The authors thank Raoul Poupon for his critical reading and fruitful discussion of the manuscript. Additional Supporting Information may be found in the online version of this article. “
“CGH, comparative genomic hybridization; CIN, chromosomal instability; DEN, diethylnitrosamine; DN, dysplastic nodules; HCC, hepatocellular carcinoma; LOH, loss of heterozygosity; MSI, microsatellite instability,

PB, phenobarbital. The stepwise progression from early dysplastic lesions Epigenetics inhibitor to fully malignant and metastatic tumors is associated with an increased occurrence of genomic alterations, a condition known as genomic instability.1 Most tumor types exhibit a form of genomic instability called chromosomal

instability (CIN), referring to the high rate by which chromosome structure (amplification, duplication, deletion, translocation, etc.) and number (aneuploidy, polyploidy) change over time in cancer cells compared with normal cells.1 Some of these chromosomal abnormalities are detected in all tumor cells but others are not, suggesting that tumor cells initially derive from a genetically unstable single cell, which continues to acquire chromosomal abnormalities over time. The latter assumption has been substantiated by the observation that in vitro growth stimulates the generation of CIN in cancer cells.1 Other forms of genomic instability have also been discovered. These include microsatellite instability (MSI), in which the expansion or contraction of the Selleckchem HIF inhibitor number of oligonucleotide repeats present in microsatellite sequences occurs,2

and forms of genomic instability that are characterized by increased frequencies of basepair mutations.3 In hepatocellular carcinoma (HCC), mounting evidence indicates that CIN is the predominant form of genomic instability, whereas MSI seems to be a rare event.4 Investigations have been performed 17-DMAG (Alvespimycin) HCl on this issue both in rodent models of liver cancer and in human HCC. In transgenic mouse models, two distinct patterns of genomic instability were found to be associated with HCC development. Transgenic mice overexpressing the c-Myc and E2F1 protooncogenes either alone or in combination display a low rate of genomic instability, whereas a high rate of genomic instability accompanies the accelerated and more aggressive hepatocarcinogenesis driven by coexpression of c-Myc and transforming growth factor alpha (TGF-α) transgenes.5 Strikingly, an opposite pattern was detected when analyzing the activation of Wnt/β-catenin pathway in the same models, with the latter cascade being frequently activated in preneoplastic and neoplastic lesions developed in c-Myc and c-Myc/E2F1 transgenic mice but rarely in c-Myc/TGF-α corresponding lesions.