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Liver: Hepatocellular carcinoma

Written2001-10Brigitte Debuire, Antoinette Lemoine
Unité de Biologie Cellulaire du Noyau, CNRS URA 2582, Département de Biologie Cellulaire et Infection, Institut Pasteur, 25, Rue du Docteur Roux, 75724 Paris Cedex 15, France

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Identity

ICD-Topo C220 LIVER
ICD-Morpho 8170/3 Hepatocellular carcinoma, NOS
Atlas_Id 5039
Phylum Digestive organs: Liver::Hepatocellular carcinoma

Clinics and Pathology

Disease Hepatocellular carcinoma (HCC) is an aggressive malignancy with a poor prognosis.
Etiology Eastern Asia and sub-Saharan Africa are the most prevalent regions. Hepatitis B virus (HBV) is a major risk factor. In some geographic areas (e.g. Asia, Southern Africa), aflatoxin B1 (AFB1) is also considered to be a significant etiologic factor. Exposure to dietary AFB1 and chronic HBV infection are synergistic risk factors in chinese areas of high-HCC incidence. HCC is also a late complication of Hepatitis C virus (HCV) infection as observed in Western countries and Japan. The prevalence of cirrhosis in individuals with HCC and chronic hepatitis B or C is reported to be 80 and 75 % respectively. Other etiologic factors include being male (sex ratio M/F = 4/1), the use of sex hormones (both androgens and progestins) and conditions associated with chronic necroinflammatory liver disease and cirrhosis such as alcohol consumption or metabolic disorders of the liver (i.e. hemochromatosis, Wilson's disease, citrullinemia or tyrosinemia).
Epidemiology one of the most common cancers worldwide affecting 250,000 to 1,000,000 individuals annually
Pathology Edmonson's staging system.
Treatment Resection with or without adjuvant chemotherapy, liver transplantation, transarterial chemo-embolisation, intrahepatic alcoholization.

Genetics

Note
  • Note Little is known about the hepatocarcinogenesis mechanisms which seem to differ according to the risk factor involved.
  • HBV impact In HBV carriers most HCCs contain DNA sequences integrated into the host chromosomal DNA. Integration is at random except in rare cases in which HBV integration at specific sites has been shown to activate endogenous genes such as retinoic acid b- receptor, cyclin A, mevalonate kinase and SERCA-1. In addition, HBx is a potent co-transactivator of viral and cellular promoters such as c-myc and c-fos.
  • Cytogenetics

    Note LOH The most frequently altered genes in HCC are tumor suppressor genes ; deletions have been reported at ten chromosome arms, 8p (48%), 17p (45%), 4q (38%), 1p (33%), 13q (31%), 16q (30%), 6q (29%), 16p (24%), 1q (22%) and 9p (20%) with a frequency higher than 20%. For chromosome arms 17p, 13q, 9p, 6q and 16p, LOH has been related to p53, RB1, p16, IGF2R and Axin 1 inactivation.

    Genes involved and Proteins

    Gene NameTP53 (Tumour protein p53 (Li-Fraumeni syndrome))
    Location 17p13.1
    Dna / Rna 11 exons
    Protein Tumor suppressor ; 5 highly conserved domains. The central portion of the gene encodes the sequence-specific DNA binding domain which mediates transcriptional activation and is the target of the majority of mutations observed in many human cancers. The P53 protein is involved in cell cycle control, senescence, DNA repair, genomic stability and apoptosis.
    Somatic mutation The frequency and type of P53 mutations differ according to the geographic origin and suspected etiology of HCC. A specific codon 249 mutation (AGG _ AGT) leading to an arginine to serine substitution (R249S) has been linked to aflatoxin exposure in 36% of tumors from Africa and 32% of tumors from China, respectively. Worldwide, the frequency of codon 249 mutations is 11%. Other codons of the p53 gene can be altered in HCC and overall this gene is mutated in about one third of these tumors. The wild type p53 protein can also be overexpressed in HCC. Experimentally, the HBx protein encoded by the x region of HBV has been shown to interact with wild type p53 and to inhibit its function. P53 antibodies have been detected in the serum of HCC patients. P53 alterations have been associated with poorly differentiated, large tumors and with a lower overall survival.

    Gene NameCTNNB1 (Catenin, beta-1)
    Location 3p22.1
    Dna / Rna 16 exons
    Protein Oncogene. Has physical and functional interactions with APC in the Wnt/wingless carcinogenesis pathway. Also forms complexes with E-cadherin. Thus, b-catenin participates in cell-to-cell interactions. It also appears to play a part in transcriptional regulation.
    Somatic mutation The b-catenin gene is mutated in about 20-25% of HCCs. The mutations occur at the 5' end of the gene (exons 2-4) and lead to an accumulation of aberrant b-catenin proteins in the nucleus. Most of b-catenin point mutations alter 1 of the 4 serine or threonine residues which are targets for phosphorylation by GSK3 and are crucial for the down-regulation of the protein. Major hot spots are on amino acids S33, T41, and S45.

