GENOMIC ABNORMALITIES IN HEPATOCARCINOGENESIS - IMPLICATIONS FOR A CHEMOPREVENTIVE STRATEGY

Carcinogenesis is a complex process characterized by the cumulative ac tivation of various oncogenes and the inactivation of suppressor genes . Epigenetic mechanisms are also involved. Mutational activation of ra s family genes occurs in most spontaneous or carcinogen-induced liver tumors, in susceptible mice, and less frequently in preneoplastic lesi ons. This suggests a pathogenetic role of these changes in hepatic car cinogenesis, in the mouse. Overexpression of various growth-related ge nes occurs in preneoplastic tissue during rat liver carcinogenesis, bu t mutational activation of protooncogenes, notably of ras family genes , seems to be a late and rare event, while c-myc amplification is a la te but frequent event in both rodent and human carcinogenesis. However , mutation of the suppressor p53 gene has been found in relatively ear ly preneoplastic lesions in rat liver, and it may be frequently seen i n human hepatocellular carcinomas. The possibility that this mutation is involved in the initiation stage of liver carcinogenesis is an attr active hypothesis which needs further evaluation. DNA hypomethylation is involved in carcinogenesis, but the mechanisms underlying this effe ct are still elusive. Hypomethylation of growth-related genes is assoc iated with their overexpression and this could favor overgrowth of pre neoplastic liver tissue. Decrease in S-adenosyl methionine/S-adenosylh omocysteine (SAM/SAH) ratio occurs in the liver of rats fed a methyl d eficient diet, which is a carcinogenic treatment, and in preneoplastic liver tissue, developing in initiated/promoted rats fed an adequate d iet. The role of low SAM/SAH ratio in carcinogenesis is substantiated by the tumor chemopreventive effect of lipotropic compounds. Treatment with exogenous SAM prevents the development of preneoplastic and neop lastic lesions in rat liver. This is associated with recovery of SAM/S AH ratio, DNA methylation and inhibition of growth-related gene expres sion. SAM effect on prenoplastic cell growth is abolished by 5-azacyti dine, a hypomethylating agent, indicating the involvement of DNA methy lation. The possibility that in SAM-treated rats, methylation and inhi bition of the expression of growth-related genes is implicated in grow th restraint is attractive and should be further evaluated. Modulation of rat liver carcinogenesis by influencing gene expression through DN A methylation or other epigenetic mechanisms could be a new approach t o chemoprevention of these tumors.