Hbv X

The HBV X open reading frame is frequently integrated and expressed. HBV X [MLS1] can bind to the C terminus of p53, inhibits its sequence-specific DNA binding and transcriptional activation and suppresses p53-induced apoptosis

{2050, 2051, 457}. HBV X may affect a wide range of p53 functions and thereby contribute to the molecular pathogenesis of HCCs. HBV X further inhibits nucleotide excision repair {858}.


Mutational activation of known oncogenes is rare. Point mutations of the c-KRAS gene and coamplification of the cyclin D1 gene were detected in only 3% {1967} and 11% {1355} of HCCs, respectively.

Recent findings, obtained by comparative genomic hybridization of amplified sequences mapped to 11q12, 12p11, and 14q12, may lead to the characterization of new genes involved in hepato-carcinogenesis {1163}.

Wnt pathway and beta-catenin

In the wingless/Wnt pathway, mutations of the p-catenin gene were detected in 26-41% of HCCs {386, 760}. Nuclear accumulation of p-catenin was observed by immunohistochemistry in all HCCs with p-catenin mutations {760}. No mutation was detected in mutation cluster region of the APC gene in any of 22 HCCs analysed {760}. Deletions on chromosomes 1p, 4q, and 16p were significantly associated with the absence of p-catenin mutation, which suggests that a p-catenin-activating mutation is involved in cases without chromosomal instability {1041}.

Genetic instability and allelic loss Frequent allelic losses have been found at loci on 1p, 4q, 5q, 8p, 11p, 13q, 16p, 16q, and 17p by restriction fragment length polymorphism analysis {2046, 200, 1970, 2203, 546, 1759, 459, 460}. Loss of heterozygosity (LOH) on chromosome 16 was detected in 52% of informative cases {1970}. The common deleted region lay between HP (16q22.1) and CTRB (16q22.3-q23.3) loci {1970}. These losses occurred more frequently in HCCs with poor differentiation, of large size, and with metastasis, and were not detected in early-stage HCCs {1970}. LOH on chromosome 16 may be involved in enhancement of tumour aggressiveness. Recent development of microsatellite markers allows an extensive allelotypic analysis {2171, 163, 1307, 1515, 659, 108}. Detailed deletion mapping revealed that allelic loss at a 1-cM-interval flanked by D4S2921 and

Prevalence of TP53 mutation 70 (codon 249; AGG > AGT); % of total HCC

Senegal (10/15)

Prevalence of TP53 mutation 70 (codon 249; AGG > AGT); % of total HCC

Senegal (10/15)

Age standardized incidence of hepatocellular carcinoma (males/105)

Average range of aflatoxin B, intake (ng/kg body weight per day)

Fig. 8.24 Correlation between TP53mutation at codon 249, dietary exposure to aflatoxin B,, and regional incidence of hepatocellular carcinoma (HCC).

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