Abstract
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.
Acknowledgements
We warmly thank the clinicians, surgeons, pathologists, hepatologists, and oncologists who contributed to the tissue collection and clinical annotations. We thank Eric Letouzé for his advice about mutational signatures and Barkha Gupta for the annotations of pathological features from several HE slides. FunGeST team (Functional Genomics of Solid Tumors) is supported by the Ligue Nationale contre le Cancer (Equipe Labellisée), Labex OncoImmunology (investissement d’avenir, France 2030), the SIRIC CARPEM (INCa), and THRIVE EU Horizon funding Mission Cancer (EU-HORIZON-MISS-2023-CAN-CER-01). L.P., J.F., and S.S.J. were supported by fellowships from China Scholarship Council. J.M.L. is supported by grants from the European Commission (Horizon Europe-Mission Cancer, THRIVE, Ref. 101136622), by an Accelerator Award from Cancer Research UK, Fondazione per la Ricerca sul Cancro (AIRC) and Fundación Científica de la Asociación Española Contra el Cáncer -FAECC (HUNTER, Ref. C9380/A26813), by the NIH (R01-CA273932-01, RO1DK56621 and RO1DK128289), the Samuel Waxman Cancer Research Foundation, by the Spanish National Health Institute (Project PID2022-139365OB-I00), funded by MICIU/AEI/10.13039/501100011033 and FEDER; by the Fundación Científica de la Asociación Española Contra el Cáncer - FAECC (Proyectos Generales: PRYGN223117LLOV); Fundación Científica de la Asociación Española Contra el Cáncer - FAECC- Reto AECC 70% Supervivencia (RETOS245779LLOV), the Generalitat de Catalunya (AGAUR, 2021-SGR 01347), AECC Excellence Program (EPAEC246711CLIN) and from “la Caixa” Foundation under agreement LCF/PR/SP23/52950009. We thank IntegraGen, Macrogen France, and the Next Generation Sequencing unit of the Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), for providing excellent sequencing services.
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J.M.L. received research support from Genentech and Roche; consultancy or lecture fees from Eisai Inc., Merck, Roche, Genentech, AstraZeneca, Bayer Pharmaceuticals, AbbVie, Sanofi, Moderna, Glycotest, Exelixis, and Boehringer Ingelheim; and served on a Data Safety Monitoring Board for Bristol Myers Squibb. J.C.N. received grants from Ipsen and Bayer. The remaining authors declare no competing interests.
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Pan, L., Hirsch, T.Z., Fang, J. et al. Integrated genomic analyses identify oncogenic pathway interplay in hepatocarcinogenesis defining specific molecular subtypes. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73212-y
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DOI: https://doi.org/10.1038/s41467-026-73212-y
