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Journal articles
Adeno-associated virus in the liver: natural history and consequences in tumor development
Tiziana La Bella
1, 2
Sandrine Imbeaud
1, 2
Camille Péneau
1, 2
Iadh Mami
1, 2
Shalini Datta
1, 2
Quentin Bayard
1, 2
Stefano Caruso
1, 2
Theo Hirsch
1, 2
Julien Calderaro
1, 3
Guillaume Morcrette
2, 1, 4
Catherine Guettier
4
Valérie Paradis
5
Giuliana Amaddeo
6
Alexis Laurent
7
Laurent Possenti
8
Laurence Chiche
9
Paulette Bioulac-Sage
10, 11
Jean-Frédéric Blanc
8, 10
Eric Letouzé
1, 2
Jean-Charles Nault
1, 2, 12
Jessica Zucman-Rossi
1, 2, 13, *
*
Corresponding author
Tiziana La Bella 1, 2
Author
Sandrine Imbeaud 1, 2
Author
Camille Péneau 1, 2
Author
Iadh Mami 1, 2
Author
Shalini Datta 1, 2
Author
Quentin Bayard 1, 2
Author
Stefano Caruso 1, 2
Author
Theo Hirsch 1, 2
Author
Julien Calderaro 1, 3
Author
Guillaume Morcrette 2, 1, 4
Author
Catherine Guettier 4
Author
Valérie Paradis 5
Author
Giuliana Amaddeo 6
Author
Alexis Laurent 7
Author
Laurent Possenti 8
Author
Laurence Chiche 9
Author
Paulette Bioulac-Sage 10, 11
Author
Jean-Frédéric Blanc 8, 10
Author
Eric Letouzé 1, 2
Author
Jean-Charles Nault 1, 2, 12
Author
Jessica Zucman-Rossi 1, 2, 13
Correspondent author IdHAL : jessica-zucman-rossi ResearcherId : http://www.researcherid.com/rid/B-5098-2009 ORCID : https://orcid.org/0000-0002-5687-0334
1
CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers (15 rue de l'Ecole de Médecine - Bâtiment B -
75270 Paris Cedex 06 - France)
- EPHE - École pratique des hautes études (4-14 Rue Ferrus, 75014 Paris - France)
- PSL - Université Paris sciences et lettres (60 rue Mazarine 75006 Paris - France)
- UPD7 - Université Paris Diderot - Paris 7 : UMR_S_1138 (5 rue Thomas-Mann - 75205 Paris cedex 13 - France)
- UPD5 - Université Paris Descartes - Paris 5 : UMR_S_1138 (12, rue de l'École de Médecine - 75270 Paris cedex 06 - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U1138 (101, rue de Tolbiac, 75013 Paris - France)
- SU - Sorbonne Université (21 rue de l’École de médecine - 75006 Paris - France)
2
U1162 - Génomique Fonctionnelle des Tumeurs Solides (Bâtiment de l'I.G.M. - 27 Rue Juliette Dodu 75010 Paris - France)
- UP13 - Université Paris 13 (France)
- UPD7 - Université Paris Diderot - Paris 7 : UMR_S 1162 (5 rue Thomas-Mann - 75205 Paris cedex 13 - France)
- UPD5 - Université Paris Descartes - Paris 5 : UMR_S 1162 (12, rue de l'École de Médecine - 75270 Paris cedex 06 - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U1162 (101, rue de Tolbiac, 75013 Paris - France)
3
Département de pathologie [CHU Henri Mondor] (France)
- AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP) (France)
- Hôpital Henri Mondor (France)
4
Service d’Anatomopathologie [Le Kremlin-Bicêtre] (France)
- AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre) (78 Rue du Général Leclerc 94270 Le Kremlin-Bicêtre - France)
5
Service d'Anatomopathologie [Clichy, France] (Hôpital Beaujon - France)
6
Service d'hépato-gastro-entérologie [APHP Henri Mondor] (94000 Créteil - France)
- UPEC UP12 - Université Paris-Est Créteil Val-de-Marne - Paris 12 (61 avenue du Général de Gaulle - 94010 Créteil cedex - France)
- Hôpital Henri Mondor (France)
- AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP) (France)
7
Service de chirurgie digestive (Créteil - France)
- AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP) (France)
- Hôpital Henri Mondor (France)
8
Hôpital Haut-Lévêque [CHU Bordeaux] (France)
- CHU Bordeaux [Bordeaux] (place Amélie Raba Léon 33076 BORDEAUX CEDEX - France)
9
Département de chirurgie digestive (Avenue de Magellan Bordeaux, Pessac F-33604, France - France)
- CHU Bordeaux [Bordeaux] (place Amélie Raba Léon 33076 BORDEAUX CEDEX - France)
10
BaRITOn - Bordeaux Research In Translational Oncology [Bordeaux] (France)
- UB - Université de Bordeaux (35, place Pey Berland - 33076 Bordeaux - France)
- CHU Bordeaux [Bordeaux] (place Amélie Raba Léon 33076 BORDEAUX CEDEX - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U1053 (101, rue de Tolbiac, 75013 Paris - France)
11
Hôpital Pellegrin (Bordeaux - France)
- CHU Bordeaux [Bordeaux] (place Amélie Raba Léon 33076 BORDEAUX CEDEX - France)
- Groupe hospitalier Pellegrin (France)
12
Hôpital Jean Verdier [AP-HP] (France)
13
HEGP - Hôpital Européen Georges Pompidou [APHP] (20, rue Leblanc, 75015 Paris - France)
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.
Document type :
Journal articles
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https://www.hal.inserm.fr/inserm-02458847
Contributor : Jessica Zucman-Rossi Connect in order to contact the contributor
Submitted on : Wednesday, January 29, 2020 - 7:04:49 AM
Last modification on : Tuesday, October 19, 2021 - 4:08:40 PM
Contributor : Jessica Zucman-Rossi Connect in order to contact the contributor
Submitted on : Wednesday, January 29, 2020 - 7:04:49 AM
Last modification on : Tuesday, October 19, 2021 - 4:08:40 PM
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Identifiers
- HAL Id : inserm-02458847, version 1
- DOI : 10.1136/gutjnl-2019-318281
- PUBMED : 31375600
Collections
INSERM | UPEC-UPEM | UPEC | UNIV-PARIS5 | UNIV-PARIS13 | SORBONNE-UNIVERSITE | UNIV-PARIS7 | CORDELIERS | EPHE | USPC | SU-SCIENCES | SORBONNE-PARIS-NORD | UNIV-PARIS | UP-SANTE | PSL | SU-TI
Citation
Tiziana La Bella, Sandrine Imbeaud, Camille Péneau, Iadh Mami, Shalini Datta, et al.. Adeno-associated virus in the liver: natural history and consequences in tumor development. Gut, BMJ Publishing Group, 2019, pp.gutjnl-2019-318281. ⟨10.1136/gutjnl-2019-318281⟩. ⟨inserm-02458847⟩
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