    Gene NameAXIN1 (axin 1)
    Location 16p13.3
    Dna / Rna 11 exons
    Protein Putative tumor suppressor.
    Somatic mutation The Axin 1 gene is mutated in about 5-10% of HCCs. Point mutations are the most frequent alterations although small deletions, homozygous deletions and small duplications can be found. The majority of Axin 1 mutations in HCC are nonsense or frameshift mutations.

    Gene NameIGF2R (insulin-like growth factor 2 receptor)
    Location 6q25.3
    Dna / Rna 48 exons
    Protein Putative tumor suppressor. IGF2R is involved in the TGF-b-mediated growth control which induces both growth inhibition and apoptotic cell death in hepatocytes.
    Somatic mutation LOH at the IGF2R locus has been reported and the IGF2R gene is mutated in 18-33% of HCCs.

    Gene NameSMAD2 (mothers against decapentaplegic homolog 2 (Drosophila))
    Location 18q21.1
    Dna / Rna 12 exons
    Protein Candidate tumor suppressor; SMAD2 ans SMAD4 (see below) are intracellular mediators of TGF-b.
    Somatic mutation SMAD2 and SMAD4 are mutated in less than 10% of HCCs.

    Gene NameSMAD4 (mothers against decapentaplegic homolog 4 (Drosophila))
    Location 18q21.2
    Dna / Rna 11 exons
    Protein Candidate tumor suppressor

    Gene NameRB1 (retinoblastoma)
    Location 13q14.2
    Dna / Rna 27 exons
    Protein pRB, 110kDa, is phosphorylated during the G1 phase of the cell cycle by members of the cyclin-dependent kinase (cdk) system. Hypophosphorylated pRB binds to members of the E2F family of transcription factors.
    Somatic mutation LOH at the RB1 gene locus and RB1 mutations have been observed in about 15% of HCCs.

    Gene NameCDKN2A (cyclin dependent kinase 2a / p16)
    Location 9p21.3
    Dna / Rna 3 exons. The INK4A-ARF locus gives two transcripts, the alpha transcript which encodes p16 INK4A and the beta transcript which encodes p19 ARF.
    Protein Inhibitor of cyclin-dependent kinases (CDK) 4 and 6.
    Somatic mutation Both somatic and germline mutations have been found in HCC. In addition, 50% of HCCs display de novo methylation of p16 INK4A, probably leading to gene silencing and loss of a cyclin-dependent kinase inhibitor protein.

    Gene NameCCND1 (B-cell leukemia/lymphoma 1)
    Location 11q13.3
    Dna / Rna 5 exons.
    Protein Involved in cell cycle control: G1 progression and G1/S transition.
    Somatic mutation Cyclin D1 gene has been shown to be amplified in 10-20% of HCCs.

    To be noted

  • At least three genes, IGF2R, SMAD2, SMAD4, involved in TGF-b-mediated growth control are altered in HCC. Overall the TGF-b pathway is altered in about 25% of HCCs.
  • RB1, p16 INK4A and cyclin D1 are involved in the regulation of the G1 phase of the cell cycle. When combined the mutations of these genes, although relatively low individually, lead to a loss of growth control in more than 30% of HCCs.
  • Other genetic alterations Insulin-like growth factor 2 ( IGF2) as well as insulin receptor substrate 1 ( IRS-1) are overexpressed in many human HCC tumor tissues and cell lines. BRCA2, p21 and p15 INK4B are rarely involved in HCC.
  • Many genes are altered in hepatocarcinogenesis but the frequency of individual gene mutations is low. Genes involved in important regulatory pathways are the targets of these mutations. Four main pathways can be distinguished : the p53 pathway involved in DNA damage response and apoptosis, the b-catenin/APC pathway involved in intercellular interactions and signal transduction, the TGF-b pathway involved in growth inhibition and hepatocyte death and the RB1 pathway involved in cell cycle control. Connections between these different pathways are most probable.
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    Citation

    This paper should be referenced as such :
    Debuire, B ; Lemoine, A
    Liver: Hepatocellular carcinoma
    Atlas Genet Cytogenet Oncol Haematol. 2002;6(1):49-52.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Tumors/HepatoCarcinID5039.html


    Other genes implicated (Data extracted from papers in the Atlas) [ 283 ]

