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). Here, ORC4 is linked to cervical squamous intraepithelial neoplasia.