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Central Role of c-Myc during Malignant Conversion in Human Hepatocarcinogenesis

¹ Laboratory of Experimental Carcinogenesis, National Cancer Institute, Center for Cancer Research, NIH, Bethesda, Maryland and ² Departments of Morphology and Molecular Pathology, University of Leuven, Leuven, Belgium

Requests for reprints: Snorri S. Thorgeirsson, Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, 37 Convent Drive, Room 4146, Bethesda, MD 20892. Phone: 301-496-5688; Fax: 301-496-0734; E-mail: snorri_s_thorgeirsson{at}mail.nih.gov.

Key Words: human hepatocellular carcinoma • microarray • Myc

Hepatocarcinogenesis is a multistage process in which precursor lesions progress into early hepatocellular carcinomas (eHCC) by sequential accumulation of multiple genetic and epigenetic alterations. To decode the molecular events during early stages of liver carcinogenesis, we performed gene expression profiling on cirrhotic (regenerative) and dysplastic nodules (DN), as well as eHCC. Although considerable heterogeneity was observed at the regenerative and dysplastic stages, overall, 460 differentially expressed genes were detected between DN and eHCC. Functional analysis of the significant gene set identified the MYC oncogene as a plausible driver gene for malignant conversion of the DNs. In addition, gene set enrichment analysis revealed global activation of the MYC up-regulated gene set in eHCC versus dysplasia. Presence of the MYC signature significantly correlated with increased expression of CSN5, as well as with higher overall transcription rate of genes located in the 8q chromosome region. Furthermore, a classifier constructed from MYC target genes could robustly discriminate eHCC from high-grade and low-grade DNs. In conclusion, our study identified unique expression patterns associated with the transition of high-grade DNs into eHCC and showed that activation of the MYC transcription signature is strongly associated with the malignant conversion of preneoplastic liver lesions. [Cancer Res 2009;69(7):2775–82]

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				Correction: Article on Activation of the MYC Signature in Early HCC Cancer Res., April 15, 2009; 69(8): 3721 - 3721. [Full Text] [PDF]