ORC4 and hepatocellular carcinoma: Critical to this understanding, we have demonstrated that hepatocyte hyperploidy in young caspase-2-deficient mice is marked by dysregulation of a distinct set of 13 proteins (AAAS, ATM, CDKN2C, IGF1, MCM4, MCM6, NAT10, ORC4, SETD6, SMARCAD1, SPOUT1/C9orf114, TAF6, and TRAF2) associated with early onset pathogenic hyperpolyploidization that correlate with increased CIN, liver disease progression, and patient survival in HCC (3, 4).