HCC is accountable for an estimated 600,000 world‐wide deaths annually and its incidence rates in USA have been doubled over the past 25 years (26,000 new cases in 2010), and are expected to double over the next 10 to 20 years. Because of diagnosis at late stage and lack of effective treatments, mortality rate of HCC remain very high. However, the molecular pathogenesis of HCC is not well understood. To uncover signaling pathways directly involved in development of HCC, we developed strategy, “comparative systems genomics”, that can estimate the significance of concordance between the human cancer and rodent cancer models. By applying this strategy, we found that 20 to 30 % of patients with HCC has gene expression patterns similar to that of mouse models developing HCC due to deletion of Mst1/2 or Sav1 (silence of Hippo pathway, SOH subtype) and HCC recurrence rate of these patients after treatment is significantly higher than those without SOH gene expression signature. Therefore, we hypothesize that inactivation of Hippo pathway is account for around 20 to 30% human HCC and its inactivation is significantly associated with high risk of recurrence after treatment.