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Nat Genet. 2015 Oct;47(10):1187-93. doi: 10.1038/ng.3389. Epub 2015 Aug 24.

Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas.

Nault JC1,2,3,4,5, Datta S1,2,3,4, Imbeaud S1,2,3,4, Franconi A1,2,3,4, Mallet M1,2,3,4, Couchy G1,2,3,4, Letouzé E1,2,3,4, Pilati C1,2,3,4, Verret B1,4, Blanc JF6,7,8, Balabaud C7,8, Calderaro J1,2,3,4,9, Laurent A10,11, Letexier M12, Bioulac-Sage P7,8,13, Calvo F1,2,3,4,14, Zucman-Rossi J1,2,3,4,15.

Author information

1
INSERM, Unité Mixte de Recherche (UMR) 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue contre le Cancer, Paris, France.
2
Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Paris, France.
3
Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche (UFR) Santé, Médecine, Biologie Humaine (SMBH), Bobigny, France.
4
Université Paris Diderot, Institut Universitaire d'Hématologie, Paris, France.
5
Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Paris-Seine Saint-Denis, Site Jean Verdier, Pôle d'Activité Cancérologique Spécialisée, Service d'Hépatologie, Bondy, France.
6
Centre Hospitalier Universitaire (CHU) de Bordeaux, Department of Hepatology, Hôpital Saint-André, Bordeaux, France.
7
INSERM, UMR 1053, Bordeaux, France.
8
Université de Bordeaux, Bordeaux, France.
9
AP-HP, Department of Pathology, CHU Henri Mondor, Créteil, France.
10
AP-HP, Department of Digestive and Hepatobiliary Surgery, CHU Henri Mondor, Créteil, France.
11
INSERM, U955, Créteil, France.
12
IntegraGen, Evry, France.
13
CHU de Bordeaux, Pellegrin Hospital, Department of Pathology, Bordeaux, France.
14
Institut Gustave Roussy, Core Europe, Villejuif, France.
15
AP-HP, Hôpital Européen Georges Pompidou, Paris, France.

Abstract

Hepatocellular carcinomas (HCCs) are liver tumors related to various etiologies, including alcohol intake and infection with hepatitis B (HBV) or C (HCV) virus. Additional risk factors remain to be identified, particularly in patients who develop HCC without cirrhosis. We found clonal integration of adeno-associated virus type 2 (AAV2) in 11 of 193 HCCs. These AAV2 integrations occurred in known cancer driver genes, namely CCNA2 (cyclin A2; four cases), TERT (telomerase reverse transcriptase; one case), CCNE1 (cyclin E1; three cases), TNFSF10 (tumor necrosis factor superfamily member 10; two cases) and KMT2B (lysine-specific methyltransferase 2B; one case), leading to overexpression of the target genes. Tumors with viral integration mainly developed in non-cirrhotic liver (9 of 11 cases) and without known risk factors (6 of 11 cases), suggesting a pathogenic role for AAV2 in these patients. In conclusion, AAV2 is a DNA virus associated with oncogenic insertional mutagenesis in human HCC.

PMID:
26301494
DOI:
10.1038/ng.3389
[Indexed for MEDLINE]

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