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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
1 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
2 U1162 - Génomique Fonctionnelle des Tumeurs Solides
3 Département de pathologie [CHU Henri Mondor]
4 Service d’Anatomopathologie [Le Kremlin-Bicêtre]
5 Service d'Anatomopathologie [Clichy, France]
6 Service d'hépato-gastro-entérologie [APHP Henri Mondor]
7 Service de chirurgie digestive
8 Hôpital Haut-Lévêque [CHU Bordeaux]
9 Département de chirurgie digestive
10 BaRITOn - Bordeaux Research In Translational Oncology [Bordeaux]
11 Hôpital Pellegrin
12 Hôpital Jean Verdier [AP-HP]
13 HEGP - Hôpital Européen Georges Pompidou [APHP]
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.
Keywords : insertional mutagenesis hepatocellular adenoma cyclin telomerase Adeno Associated Virus AAV2 AAV13 hepatocellular carcinoma
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Submitted on : Wednesday, January 29, 2020 - 7:04:49 AM
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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

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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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