Cancer gene discovery in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a deadly cancer, whose incidence is increasing worldwide. Albeit the main risk factors for HCC development have been clearly identified, such as hepatitis B and C virus infection and alcohol abuse, there is still preliminary understanding of the key drivers of this malignancy. Recent data suggest that genomic analysis of cirrhotic tissue - the pre-neoplastic carcinogenic field - may provide a read-out to identify at risk populations for cancer development. Given this contextual complexity, it is of utmost importance to characterize the molecular pathogenesis of this disease, and pinpoint the dominant pathways/drivers by integrative oncogenomic approaches and/or sophisticated experimental models. Identification of the dominant proliferative signals and key aberrations will allow for a more personalized therapy. Pathway-based approaches and functional experimental studies have aided in identifying the activation of different signaling cascades in HCC (e.g. epidermal growth factor, insulin-like growth factor, RAS, MTOR, WNT-βcatenin, etc.). However, the introduction of new high-throughput genomic technologies (e.g. microarrays, deep sequencing, etc.), and increased sophistication of computational biology (e.g. bioinformatics, biomodeling, etc.), opens the field to new strategies in oncogene and tumor suppressor discovery. These oncogenomic approaches are framed within emerging new disciplines such as systems biology, which integrates multiple inputs to explain cancer onset and progression. In addition, the consolidation of sophisticated animal models, such as mosaic cancer mouse models or the use of transposons for mutagenesis screens, have been instrumental for the identification of novel tumor drivers. We herein review some classical as well as some recent fast track approaches for oncogene discovery in HCC, and provide a comprehensive landscape of the currently known spectrum of molecular aberrations involved in hepatocarcinogenesis. © 2010 European Association for the Study of the Liver.