Myeloblastosis-associated virus 2 (MAV-2) is a highly tumorigenic simple avian retrovirus. Chickens infected in 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, and RON Insertionally mutated genes correlated with tumor type: HRAS was hit in HHSs, MET in ICCs, RON mostly in ICCs, and EGFR mostly in HCCs. The provirus insertions led to the overexpression of the affected genes and, in the case of EGFR and RON, also to the truncation of exons encoding the extracellular ligand-binding domains of these transmembrane receptors. The structures of truncated EGFR and RON closely mimic the structures of oncogenic variants of these genes frequently found in human tumors (EGFRvIII and sfRON).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.

• Keywords
• avian retroviruses, insertional mutagenesis, retroviral oncogenesis,
• MeSH
• Cholangiocarcinoma genetics   virology   MeSH
• Genes, erbB-1 * MeSH
• Hemangiosarcoma genetics   virology   MeSH
• Carcinoma, Hepatocellular genetics   virology   MeSH
• Virus Integration MeSH
• Mutagenesis, Insertional * MeSH
• Carcinogenesis * MeSH
• Chickens genetics   MeSH
• Humans MeSH
• Liver Neoplasms genetics   virology   MeSH
• Oncogenes MeSH
• Proto-Oncogene Proteins c-met genetics   MeSH
• Proviruses genetics   physiology   MeSH
• Avian Proteins genetics   MeSH
• Receptor Protein-Tyrosine Kinases genetics   MeSH
• Avian Myeloblastosis Virus genetics   physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Proto-Oncogene Proteins c-met MeSH
• Avian Proteins MeSH
• RON protein MeSH Browser
• Receptor Protein-Tyrosine Kinases MeSH