Genetic mechanisms of hepatocarcinogenesis.

The development of hepatocellular carcinoma (HCC) is amultistep process associated with changes in host geneexpression, some of which correlate with the appearanceand progression of tumor. Preneoplastic changes in geneexpression result from altered DNA methylation, theactions of hepatitis B and C viruses, and point mutationsor loss of heterozygosity (LOH) in selected cellulargenes. Tumor progression is characterized by LOHinvolving tumor suppressor genes on many chromosomesand by gene amplification of selected oncogenes. Thechanges observed in di•erent HCC nodules are oftendistinct, suggesting heterogeneity on the molecular level.These observations suggest that there are multiple,perhaps redundant negative growth regulatory pathwaysthat protect cells against transformation. An under-standing of the molecular pathogenesis of HCC mayprovide new markers for tumor staging, for assessmentof the relative risk of tumor formation, and open newopportunities for therapeutic intervention.Oncogene (2002) 21, 2593–2604. DOI: 10.1038/sj/onc/1205434Keywords: hepatocellular carcinoma; hepatitis viruses;loss of heterozygosity; mutationsIntroductionOne of the most frequent tumor types worldwide ishepatocellular carcinoma (HCC). It is most commonlyassociated with chronic hepatitis B virus (HBV) andhepatitis C virus (HCV) infections, with chronicexposure to the mycotoxin, aflatoxin B