    Genes ABCC10 ACLY ACVRL1 AFAP1L2 AFP AIFM1 AKT1 AKT3 AMFR
    ANG ANP32A APAF1 AREG ASPM ATF5 ATP5B AURKA AURKB AXIN1
    AXIN2 BCAR1 CCND1 BCL2L14 BCL2L1 BIRC6 BMP4 BNIP3L BRAF BABAM2
    BUB1 BYSL TIGAR CALR CASP8 CBFA2T3 CCNA1 CCNB1 CCR1 CD151
    CD44 CD82 CDC25A CDC25A CDC42 CDH17 CDKN2B CEACAM1 CEBPA CHFR
    CKS2 CLDN10 CLDN6 CLDN9 CLIC1 COL16A1 COL1A2 CPM CRYAB CSE1L
    CSF1R CSTA CSTB CTDSPL CTNNB1 CXCL10 CXCL17 CYB5A CYP2W1 DDC
    DDR1 DGKA DIABLO DIRAS3 DKK3 DLC1 DNAJA3 DNMT1 DNMT3B DPP4
    DUSP1 E2F4 ECM1 EDIL3 EEF1A1 EFEMP1 EGR1 EHMT2 EIF2AK2 ELF4
    ENO1 ENOX2 ENPP2 EPHA2 ERGIC3 ETS2 EZH2 AMER1 FAT1 FBLN1
    FBXO31 FGF1 FGF2 FGF2 FGF2 FGFR1 FGFR4 FHL2 FOXC1 FOXQ1
    FST FSTL3 FUBP1 FUT8 GATA2 GLI2 GLS2 GNAS GPC3 GRN
    HDAC2 HFE HGF HLA-G HLTF HNRNPD HTATIP2 ICAM1 ID1 IDH2
    IDO1 IGF2BP1 IGF2R IL17A ING1 ING2 ING3 ING4 INPP4B INPPL1
    IRS1 IRS2 ITGA1 JAK1 KCNH1 PCLAF KIF14 KRAS LATS2 LDOC1
    LIN28B MAPK12 MAPK13 MAPK7 MARK4 MCC MIF RIOX2 MIR100 MIR106B
    MIR122 MIR135A1 MIR150 MIR183 MIR191 MIR200C MIR22 MIR23A MIR26A1 MIR296
    MIR373 MIR429 MIR449A MIR744 MIR10B MIR21 MIR221 MKI67 MME MTUS1
    MYBL2 NANOG NCOA3 NCR2 NDRG1 NDRG2 NDUFA13 NFATC2 NME1
    NNMT NR1H4 NR4A1 NRAS NRF1 NUAK1 OPCML OSGIN1 TP53 PRKN
    PARK7 PDCD5 PEBP1 PEG10 PFKFB2 PHLPP2 PIWIL1 PLAUR PPP1R8 PRDM2
    PTGS2 PTK2 PTMA PTPN13 PTPN14 PTPN9 RAB31 RACGAP1 RAF1 RASSF2
    RHOA RHOC RND3 ROBO1 ROCK2 RRM2 RUVBL1 RUVBL2 S100PBP SCD
    SEPT7 SERPINB3 SHC1 SIAH1 SIRT1 SLC1A5 SLC22A3 SMAD2 SMAD4 SMYD3
    SNAI1 SOCS1 SOCS2 SOCS6 SOX4 SPRY1 SSX2 STARD13 STAT5B STMN1
    SULF1 SULF2 TALDO1 TBX3 TEK TFF3 TFRC TGFBR2 TGFBR3 THBS1
    THRB TMSB10 TP53BP2 TP63 TPD52 TPX2 TRPV1 TRPV2 TSPAN1 TSPAN8
    TSPY1 TWIST1 TWIST2 TXN UBD UBE2C VAV3 VCP WIF1 WWOX
    YAP1 ZBTB7A ZFP36L1

    External links

    arrayMap Topo ( C22) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
     
     
    Other databasecBioPortal: Liver Hepatocellular Carcinoma (AMC, Hepatology in press)
    Other databasecBioPortal: Liver Hepatocellular Carcinoma (RIKEN, Nature Genetics 2012)
    Other databasecBioPortal: Liver Hepatocellular Carcinoma (TCGA, Provisional)
    Other databaseLiver hepatocellular carcinoma (LIHC) TCGA Copy Number Portal
    Other databaseHepatocarcinoma ( intOGen )
    Other databaseHepatocarcinoma ( intOGen )
    Other databaseLiver Cancer (ACRG)(OASIS Portal)
    Other databaseLiver Hepatocellular Carcinoma (TCGA)(OASIS Portal)
    Other databaseLiver Hepatocellular Carcinoma [ Genomic Data Commons - NCI TCGA-LIHC]
    Disease databaseLiver: Hepatocellular carcinoma
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed


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