Liver: Hepatocellular carcinoma

2001-10-01   Brigitte Debuire , Antoinette Lemoine 

1.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

Clinics and Pathology

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, Wilsons disease, citrullinemia or tyrosinemia).

Epidemiology

one of the most common cancers worldwide affecting 250,000 to 1,000,000 individuals annually

Pathology

Edmonsons 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.
  • Genes Involved and Proteins

    Gene name

    TP53 (Tumour protein p53 (Li-Fraumeni syndrome))

    Location

    17p13.1

    Dna rna description

    11 exons

    Protein description

    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 mutations

    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 name

    CTNNB1 (Catenin, beta-1)

    Location

    3p22.1

    Dna rna description

    16 exons

    Protein description

    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 mutations

    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 name

    AXIN1 (axin 1)

    Location

    16p13.3

    Dna rna description

    11 exons

    Protein description

    Putative tumor suppressor.

    Somatic mutations

    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 name

    IGF2R (insulin-like growth factor 2 receptor)

    Location

    6q25.3

    Dna rna description

    48 exons

    Protein description

    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 mutations

    LOH at the IGF2R locus has been reported and the IGF2R gene is mutated in 18-33% of HCCs.

    Gene name

    SMAD2 (mothers against decapentaplegic homolog 2 (Drosophila))

    Location

    18q21.1

    Dna rna description

    12 exons

    Protein description

    Candidate tumor suppressor; SMAD2 ans SMAD4 (see below) are intracellular mediators of TGF-b.

    Somatic mutations

    SMAD2 and SMAD4 are mutated in less than 10% of HCCs.

    Gene name

    SMAD4 (mothers against decapentaplegic homolog 4 (Drosophila))

    Location

    18q21.2

    Dna rna description

    11 exons

    Protein description

    Candidate tumor suppressor

    Gene name

    RB1 (retinoblastoma)

    Location

    13q14.2

    Dna rna description

    27 exons

    Protein description

    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 mutations

    LOH at the RB1 gene locus and RB1 mutations have been observed in about 15% of HCCs.

    Gene name

    CDKN2A (cyclin dependent kinase 2a / p16)

    Location

    9p21.3

    Dna rna description

    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 description

    Inhibitor of cyclin-dependent kinases (CDK) 4 and 6.

    Somatic mutations

    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 name

    CCND1 (B-cell leukemia/lymphoma 1)

    Location

    11q13.3

    Dna rna description

    5 exons.

    Protein description

    Involved in cell cycle control: G1 progression and G1/S transition.

    Somatic mutations

    Cyclin D1 gene has been shown to be amplified in 10-20% of HCCs.

    To be Noted

    Note

  • 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.
  • Bibliography

    Pubmed IDLast YearTitleAuthors
    104022501999The transcriptional function of the hepatitis B virus X protein and its role in hepatocarcinogenesis (Review).Andrisani OM et al
    91579951997Concerted nonsyntenic allelic losses in hyperploid hepatocellular carcinoma as determined by a high-resolution allelotype.Boige V et al
    90102351997Further characterisation of the p53 responsive element--identification of new candidate genes for trans-activation by p53.Bourdon JC et al
    16727321991Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa.Bressac B et al
    13257331992Hepatitis B viruses and hepatocellular carcinoma.Buendia MA et al
    108718382000Hepatitis B virus-related insertional mutagenesis implicates SERCA1 gene in the control of apoptosis.Chami M et al
    91857561997Germ-line mutations of the p16INK4(MTS1) gene occur in a subset of patients with hepatocellular carcinoma.Chaubert P et al
    74930291995M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity.De Souza AT et al
    30143471986Hepatitis B virus DNA integration in a sequence homologous to v-erb-A and steroid receptor genes in a hepatocellular carcinoma.Dejean A et al
    97552581998Hepatocellular carcinoma.Di Bisceglie AM et al
    83026061994Insertional activation of mevalonate kinase by hepatitis B virus DNA in a human hepatoma cell line.Graef E et al
    97959121998Pathogenesis of hepatitis B and C-induced hepatocellular carcinoma.Idilman R et al
    98630181999Mutation analysis of transforming growth factor beta type II receptor, Smad2, and Smad4 in hepatocellular carcinoma.Kawate S et al
    87605831996Infrequent alterations of the p16INK4A gene in liver cancer.Kita R et al
    113759572001Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis.Laurent-Puig P et al
    106092701999[Hepatocellular carcinoma].Lemoine A et al
    96571011998Microsatellite instability and loss of heterozygosity at DNA mismatch repair gene loci occurs during hepatic carcinogenesis.Macdonald GA et al
    89939811997Recurrent chromosomal abnormalities in hepatocellular carcinoma detected by comparative genomic hybridization.Marchio A et al
    96355721998Activation of the beta-catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3.Miyoshi Y et al
    94141721997Hepatocellular carcinoma: from gene to public health.Montesano R et al
    16552541991Aberrations of the tumor suppressor p53 and retinoblastoma genes in human hepatocellular carcinomas.Murakami Y et al
    92050991997Comprehensive allelotyping of human hepatocellular carcinoma.Nagai H et al
    16613381991Deletions and rearrangements of the retinoblastoma gene in hepatocellular carcinoma, insulinoma and some neurogenic tumors as found in a study of 121 tumors.Nakamura T et al
    82055251994Amplification and overexpression of the cyclin D1 gene in aggressive human hepatocellular carcinoma.Nishida N et al
    105183031999Genetic aspects of hepatocellular carcinogenesis.Ozturk M et al
    97699501997TP53 and hepatocellular carcinoma.Puisieux A et al
    100273371999Clinical significance of circulating anti-p53 antibodies in European patients with hepatocellular carcinoma.Saffroy R et al
    99269331999Microsatellite instability in European hepatocellular carcinoma.Salvucci M et al
    107001762000AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1.Satoh S et al
    19678221990Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma.Wang J et al
    104908211999Smad2 and Smad4 gene mutations in hepatocellular carcinoma.Yakicier MC et al
    92942141997Loss of the gene encoding mannose 6-phosphate/insulin-like growth factor II receptor is an early event in liver carcinogenesis.Yamada T et al
    82403181993Amplification and overexpression of cyclin D1 in human hepatocellular carcinoma.Zhang YJ et al
    96717671998Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas.de La Coste A et al

    External Links

    Citation

    Brigitte Debuire ; Antoinette Lemoine

    Liver: Hepatocellular carcinoma

    Atlas Genet Cytogenet Oncol Haematol. 2001-10-01

    Online version: http://atlasgeneticsoncology.org/solid-tumor/5039/hepatocarcinid5039