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<p>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 <i>CTNNB1</i><sup><i>ex3</i></sup><i>/APC</i> (25%), <i>TP53</i> (21%), and <i>AXIN1/IRF2</i> (11%), while four rare subtypes involve <i>TP53+CTNNB1</i><sup><i>ex3</i></sup> (6%), <i>BAP1</i> (6%), <i>CCNA2/E1</i> (6%), and <i>HNF1A</i> (1%). Two additional immune-related subtypes, U<sup>Hot</sup> (17%) and U<sup>Interm</sup> (8%), have undetermined drivers. Using transcriptomic scores, we demonstrate that <i>AXIN1</i> and <i>TP53</i> mutations increase β-catenin activity and reduce p53 activity, whereas <i>BAP1</i> loss functionally inactivates <i>TP53</i>. The rare <i>TP53+CTNNB1</i><sup><i>ex3</i></sup> subtype is highly aggressive, associated with poorer outcomes, exhibiting features of both <i>CTNNB1</i><sup><i>ex3-</i></sup> and <i>TP53</i>-mutated HCC, with <i>TP53</i> mutation occurring prior to <i>CTNNB1</i> alteration. The refined molecular classification provides a clinically relevant framework for precision medicine in HCC.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月19日

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  • Long Pan,
  • Théo Z. Hirsch,
  • Jing Fang,
  • Agnieszka Seretny,
  • Sandrine Imbeaud,
  • Shuoshuo Jin,
  • Olatunji Oluwole Gege,
  • Sandra Rebouissou,
  • Sabrina Sidali,
  • Naïma Ammiche,
  • Julien Calderaro,
  • Giuliana Amaddeo,
  • Jean-Frédéric Blanc,
  • Brigitte Le Bail,
  • Marianne Ziol,
  • Séverine Celton-Morizur,
  • Valérie Paradis,
  • Josep M. Llovet,
  • Darjus Felix Tschaharganeh,
  • Jean-Charles Nault,
  • Chantal Desdouets,
  • Stefano Caruso,
  • Jessica Zucman-Rossi

摘要

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.