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: 23.52). 03/2011; 19(3):347-58. DOI: 10.1016/j.ccr.2011.01.040
Source: PubMed


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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Available from: Scott Powers, Oct 03, 2015
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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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    ABSTRACT: Hepatocellular carcinoma is related to various etiologies including hepatitis B, hepatitis C, high alcohol intake, aflatoxin B1 and metabolic syndrom. Most of the time HCC developped on cirrhosis. Consequently, the mechanims of carcinogenesis of these different risk factors are difficult to separate from the events leading to cirrhosis. In contrast, aflatoxin B1 and hepatitis B have a clear direct oncogenic role through point mutations in the TP53 tumor supressor gene and insertionnal mutagenesis respectively. Finally, next-generation sequencing and transcriptome analysis will refine our knowledge of the relationship between etiology and the genetic events that draw the mutationnal landscape of hepatocellular carcinoma.
    Baillière&#x027 s Best Practice and Research in Clinical Gastroenterology 10/2014; 28(5). DOI:10.1016/j.bpg.2014.08.006 · 3.48 Impact Factor
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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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    ABSTRACT: Chromosomal structural variations play an important role in determining the transcriptional landscape of human breast cancers. To assess the nature of these structural variations, we analyzed eight breast tumor samples with a focus on regions of gene amplification using mate-pair sequencing of long-insert genomic DNA with matched transcriptome profiling. We found that tandem duplications appear to be early events in tumor evolution, especially in the genesis of amplicons. In a detailed reconstruction of events on chromosome 17, we found large unpaired inversions and deletions connect a tandemly duplicated ERBB2 with neighboring 17q21.3 amplicons while simultaneously deleting the intervening BRCA1 tumor suppressor locus. This series of events appeared to be unusually common when examined in larger genomic data sets of breast cancers albeit using approaches with lesser resolution. Using siRNAs in breast cancer cell lines, we showed that the 17q21.3 amplicon harbored a significant number of weak oncogenes that appeared consistently coamplified in primary tumors. Down-regulation of BRCA1 expression augmented the cell proliferation in ERBB2-transfected human normal mammary epithelial cells. Coamplification of other functionally tested oncogenic elements in other breast tumors examined, such as RIPK2 and MYC on chromosome 8, also parallel these findings. Our analyses suggest that structural variations efficiently orchestrate the gain and loss of cancer gene cassettes that engage many oncogenic pathways simultaneously and that such oncogenic cassettes are favored during the evolution of a cancer.
    Genome Research 09/2014; 24(10). DOI:10.1101/gr.164871.113 · 14.63 Impact Factor
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    • "The 1.8 Mb amplicon core in the 11q13 region was one of the most frequently amplified chromosomal regions in human cancers and correlated with a poor prognosis 7,29. Although cyclin D1 (CCND1) and fibroblast growth factor 19 (FGF19) have been considered the possible drivers of the 11q13 amplicon 30, it remains unknown whether any gene(s) amplified from the core can malignantly transform normal tissues. "
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    Cancer Medicine 06/2014; 3(3). DOI:10.1002/cam4.232 · 2.50 Impact Factor
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