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      Whole-exome mutational landscape of metastasis in patient-derived hepatocellular carcinoma cells

      research-article
      a , b , c , 1 , a , b , c , 1 , a , b , c , a , b , c , a , b , c , a , b , c , a , b , c ,
      Genes & Diseases
      Chongqing Medical University
      Clonal evolution, Encyclopedia of genes and genomes (KEGG), Gene ontology (GO), Genome-wide association, Hepatocellular carcinoma, Metastatic potentiality, Somatic gene mutation, Whole exome sequencing, bZIP, basic-region leucine zipper, BTB, Broad-complex, Tramtrack, and Bric-a-brac, CDS, coding for amino acids in protein, CNC, cap’n’collar, CTR, C-terminal region, CUL3, Cullin3, DGR, DC domain harboring six Kelch-repeat domain, FA, fatty acid, GO, Gene Ontology, HCC, hepatocellular carcinoma, IVR, intervening region, KEGG, Kyoto Encyclopedia of Genes and Genomes, NTR, N-terminal region, OS, overall survival, SNP, single nucleotide polymorphism, WES, whole exome sequencing

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          Abstract

          In order to explore the genomic basis for liver cancer metastasis, whole-exome sequencing (WES) was performed on patient-derived hepatocellular carcinoma (HCC) cell lines with differential metastatic potentials and analyzed their clonal evolution relationships. An evolutionary tree based on genomic single nucleotide polymorphism (SNP) was constructed in MegaX software. The WES data showed that the average percentage of heterogeneous mutations in each HCC cell lines was 16.55% (range, 15.38%–18.17%). C: G > T: A and T: A > C: G somatic transitions were the two most frequent substitutions. In these metastatic HCC cell lines, non-silent gene mutations were found in 21.88% of known driver genes and 10 classical signaling pathways. The protein interaction network was constructed by STRING, and hub genes were found in the shared trunk mutation genes and the heterogeneous branch mutations respectively. In cBioPortal database, some of the selected hub genes were found to be associated with poor overall survival (OS) of HCC patients. Among the mutated HCC driver genes, a novel KEAP1 mutation with a homozygous frameshift truncation at the c-terminal Nrf2 binding region was detected and verified in MHCC97-H and HCC97LM3 cells. In conclusion, WES data demonstrate that HCC cell lines from tumor biopsy specimens of the same patient have obtained different metastatic potentials through repeated selection in rodents in vivo, and they do indeed have a genetic relationship at the genomic level.

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          Most cited references35

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          Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution.

          The Keap1–Nrf2 regulatory pathway plays a central role in the protection of cells against oxidative and xenobiotic damage. Under unstressed conditions, Nrf2 is constantly ubiquitinated by the Cul3–Keap1 ubiquitin E3 ligase complex and rapidly degraded in proteasomes. Upon exposure to electrophilic and oxidative stresses, reactive cysteine residues of Keap1 become modified, leading to a decline in the E3 ligase activity, stabilization of Nrf2 and robust induction of a battery of cytoprotective genes. Biochemical and structural analyses have revealed that the intact Keap1 homodimer forms a cherry-bob structure in which one molecule of Nrf2 associates with two molecules of Keap1 by using two binding sites within the Neh2 domain of Nrf2. This two-site binding appears critical for Nrf2 ubiquitination. In many human cancers, missense mutations in KEAP1 and NRF2 genes have been identified. These mutations disrupt the Keap1–Nrf2 complex activity involved in ubiquitination and degradation of Nrf2 and result in constitutive activation of Nrf2. Elevated expression of Nrf2 target genes confers advantages in terms of stress resistance and cell proliferation in normal and cancer cells. Discovery and development of selective Nrf2 inhibitors should make a critical contribution to improved cancer therapy.
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            Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer.

            Liver cancer, which is most often associated with virus infection, is prevalent worldwide, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 liver cancers from Japanese individuals. Our comprehensive analysis identified point mutations, structural variations (STVs), and virus integrations, in noncoding and coding regions. We discovered mutational signatures related to liver carcinogenesis and recurrently mutated coding and noncoding regions, such as long intergenic noncoding RNA genes (NEAT1 and MALAT1), promoters, CTCF-binding sites, and regulatory regions. STV analysis found a significant association with replication timing and identified known (CDKN2A, CCND1, APC, and TERT) and new (ASH1L, NCOR1, and MACROD2) cancer-related genes that were recurrently affected by STVs, leading to altered expression. These results emphasize the value of whole-genome sequencing analysis in discovering cancer driver mutations and understanding comprehensive molecular profiles of liver cancer, especially with regard to STVs and noncoding mutations.
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              Oncotator: cancer variant annotation tool.

              Oncotator is a tool for annotating genomic point mutations and short nucleotide insertions/deletions (indels) with variant- and gene-centric information relevant to cancer researchers. This information is drawn from 14 different publicly available resources that have been pooled and indexed, and we provide an extensible framework to add additional data sources. Annotations linked to variants range from basic information, such as gene names and functional classification (e.g. missense), to cancer-specific data from resources such as the Catalogue of Somatic Mutations in Cancer (COSMIC), the Cancer Gene Census, and The Cancer Genome Atlas (TCGA). For local use, Oncotator is freely available as a python module hosted on Github (https://github.com/broadinstitute/oncotator). Furthermore, Oncotator is also available as a web service and web application at http://www.broadinstitute.org/oncotator/.
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                Author and article information

                Contributors
                Journal
                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                2352-4820
                2352-3042
                15 May 2020
                September 2020
                15 May 2020
                : 7
                : 3
                : 380-391
                Affiliations
                [a ]Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing, China
                [b ]Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China
                [c ]Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
                Author notes
                []Corresponding author. Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing, China. yongliao@ 123456cqmu.edu.cn y8982000@ 123456yahoo.com
                [1]

                The two authors have equal contribution.

                Article
                S2352-3042(20)30068-4
                10.1016/j.gendis.2020.05.003
                7452411
                32884992
                d2b754f0-1c28-4cd0-8040-e1057b120ae6
                © 2020 Chongqing Medical University. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 10 February 2020
                : 29 April 2020
                : 9 May 2020
                Categories
                Article

                clonal evolution,encyclopedia of genes and genomes (kegg),gene ontology (go),genome-wide association,hepatocellular carcinoma,metastatic potentiality,somatic gene mutation,whole exome sequencing,bzip, basic-region leucine zipper,btb, broad-complex, tramtrack, and bric-a-brac,cds, coding for amino acids in protein,cnc, cap’n’collar,ctr, c-terminal region,cul3, cullin3,dgr, dc domain harboring six kelch-repeat domain,fa, fatty acid,go, gene ontology,hcc, hepatocellular carcinoma,ivr, intervening region,kegg, kyoto encyclopedia of genes and genomes,ntr, n-terminal region,os, overall survival,snp, single nucleotide polymorphism,wes, whole exome sequencing

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