Integrated genomic analyses identify oncogenic pathway interplay in hepatocarcinogenesis defining specific molecular subtypes.

Hepatocellular carcinoma (HCC) is a genomically diverse disease, and molecular classification is essential for understanding its biology and improving patient care. Here, integrative analyses of 529 HCC samples across genomic, transcriptomic, epigenomic, and proteomic layers identify nine robust molecular subtypes, validated in 807 external cases. Three common subtypes are defined by alterations in CTNNB1ex3/APC (25%), TP53 (21%), and AXIN1/IRF2 (11%), while four rare subtypes involve TP53+CTNNB1ex3 (6%), BAP1 (6%), CCNA2/E1 (6%), and HNF1A (1%). Two additional immune-related subtypes, UHot (17%) and UInterm (8%), have undetermined drivers. Using transcriptomic scores, we demonstrate that AXIN1 and TP53 mutations increase β-catenin activity and reduce p53 activity, whereas BAP1 loss functionally inactivates TP53. The rare TP53+CTNNB1ex3 subtype is highly aggressive, associated with poorer outcomes, exhibiting features of both CTNNB1ex3- and TP53-mutated HCC, with TP53 mutation occurring prior to CTNNB1 alteration. The refined molecular classification provides a clinically relevant framework for precision medicine in HCC.