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Gut. 2019 Aug 2. pii: gutjnl-2019-318281. doi: 10.1136/gutjnl-2019-318281. [Epub ahead of print]

Adeno-associated virus in the liver: natural history and consequences in tumour development.

Author information

1
Centre de Recherche des Cordeliers, Sorbonne Universités, INSERM, Paris, Île-de-France, France.
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
Indian Statistical Institute, University of Kalyani, Kalyani, West Bengal, India.
4
Pathology Department, APHP, CHU Henri Mondor, Créteil, Île-de-France, France.
5
Pathology Department, APHP, Bicetre-Paul Brousse Hospitals, Le Kremlin Bicêtre, Île-de-France, France.
6
Physiopathogenesis and treatment of liver diseases, INSERM, Paris, Île-de-France, France.
7
Pathology Department, APHP, Beaujon Hospital, Paris, Île-de-France, France.
8
The Research Center on Inflammation labeled, INSERM, Paris, Île-de-France.
9
Hepatology Department, APHP, Henri Mondor Hospital, Créteil, Île-de-France, France.
10
Molecular virology and immunology, INSERM, Institut Mondor de Recherche Biomédicale, Créteil, Île-de-France, France.
11
Department of Digestive Surgery, APHP, Henri Mondor Hospital, Créteil, Île-de-France, France.
12
Department of Hepato-Gastroenterology and Digestive Oncology, CHU de Bordeaux, Haut-Lévêque Hospital, Bordeaux, Aquitaine, France.
13
Department of Digestive Surgery, Centre Médico Chirurgical Magellan, CHU de Bordeaux, Haut-Lévêque Hospital, Bordeaux, Aquitaine, France.
14
Department of Pathology, CHU de Bordeaux, Pellegrin Hospital, Bordeaux, Aquitaine, France.
15
Bordeaux Research in Translational Oncology, Université Bordeaux, Bordeaux, Aquitaine, France.
16
Department of Hepatology, Université Paris Nord, APHP, Hospital Jean Verdier, Bondy, Île-de-France, France.
17
Department of Oncology, APHP, Hospital Européen Georges Pompidou, Paris, Île-de-France, France.
#
Contributed equally

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:

carcinogenesis; chronic viral hepatitis; hepatocellular carcinoma; liver; oncogenes

PMID:
31375600
DOI:
10.1136/gutjnl-2019-318281

Conflict of interest statement

Competing interests: None declared.

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