Hepatocellular carcinoma (HCC) is a malignancy with major worldwide prevalence and a poor overall prognosis. About 75％ of all HCC cases are initially diagnosed as multiple tumors, presenting a particular challenge for aggressive surgical therapy. Multiple HCC may result from multicentric occurrence (MO-HCC) or intrahepatic metastases (IM-HCC), corresponding to highly dissimilar clinical outcomes. Reliable distinction of these two mechanisms is therefore paramount in optimizing the management of multiple HCC. In a recent work, Miao et al. adopted a multi-omics approach to find key parameters of different clonality in MO-HCC vs. IM-HCC and link these data to tumor behavior and prognosis in a cohort of patients with HBV-related HCC. The mitotic checkpoint regulator TTK has emerged from this analysis as a novel biomarker that may predict aggressive behavior and early postoperative recurrence of HCC.