Abstract A39: An oncogenomics-based <i>in vivo</i> cDNA screen pinpoints coamplified <i>Ccnd1</i> and <i>Fgf19</i> as therapeutic targets for liver cancer

Abstract Human cancer genome profiling is becoming increasingly effective at revealing novel recurrent genomic aberrations, but it remains challenging to identify the underlying driver genes. Here we describe an oncogenomic cDNA screen used to identify genes involved in liver tumorigenesis. Using array CGH analysis, we first identified recurrent focal amplicons present in hepatocellular carcinoma (HCC). Next, we assayed their tumorigenic potential by introducing pools of cDNAs corresponding to genes found in focal amplicons into sensitized liver progenitor cells. We identified 18 genes that promote tumor formation, including known oncogene Ccnd1 and co-amplified Fgf19, which we show cooperate during tumorigenesis. These two closely linked genes are co-amplified and co-overexpressed in 15% of human HCC. Knockdown of either Ccnd1 or Fgf19 inhibited colony formation of amplified human HCC cell lines and inhibited tumorigenicity. Knockdown in non-amplified human cell lines was without phenotypic effect. Downstream analysis revealed that FGF-19 leads to the activation of β-catenin and increased levels of CyclinD1. These results show that gene amplification predicts response to both Ccnd1 and Fgf19 inhibition, and that oncogenomic cDNA screens are an effective new tool to identify therapeutic strategies that are directly linked to cancer genotypes. Citation Information: Cancer Res 2009;69(23 Suppl):A39.