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).

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

Edmonsons staging system.

Resection with or without adjuvant chemotherapy, liver transplantation, transarterial chemo-embolisation, intrahepatic alcoholization.

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

17p13.1

11 exons

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.

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.

CTNNB1 (Catenin, beta-1)

3p22.1

16 exons

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.

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.

AXIN1 (axin 1)

16p13.3

11 exons

Putative tumor suppressor.

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.

IGF2R (insulin-like growth factor 2 receptor)

6q25.3

48 exons

Putative tumor suppressor. IGF2R is involved in the TGF-b-mediated growth control which induces both growth inhibition and apoptotic cell death in hepatocytes.

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

SMAD2 (mothers against decapentaplegic homolog 2 (Drosophila))

18q21.1

12 exons

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

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

SMAD4 (mothers against decapentaplegic homolog 4 (Drosophila))

18q21.2

11 exons

Candidate tumor suppressor

RB1 (retinoblastoma)

13q14.2

27 exons

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.

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

CDKN2A (cyclin dependent kinase 2a / p16)

9p21.3

3 exons. The INK4A-ARF locus gives two transcripts, the alpha transcript which encodes p16 INK4A and the beta transcript which encodes p19 ARF.

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

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.

CCND1 (B-cell leukemia/lymphoma 1)

11q13.3

5 exons.

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

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