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Hepatocellular carcinoma (HCC) is one of the most frequent solid tumors worldwide and represents the third cause of mortality among deaths from cancer. It has been extensively studied in terms of genetic alteration in the last 10 years and our knowledge has dramatically increased in this field, leading to the definition of different altered pathways in hepatocarcinogenesis. Recently, a comprehensive study of genetic and transcriptomic alterations in a large series of HCC tumors enabled the identification of a six-group molecular-based classification of HCC, defined by a simple 16-gene signature. This classification is closely related to specific alteration of WNT and AKT oncogenic pathways. Together with the analysis of defined oncogenic proteins, such global classifications could be useful in the prediction of future-targeted therapy efficiency.