Review of genetic and epigenetic alterations in hepatocarcinogenesis.
Hepatocellular carcinoma (HCC) is associated with multiple risk factors and is believed to arise from pre-neoplastic lesions, usually in the background of cirrhosis. However, the genetic and epigenetic events of hepatocarcinogenesis are relatively poorly understood. HCC display gross genomic alterations, including chromosomal instability (CIN), CpG island methylation, DNA rearrangements associated with hepatitis B virus (HBV) DNA integration, DNA hypomethylation and, to a lesser degree, microsatellite instability. Various studies have reported CIN at chromosomal regions, 1p, 4q, 5q, 6q, 8p, 10q, 11p, 16p, 16q, 17p and 22q. Frequent promoter hypermethylation and subsequent loss of protein expression has also been demonstrated in HCC at tumor suppressor gene (TSG), p16, p14, p15, SOCS1, RIZ1, E-cadherin and 14-3-3 sigma. An interesting observation emerging from these studies is the presence of a methylator phenotype in hepatocarcinogenesis, although it does not seem advantageous to have high levels of microsatellite instability. Methylation also appears to be an early event, suggesting that this may precede cirrhosis. However, these genes have been studied in isolation and global studies of methylator phenotype are required to assess the significance of epigenetic silencing in hepatocarcinogenesis. Based on previous data there are obvious fundamental differences in the mechanisms of hepatic carcinogenesis, with at least two distinct mechanisms of malignant transformation in the liver, related to CIN and CpG island methylation. The reason for these differences and the relative importance of these mechanisms are not clear but likely relate to the etiopathogenesis of HCC. Defining these broad mechanisms is a necessary prelude to determine the timing of events in malignant transformation of the liver and to investigate the role of known risk factors for HCC.
Herath
Nirmitha I
NI
Leukaemia Foundation Laboratory, Queensland Institute of Medical Research, Clinical Research Center, Royal Brisbane Hospital Research Foundation, Brisbane, Queensland, Australia. nirmathH@qimr.edu.au
Leggett
Barbara A
BA
MacDonald
Graeme A
GA
D000818:Animals; D020137:Base Pair Mismatch; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D043171:Chromosomal Instability; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics* / Q000378:metabolism; D004777:Environment; D044127:Epigenesis, Genetic; D006801:Humans; D015994:Incidence; D008113:Liver Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D018895:Microsatellite Repeats / Q000235:genetics; D011230:Precancerous Conditions / Q000235:genetics* / Q000378:metabolism
D004273:DNA, Neoplasm