title: Lentiviral vector-based insertional mutagenesis identifies genes associated with liver cancer.
abstract: Transposons and γ-retroviruses have been efficiently used as insertional mutagens in different tissues to identify molecular culprits of cancer. However, these systems are characterized by recurring integrations that accumulate in tumor cells and that hamper the identification of early cancer-driving events among bystander and progression-related events. We developed an insertional mutagenesis platform based on lentiviral vectors (LVVs) by which we could efficiently induce hepatocellular carcinoma (HCC) in three different mouse models. By virtue of the LVV's replication-deficient nature and broad genome-wide integration pattern, LVV-based insertional mutagenesis allowed identification of four previously unknown liver cancer-associated genes from a limited number of integrations. We validated the oncogenic potential of all the identified genes in vivo, with different levels of penetrance. The newly identified genes are likely to play a role in human cancer because they are upregulated, amplified and/or deleted in human HCCs and can predict clinical outcomes of patients.
authors: San Raffaele-Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.
authors: Marco
authors: M
authors: Ranzani
authors: Daniela
authors: D
authors: Cesana
authors: Cynthia C
authors: CC
authors: Bartholomae
authors: Francesca
authors: F
authors: Sanvito
authors: Mauro
authors: M
authors: Pala
authors: Fabrizio
authors: F
authors: Benedicenti
authors: Pierangela
authors: P
authors: Gallina
authors: Lucia Sergi
authors: LS
authors: Sergi
authors: Stefania
authors: S
authors: Merella
authors: Alessandro
authors: A
authors: Bulfone
authors: Claudio
authors: C
authors: Doglioni
authors: Christof
authors: C
authors: von Kalle
authors: Yoon Jun
authors: YJ
authors: Kim
authors: Manfred
authors: M
authors: Schmidt
authors: Giovanni
authors: G
authors: Tonon
authors: Luigi
authors: L
authors: Naldini
authors: Eugenio
authors: E
authors: Montini
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics*; D051379:Mice; D016254:Mutagenesis, Insertional; D009857:Oncogenes; D051059:PTEN Phosphohydrolase / Q000172:deficiency; D011228:Prealbumin / Q000235:genetics; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C508032:Ifnar1 protein, mouse; D011228:Prealbumin; D053633:Receptor, Interferon alpha-beta; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse