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In this issue

SUSCEPTIBILITY TO HEPATOCARCINOGENESIS IN COP RATS Hepatocarcinoma (HCC) is most prevalent in certain areas of Africa and Asia, where infection with hepatitis viruses B and C together with exposure to aflatoxin B1 is common. Other etiologic factors include alcohol consumption, estrogenic steroids, exposure to some naturally occurring carcinogens in food and several rare genetic syndromes. As in other cancers, multiple lowpenetrance genes probably segregate to confer differences in predisposition among individuals. The polygenic characteristics of inheritance as well as variations in penetrance make identification of these tumor-modifier genes in humans by linkage extremely challenging. In contrast, these studies are amenable to study in rodent experimental models of cancer and it can reasonably be expected that the identification of such genes in rodents will make it possible to identify human homologues. Clonal expansion of initiated cells in rat liver carcinogenesis is characterized by the progressive development of preneoplastic hepatocytic foci that evolve into nodules exhibiting rapid growth and that have a number of morphologic, biochemical and molecular properties in common with preneoplastic and neoplastic human liver lesions. Most early preneoplastic and neoplastic liver lesions undergo a progressive decrease in growth rate and finally regress via “remodeling”, whereas persistent lesions evolve into HCCs. Neoplastic liver lesions induced in rat strains genetically resistant to liver cancer development (Wistar, BN, DRH and Cop) exhibit a lower growth rate and higher levels of remodeling than lesions in F344 rats, which are highly susceptible to HCC development. Previous studies have shown that BFF1 rats, generated by crossing the resistant BN with the susceptible F344 strain, are almost completely resistant to hepatocarcinogenesis. By quantitative trait loci analysis in F1 backcross and intercross rats a number of susceptibility and resistance loci with genetic linkage to the volume and number of liver lesions have been identified. This suggests that phenotypic reversion is genetically controlled but does not indicate whether different genetic mechanisms are implicated in the development of nonremodeling and remodeling lesions. In this issue, de Miglio and colleagues (pages 9 –16) report that susceptibility to hepatocarcinogenesis in Cop rats is controlled by a complex array of genes with several gene– gene interactions and that different genetic mechanisms control remodeling and nonremodeling liver nodules. Frequent deregulation in human liver cancer of genes positioned in chromosomal segments syntenic to rat susceptibility/resistance loci suggests some similarities between the genetic mechanisms involved in hepatocarcinogenesis in rats and humans. LOSS OF CYCLIN E1 RESPONSIBLE FOR