Article

Identification of a Therapeutic Strategy Targeting Amplified FGF19 in Liver Cancer by Oncogenomic Screening

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Cancer cell (Impact Factor: 23.89). 03/2011; 19(3):347-58. DOI: 10.1016/j.ccr.2011.01.040
Source: PubMed

ABSTRACT We screened 124 genes that are amplified in human hepatocellular carcinoma (HCC) using a mouse hepatoblast model and identified 18 tumor-promoting genes, including CCND1 and its neighbor on 11q13.3, FGF19. Although it is widely assumed that CCND1 is the main driving oncogene of this common amplicon (15% frequency in HCC), both forward-transformation assays and RNAi-mediated inhibition in human HCC cells established that FGF19 is an equally important driver gene in HCC. Furthermore, clonal growth and tumorigenicity of HCC cells harboring the 11q13.3 amplicon were selectively inhibited by RNAi-mediated knockdown of CCND1 or FGF19, as well as by an anti-FGF19 antibody. These results show that 11q13.3 amplification could be an effective biomarker for patients most likely to respond to anti-FGF19 therapy.

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    • "Moreover, the ras/raf/map kinase pathway is a key signalling pathway, with rare activating mutations in PIK3CA (1%), RAS (1%) and, more frequently, mutations in RPS6KA3 (8%). Amplification of FGF19 has been described in up to 15% of HCC [99]. One study reported the association of 6p21.1 amplification with HCC developing on NASH. "
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    • "Deletions at this locus routinely inactivate both cell-cycle regulators (Bates et al. 1998; Stott et al. 1998). Recent evidence also suggests that oncogenes and tumor suppressor genes (TSGs) are clustered, including several TSGs on 8p21-23 in hepatocellular carcinoma, three oncogenes (NKX2-1, NKX2-8, and PAX9) on 14q13 in lung cancer, two oncogenes (CCND1 and FGF19) on 11q13, and two oncogenes (BIRC2 and YAP1) on 11q22 in liver cancer (Zender et al. 2006; Kendall et al. 2007; Sawey et al. 2011; Solimini et al. 2012; Xue et al. 2012). Similar to the results presented here, phenotypes induced by the manipulation of individual genes are relatively weak, whereas the concerted deregulation of entire cancer gene clusters result in more significant effects. "
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    • "Moreover, whole genome sequencing of HCCs and putative secondary growths have defined genetic changes associated with intrahepatic metastasis [7]. However, the identification of driver mutations in HCC is still a challenging task [8]. Mouse models are valuable tools to identify the contribution of defined genetic changes to HCC formation. "
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