High-resolution characterization of a hepatocellular carcinoma genome

Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
Nature Genetics (Impact Factor: 29.35). 05/2011; 43(5):464-9. DOI: 10.1038/ng.804
Source: PubMed


Hepatocellular carcinoma, one of the most common virus-associated cancers, is the third most frequent cause of cancer-related death worldwide. By massively parallel sequencing of a primary hepatitis C virus-positive hepatocellular carcinoma (36× coverage) and matched lymphocytes (>28× coverage) from the same individual, we identified more than 11,000 somatic substitutions of the tumor genome that showed predominance of T>C/A>G transition and a decrease of the T>C substitution on the transcribed strand, suggesting preferential DNA repair. Gene annotation enrichment analysis of 63 validated non-synonymous substitutions revealed enrichment of phosphoproteins. We further validated 22 chromosomal rearrangements, generating four fusion transcripts that had altered transcriptional regulation (BCORL1-ELF4) or promoter activity. Whole-exome sequencing at a higher sequence depth (>76× coverage) revealed a TSC1 nonsense substitution in a subpopulation of the tumor cells. This first high-resolution characterization of a virus-associated cancer genome identified previously uncharacterized mutation patterns, intra-chromosomal rearrangements and fusion genes, as well as genetic heterogeneity within the tumor.

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    • "Mutations are primarily prevalent in TP53 (31%), CTNNB1 (19%), AXIN1 (16%), NFE2L2 (14%), ARID2 (13%), and PIK3CA (7%).[7] However, systematic efforts to delineate the molecular profile of HCC in a large group of tumor samples from patients are still underway ([8] Here we report the results of targeted next generation sequencing (NGS) and treatment outcomes in a case series of 14 patients with advanced/metastatic HCC. "
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    ABSTRACT: Understanding genetic aberrations in cancer leads to discovery of new targets for cancer therapies. The genomic landscape of hepatocellular carcinoma (HCC) has not been fully described. Therefore, patients with refractory advanced/metastatic HCC referred for experimental therapies, who had adequate tumor tissue available, had targeted next generation sequencing (NGS) of their tumor samples using the Illumina HiSeq 2000 platform (Foundation One, Foundation Medicine, MA) and their treatment outcomes were analyzed. In total, NGS was obtained for 14 patients (median number of prior therapies, 1) with advanced/metastatic HCC. Of these 14 patients, 10 (71%) were men, 4 (29%) women, 6 (43%) had hepatitis B or C-related HCC. NGS revealed at least 1 molecular abnormality in 12 patients (range 0-8, median 2). Detected molecular aberrations led to putative activation of the PI3K/AKT/mTOR pathway (n=3 [mTOR, PIK3CA, NF1]), Wnt pathway (n=6 [CTNNA1, CTNNB1]), MAPK pathway (n=2 [MAP2K1, NRAS]), and aberrant DNA repair mechanisms, cell cycle control and apoptosis (n=18 [ATM, ATR, BAP1, CCND1, CDKN2A, CDK4, FGF3, FGF4, FGF19, MCL1, MDM2, RB1, TP53]). Of the 3 patients with molecular aberrations putatively activating the PI3K/AKT/mTOR pathway, 2 received therapies including a mTOR inhibitor and all demonstrated therapeutic benefit ranging from a partial response to minor shrinkage per RECIST (-30%, -15%; respectively). In conclusion, genomic alterations are common in advanced HCC. Refractory patients with alterations putatively activating the PI3K/AKT/mTOR pathway demonstrated early signals of clinical activity when treated with therapies targeting mTOR.
    Oncotarget 05/2014; 5(10):3012-22. DOI:10.18632/oncotarget.1687 · 6.36 Impact Factor
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    • "Consistent with the known association of aberrant constitutive activation of STAT5 with human cancers/tumours of haematological and non-haematological origins, several potential oncogenes were identified as putative downstream target genes. These include, TLE4 [27], ACSL6 [28], TOP1 [28], TCEA1, TSC22D1[29], KIF1A [30], HERC2[30], LRP1B [31], CDH10[32], [33], ST6GAL2[32], FAT1[33], CHD1[34], GRID1[35], [36], IGFBP3[35], ADAM22[37], CHD6 [38] and and FRA2 [15]. Thus, the functional classification of potential STAT5-regulated genes confirmed known functions of STAT5 and furthermore provided novel insight into potential unknown cellular functions and oncogenes regulated by these proteins. "
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    ABSTRACT: Signal transducers and activators of transcription 5(STAT5) are cytokine induced signaling proteins, which regulate key immunological processes, such as tolerance induction, maintenance of homeostasis, and CD4 T-effector cell differentiation. In this study, transcriptional targets of STAT5 in CD4 T cells were studied by Chromatin Immunoprecipitation (ChIP). Genomic mapping of the sites cloned and identified in this study revealed the striking observation that the majority of STAT5-binding sites mapped to intergenic (>50 kb upstream) or intronic, rather than promoter proximal regions. Of the 105 STAT5 responsive binding sites identified, 94% contained the canonical (IFN-γ activation site) GAS motifs. A number of putative target genes identified here are associated with tumor biology. Here, we identified Fos-related antigen 2 (FRA2) as a transcriptional target of IL-2 regulated STAT5. FRA2 is a basic -leucine zipper (bZIP) motif ‘Fos’ family transcription factor that is part of the AP-1 transcription factor complex and is also known to play a critical role in the progression of human tumours and more recently as a determinant of T cell plasticity. The binding site mapped to an internal intron within the FRA2 gene. The epigenetic architecture of FRA2, characterizes a transcriptionally active promoter as indicated by enrichment for histone methylation marks H3K4me1, H3K4me2, H3K4me3, and transcription/elongation associated marks H2BK5me1 and H4K20me1. FRA2 is regulated by IL-2 in activated CD4 T cells. Consistently, STAT5 bound to GAS sequence in the internal intron of FRA2 and reporter gene assays confirmed IL-2 induced STAT5 binding and transcriptional activation. Furthermore, addition of JAK3 inhibitor (R333) or Daclizumab inhibited the induction in TCR stimulated cells. Taken together, our data suggest that FRA2 is a novel STAT5 target gene, regulated by IL-2 in activated CD4 T cells.
    PLoS ONE 02/2014; 9(2):e90370. DOI:10.1371/journal.pone.0090370 · 3.23 Impact Factor
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    • "These new technologies have been used to identify potential driver mutations in the development of liver cancer through whole-genome and -exome sequencing. The first sequencing of the primary liver cancer genome revealed a total of 11,731 somatic mutations [29]. Following studies showed that the CTNNB1, TP53, and EGFR genes were frequently mutated in liver cancer [30-33]. "
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    ABSTRACT: Development of liver cancers is driven largely by genomic alterations that deregulate signaling pathways, influencing growth and survival of cancer cells. Because of the hundreds or thousands of genomic/epigenomic alterations that have accumulated in the cancer genome, it is very challenging to find and test candidate genes driving tumor development and progression. Systematic studies of the liver cancer genome have become available in recent years. These studies have uncovered new potential driver genes, including those not previously known to be involved in the development of liver cancer. Novel approaches combining multiple datasets from patient tissues have created an unparalleled opportunity to uncover potential new therapeutic targets and prognostic/predictive biomarkers for personalized therapy that can improve clinical outcomes of the patients with liver cancer.
    12/2013; 11(4):180-185. DOI:10.5808/GI.2013.11.4.180
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