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Myeloblastosis-associated virus 2 (MAV-2) is a highly tumorigenic simple avian retrovirus. Chickens infectedin ovo with MAV-2 develop tumors in the kidneys, lungs, and liver with a short latency, less than 8 weeks. Here we report the results of molecular analyses of MAV-2-induced liver tumors that fall into three classes: hepatic hemangiosarcomas (HHSs), intrahepatic cholangiocarcinomas (ICCs), and hepatocellular carcinomas (HCCs). Comprehensive inverse PCR-based screening of 92 chicken liver tumors revealed that in ca. 86% of these tumors, MAV-2 provirus had integrated into one of four gene loci:HRAS ,EGFR ,MET , andRON . Insertionally mutated genes correlated with tumor type:HRAS was hit in HHSs,MET in ICCs,RON mostly in ICCs, andEGFR mostly in HCCs. The provirus insertions led to the overexpression of the affected genes and, in the case ofEGFR andRON , also to the truncation of exons encoding the extracellular ligand-binding domains of these transmembrane receptors. The structures of truncatedEGFR andRON closely mimic the structures of oncogenic variants of these genes frequently found in human tumors (EGFRvIII andsfRON ).IMPORTANCE These data describe the mechanisms of oncogenesis induced in chickens by the MAV-2 retrovirus. They also show that molecular processes converting cellular regulatory genes to cancer genes may be remarkably similar in chickens and humans. We suggest that the MAV-2 retrovirus-based model can complement experiments performed using mouse models and provide data that could translate to human medicine.

journal of virology

HRAS , EGFR , MET , and RON Genes Are Recurrently Activated by Provirus Insertion in Liver Tumors Induced by the Retrovirus Myeloblastosis-Associated Virus 2