HB patients GENOMIC STUDY TRANSCRIPTOMIC STUDY METHYLATION STUDY CytoScan HD ®-array RNA-sequencing/ ddPCR HTA ®-array/ RT-qPCR 850K (EPIC)-array/ QUAlu Dysregulation of global RNA & BLCAP editing Overexpression of 14q32 DLK1-DIO3 genes 16 + VIM-gene signature (C1/C2/C2B) 2 epigenomic HB subtypes (Epi-CA & Epi-CB) CLINICAL PARAMETERS: prognostic marker identification Poor prognostic factors:-4q,-18, 17q11.2 AI (NF1) CHKA new therapeutic target Molecular risk stratification MRS1 MRS2 MRS3 Strong 14q32 Epi-CB Time Survival Highlights Hepatoblastoma (HB) involves global dysregulation of RNA editing, including in the tumor suppressor BLCAP. Overexpression of a 300 kb region within the 14q32 DLK1/DIO3 locus is a new hallmark of HB. We identified 2 epigenomic HB subtypes-Epi-CA and Epi-CB-with distinct degrees of DNA hypomethylation and CpG island hypermethylation. The molecular risk stratification of HB, based on the 14q32-signature and epigenomic subtypes, is associated with patient outcomes. The enzyme CHKA could be a novel therapeutic target for patients with HB.

CoNClUSIoNS: Lenvatinib plus anti-PD1 exerted unique immunomodulatory effects through activation of immune pathways, reduction of Treg cell infiltrate, and inhibition of TGFß signaling. A gene signature enabled the identification of ~20% of human HCCs that, although nonresponding to single agents, could benefit from the proposed combination. (Hepatology 2021;74:2652-2669. L iver cancer is the second-leading cause of cancer-related death and a major health problem globally. (1) HCC is the most common form of liver cancer, accounting for >90% of

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