This study describes an integrative approach to identify and validate oncogenes in liver cancer using a mouse model and comparative oncogenomics. The researchers developed a mouse model of hepatocellular carcinoma (HCC) by transplanting genetically modified liver progenitor cells into recipient mice. They identified a recurrent amplification at chromosome 9qA1 in mouse tumors and its syntenic region 11q22 in human HCCs. Gene-expression analyses revealed clAP1 and Yap as candidate oncogenes in this region. In the context of their amplification, both genes accelerated tumorigenesis and were required for rapid tumor growth. Furthermore, clAP1 and Yap cooperated to promote tumorigenesis. This study establishes a tractable model of liver cancer, identifies two oncogenes that cooperate by virtue of their coamplification, and suggests an efficient strategy for annotating human cancer genes.This study describes an integrative approach to identify and validate oncogenes in liver cancer using a mouse model and comparative oncogenomics. The researchers developed a mouse model of hepatocellular carcinoma (HCC) by transplanting genetically modified liver progenitor cells into recipient mice. They identified a recurrent amplification at chromosome 9qA1 in mouse tumors and its syntenic region 11q22 in human HCCs. Gene-expression analyses revealed clAP1 and Yap as candidate oncogenes in this region. In the context of their amplification, both genes accelerated tumorigenesis and were required for rapid tumor growth. Furthermore, clAP1 and Yap cooperated to promote tumorigenesis. This study establishes a tractable model of liver cancer, identifies two oncogenes that cooperate by virtue of their coamplification, and suggests an efficient strategy for annotating human cancer genes.