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Original article
Adeno-associated virus in the liver: natural history and consequences in tumour development
  1. Tiziana La Bella1,2,
  2. Sandrine Imbeaud1,2,
  3. Camille Peneau1,2,
  4. Iadh Mami1,2,
  5. Shalini Datta1,2,3,
  6. Quentin Bayard1,2,
  7. Stefano Caruso1,2,
  8. Theo Z Hirsch1,2,
  9. Julien Calderaro1,2,4,
  10. Guillaume Morcrette1,2,5,6,
  11. Catherine Guettier5,6,
  12. Valerie Paradis2,7,8,
  13. Giuliana Amaddeo9,10,
  14. Alexis Laurent11,
  15. Laurent Possenti12,
  16. Laurence Chiche13,
  17. Paulette Bioulac-Sage14,15,
  18. Jean-Frederic Blanc12,14,15,
  19. Eric Letouze1,2,
  20. Jean-Charles Nault1,2,16,
  21. Jessica Zucman-Rossi1,2,17
  1. 1 Centre de Recherche des Cordeliers, Sorbonne Universités, INSERM, Paris, Île-de-France, France
  2. 2 Functional Genomics of Solid Tumor, Labex Immuno- Oncology, équipe labellisée Ligue Contre le Cancer, Université de Paris, Université Paris 13, Paris, Île-de-France, France
  3. 3 Indian Statistical Institute, University of Kalyani, Kalyani, West Bengal, India
  4. 4 Pathology Department, APHP, CHU Henri Mondor, Créteil, Île-de-France, France
  5. 5 Pathology Department, APHP, Bicetre-Paul Brousse Hospitals, Le Kremlin Bicêtre, Île-de-France, France
  6. 6 Physiopathogenesis and treatment of liver diseases, INSERM, Paris, Île-de-France, France
  7. 7 Pathology Department, APHP, Beaujon Hospital, Paris, Île-de-France, France
  8. 8 The Research Center on Inflammation labeled, INSERM, Paris, Île-de-France
  9. 9 Hepatology Department, APHP, Henri Mondor Hospital, Créteil, Île-de-France, France
  10. 10 Molecular virology and immunology, INSERM, Institut Mondor de Recherche Biomédicale, Créteil, Île-de-France, France
  11. 11 Department of Digestive Surgery, APHP, Henri Mondor Hospital, Créteil, Île-de-France, France
  12. 12 Department of Hepato-Gastroenterology and Digestive Oncology, CHU de Bordeaux, Haut-Lévêque Hospital, Bordeaux, Aquitaine, France
  13. 13 Department of Digestive Surgery, Centre Médico Chirurgical Magellan, CHU de Bordeaux, Haut-Lévêque Hospital, Bordeaux, Aquitaine, France
  14. 14 Department of Pathology, CHU de Bordeaux, Pellegrin Hospital, Bordeaux, Aquitaine, France
  15. 15 Bordeaux Research in Translational Oncology, Université Bordeaux, Bordeaux, Aquitaine, France
  16. 16 Department of Hepatology, Université Paris Nord, APHP, Hospital Jean Verdier, Bondy, Île-de-France, France
  17. 17 Department of Oncology, APHP, Hospital Européen Georges Pompidou, Paris, Île-de-France, France
  1. Correspondence to Professor Jessica Zucman-Rossi; jessica.zucman{at}gmail.com, jessica.zucman{at}gmail.com

Abstract

Objective Adeno-associated virus (AAV) is a defective mono-stranded DNA virus, endemic in human population (35%–80%). Recurrent clonal AAV2 insertions are associated with the pathogenesis of rare human hepatocellular carcinoma (HCC) developed on normal liver. This study aimed to characterise the natural history of AAV infection in the liver and its consequence in tumour development.

Design Viral DNA was quantified in tumour and non-tumour liver tissues of 1461 patients. Presence of episomal form and viral mRNA expression were analysed using a DNAse/TaqMan-based assay and quantitative RT-PCR. In silico analyses using viral capture data explored viral variants and new clonal insertions.

Results AAV DNA was detected in 21% of the patients, including 8% of the tumour tissues, equally distributed in two major viral subtypes: one similar to AAV2, the other hybrid between AAV2 and AAV13 sequences. Episomal viral forms were found in 4% of the non-tumour tissues, frequently associated with viral RNA expression and human herpesvirus type 6, the candidate natural AAV helper virus. In 30 HCC, clonal AAV insertions were recurrently identified in CCNA2, CCNE1, TERT, TNFSF10, KMT2B and GLI1/INHBE. AAV insertion triggered oncogenic overexpression through multiple mechanisms that differ according to the localisation of the integration site.

Conclusion We provided an integrated analysis of the wild-type AAV infection in the liver with the identification of viral genotypes, molecular forms, helper virus relationship and viral integrations. Clonal AAV insertions were positive selected during HCC development on non-cirrhotic liver challenging the notion of AAV as a non-pathogenic virus.

  • hepatocellular carcinoma
  • oncogenes
  • carcinogenesis
  • liver
  • chronic viral hepatitis
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Footnotes

  • TLB and SI contributed equally.

  • Contributors Study design: J-CN, JZ-R, TLB, SI. Generation of experimental data: TLB, SI, CP, IM, SD. Analysis and interpretation of data: TLB, SI, CP, IM, SD, QB, SC, TZH, EL, J-CN, JZ-R. Collection of samples and related histological and clinical data: J-CN, JZ-R, JC, GM, CG, VP, GA, AL, LP, LC, PB-S, J-FB and investigators. Drafting of the manuscript: JZ-R, TLB, SI. Revision of the manuscript and approval of the final version of the manuscript: JZ-R, J-CN, TLB, SI, IM, SD, QB, SC, TZH, EL, JC, GM, CG, VP, GA, AL, LP, LC, PB-S, J-FB.

  • Funding This work was supported by INSERM, by INCa within the ICGC project, France Génomique, Cancéropole Ile de France (ExhauTrans project), ITMO Cancer AVIESAN (Alliance Nationale pour les Sciences de la Vie et de la Santé, National Alliance for Life Sciences & Health) within the framework of the Cancer Plan (“HTE program-HetColi network” and “Cancer et environnement program”), the Réseau national CRB Foie, Ligue Nationale contre le cancer: project équipe Labellisée, Fondation Schueller Bettencourt “coup d’élan”, Prix Ligue contre le Cancer comité de Paris René et Andrée Duquesne 2018, the SIRIC CARPEM and Fondation Mérieux, Labex OncoImmunology (investissement d’avenir) ANRS and the French Liver Biobanks network—INCa, BB-0033-00085, Hepatobio bank. QB is supported by a fellowship from the HOB doctoral school and the ministry of Education and Research, TLB is supported by an “Attractivité IDEX" fellowship from IUH and CP is supported by a doctoral fellowship funded by ANRS.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement The sequencing data reported in this paper have been deposited to Genbank (accessions: KT258720-KT258730, MK139243-MK139299, MK163929-MK163942 and MK231253-MK231264) and EGA (European Genome-phenome Archive) database (RNA-seq accessions: EGAS00001002879, EGAS00001001284 and EGAS00001003310). All supplemental data and sequences are available at http://zucmanlab.com/wp-content/uploads/2019/05/Zucman-CaptureVirusProbes.xlsx.

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