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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).

D4S2930 loci on 4q35 was frequent in HCCs with poor differentiation and of large size {108}. Inactivation of unidentified tumour suppressor genes within this region may contribute to progression of HCCs.

Microsatellite instability is another pathway for genetic instability other than chromosomal instability. Only 11% of HCCs had replication errors in one study, and the incidence of replication errors correlated significantly with poor differentiation and portal vein involvement of HCCs {961}.

Cell cycle regulators

The gene product of p16INK4 binds to cyclin-dependent kinase (CDK) 4 and prevents CDK4 from forming an active complex with cyclin D. p16 protein loss may contribute to both early- and late-stage hepatocarcinogenesis, because it was observed in 22% of early-stage HCCs and occurred approximately twice as often in advanced HCCs as in early-stage HCCs {763}. Neither p16 homozy-gous deletion/mutation nor loss of p16 mRNA expression was observed in HCCs lacking p16 protein {763}, suggesting post-transcriptional inactivation. DNA methylation around the promoter region of the p16 gene has been observed in HCC {1187}. Expression of p21WAF1/CIP1 mRNA, a universal CDK inhibitor, was reduced markedly in 38% of HCCs {762}. p21 mRNA expression of HCCs with TP53 mutations was significantly lower than that of HCCs with wild-type TP533 {762}. p21 expression is regulated predominantly by dependence on TP53in HCCs. mRNA expression of p27Kip1, another universal CDK inhibitor, was reduced in 52% of HCCs {764}.

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