In conclusion, viral insertions and structural rearrangements activating CCNA2 and CCNE1 define a homogeneous subgroup of aggressive HCC developed in non-cirrhotic liver, sharing similar transcriptional profiles and frequent inactivation of RB1 and PTEN. These tumors display a specific rearrangement signature induced by replication stress that sustains tumor growth by activating TERT but may constitute a targetable vulnerability. Here, PTEN is linked to neoplasm.