A mouse model of liver cancer was developed using liver progenitor cells with defined cancer-predisposing lesions. Genome-wide analyses of tumors in this model and in human hepatocellular carcinomas (HCCs) revealed a recurrent amplification at mouse chromosome 9qA1, the syntenic region of human chromosome 11q22. Gene-expression analyses identified cIAP1, an inhibitor of apoptosis, and Yap, a transcription factor, as candidate oncogenes in the amplicon. Both cIAP1 and Yap accelerated tumorigenesis and were required for the rapid growth of amplicon-containing tumors. cIAP1 and Yap cooperated to promote tumorigenesis. The study established a tractable model of liver cancer, identified two oncogenes that cooperate due to their coamplification in the same genomic locus, and suggested an efficient strategy for the annotation of human cancer genes. The study used a mouse model to identify and validate oncogenes in liver cancer. It found that cIAP1 and Yap, which are coamplified in the same genomic region, cooperate to promote tumorigenesis. The results highlight the utility of integrating mouse models and cancer genomics for the functional annotation of cancer genes. The study also identified a recurrent amplicon at chromosome 9qA1 in murine HCCs and found that this region is syntenic to the human 11q22 region. Comparative oncogenomics revealed that the 11q22 amplicon is present in human HCCs and other cancers, suggesting that genes in this region may be involved in tumorigenesis. The study identified cIAP1 and Yap as oncogenes in liver cancer. cIAP1 has oncogenic properties and is required for rapid tumor growth. Yap also has oncogenic properties and contributes to rapid tumor growth. The study demonstrated that cIAP1 and Yap cooperate to promote tumorigenesis. The findings suggest that the coamplification of cIAP1 and Yap in the same genomic region is crucial for tumorigenesis. The study also highlights the importance of integrating mouse models and cancer genomics for the functional annotation of cancer genes. The results provide a framework for identifying and validating oncogenes in human cancers.A mouse model of liver cancer was developed using liver progenitor cells with defined cancer-predisposing lesions. Genome-wide analyses of tumors in this model and in human hepatocellular carcinomas (HCCs) revealed a recurrent amplification at mouse chromosome 9qA1, the syntenic region of human chromosome 11q22. Gene-expression analyses identified cIAP1, an inhibitor of apoptosis, and Yap, a transcription factor, as candidate oncogenes in the amplicon. Both cIAP1 and Yap accelerated tumorigenesis and were required for the rapid growth of amplicon-containing tumors. cIAP1 and Yap cooperated to promote tumorigenesis. The study established a tractable model of liver cancer, identified two oncogenes that cooperate due to their coamplification in the same genomic locus, and suggested an efficient strategy for the annotation of human cancer genes. The study used a mouse model to identify and validate oncogenes in liver cancer. It found that cIAP1 and Yap, which are coamplified in the same genomic region, cooperate to promote tumorigenesis. The results highlight the utility of integrating mouse models and cancer genomics for the functional annotation of cancer genes. The study also identified a recurrent amplicon at chromosome 9qA1 in murine HCCs and found that this region is syntenic to the human 11q22 region. Comparative oncogenomics revealed that the 11q22 amplicon is present in human HCCs and other cancers, suggesting that genes in this region may be involved in tumorigenesis. The study identified cIAP1 and Yap as oncogenes in liver cancer. cIAP1 has oncogenic properties and is required for rapid tumor growth. Yap also has oncogenic properties and contributes to rapid tumor growth. The study demonstrated that cIAP1 and Yap cooperate to promote tumorigenesis. The findings suggest that the coamplification of cIAP1 and Yap in the same genomic region is crucial for tumorigenesis. The study also highlights the importance of integrating mouse models and cancer genomics for the functional annotation of cancer genes. The results provide a framework for identifying and validating oncogenes in human cancers.