RT Journal Article
SR Electronic
T1 Adeno-associated virus in the liver: natural history and consequences in tumour development
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 737
OP 747
DO 10.1136/gutjnl-2019-318281
VO 69
IS 4
A1 Tiziana La Bella
A1 Sandrine Imbeaud
A1 Camille Peneau
A1 Iadh Mami
A1 Shalini Datta
A1 Quentin Bayard
A1 Stefano Caruso
A1 Theo Z Hirsch
A1 Julien Calderaro
A1 Guillaume Morcrette
A1 Catherine Guettier
A1 Valerie Paradis
A1 Giuliana Amaddeo
A1 Alexis Laurent
A1 Laurent Possenti
A1 Laurence Chiche
A1 Paulette Bioulac-Sage
A1 Jean-Frederic Blanc
A1 Eric Letouze
A1 Jean-Charles Nault
A1 Jessica Zucman-Rossi
YR 2020
UL http://gut.bmj.com/content/69/4/737.abstract
AB 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.