris, France.

    • Jean-Charles Nault
    • , Shalini Datta
    • , Sandrine Imbeaud
    • , Andrea Franconi
    • , Maxime Mallet
    • , Gabrielle Couchy
    • , Eric Letouzé
    • , Camilla Pilati
    • , Julien Calderaro
    • , Fabien Calvo
    •  & Jessica Zucman-Rossi
  3. Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche (UFR) Santé, Médecine, Biologie Humaine (SMBH), Bobigny, France.

    • Jean-Charles Nault
    • , Shalini Datta
    • , Sandrine Imbeaud
    • , Andrea Franconi
    • , Maxime Mallet
    • , Gabrielle Couchy
    • , Eric Letouzé
    • , Camilla Pilati
    • , Julien Calderaro
    • , Fabien Calvo
    •  & Jessica Zucman-Rossi
  4. Université Paris Diderot, Institut Universitaire d'Hématologie, Paris, France.

    • Jean-Charles Nault
    • , Shalini Datta
    • , Sandrine Imbeaud
    • , Andrea Franconi
    • , Maxime Mallet
    • , Gabrielle Couchy
    • , Eric Letouzé
    • , Camilla Pilati
    • , Benjamin Verret
    • , Julien Calderaro
    • , Fabien Calvo
    •  & Jessica Zucman-Rossi
  5. Assistance Publique–Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Paris–Seine Saint-Denis, Site Jean Verdier, Pôle d'Activité Cancérologique Spécialisée, Service d'Hépatologie, Bondy, France.

    • Jean-Charles Nault
  6. Centre Hospitalier Universitaire (CHU) de Bordeaux, Department of Hepatology, Hôpital Saint-André, Bordeaux, France.

    • Jean-Frédéric Blanc
  7. INSERM, UMR 1053, Bordeaux, France.

    • Jean-Frédéric Blanc
    • , Charles Balabaud
    •  & Paulette Bioulac-Sage
  8. Université de Bordeaux, Bordeaux, France.

    • Jean-Frédéric Blanc
    • , Charles Balabaud
    •  & Paulette Bioulac-Sage
  9. AP-HP, Department of Pathology, CHU Henri Mondor, Créteil, France.

    • Julien Calderaro
  10. AP-HP, Department of Digestive and Hepatobiliary Surgery, CHU Henri Mondor, Créteil, France.

    • Alexis Laurent
  11. INSERM, U955, Créteil, France.

    • Alexis Laurent
  12. IntegraGen, Evry, France.

    • Mélanie Letexier
  13. CHU de Bordeaux, Pellegrin Hospital, Department of Pathology, Bordeaux, France.

    • Paulette Bioulac-Sage
  14. Institut Gustave Roussy, Core Europe, Villejuif, France.

    • Fabien Calvo
  15. AP-HP, Hôpital Européen Georges Pompidou, Paris, France.

    • Jessica Zucman-Rossi

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Contributions

J.-C.N., S.D., S.I. and J.Z.-R. designed the study and wrote the manuscript. J.Z.-R. conceived and directed the research. J.-C.N., S.D., A.F., M.M., G.C., C.P. and B.V. performed the experiments. J.-C.N., S.D., S.I., A.F., M.M., G.C., E.L., C.P., B.V., F.C. and J.Z.-R. analyzed and interpreted the data. S.I., E.L. and M.L. performed bioinformatics and statistical analysis. J.-F.B., C.B., J.C., A.L. and P.B.-S. provided essential biological resources and collected clinical data. All authors approved the final manuscript and contributed to critical revisions to its intellectual context.

Competing interests

IntegraGen performed all the next-generation sequencing, and M.L. is an employee of IntegraGen. All other authors declare no competing financial interests.

Corresponding author

Correspondence to Jessica Zucman-Rossi.

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https://doi.org/10.1038/ng.3389

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