A WNT/β-catenin-associated transcriptional program predicts survival outcomes in patients with hepatocellular carcinoma
BACKGROUND: Hepatocellular carcinoma (HCC) is the most common form of liver cancer and a major cause of cancer-related deaths worldwide. Despite the wealth of genomics data, treatment and prognosis are still dependent on clinical and pathological factors. The molecular heterogeneity characterizing HCC is denoted by the different etiology and the related array of signaling pathways involved in tumor initiation and progression. Aberrant activation of the Wnt/β-catenin pathway is among the most frequent alterations in HCC, and stems from somatic mutations, functional over-activity of the transcription machinery and epigenetic cues. METHODS: Targeted DNA and RNA sequencing were combined to investigate the Wnt/β-catenin pathway and the effects of its dysregulation in the TCGA HCC cohort. For external validation, an independent cohort of78 Caucasian patients affected by HCC was used. RESULTS: We have identified a Wnt/β-catenin-related transcriptional signature denoting pathway activity regardless of the presence of pathway-related activating mutations. This model predicts survival outcomes in two independent cohorts of HCC patients (TCGA cohort, N = 177; Rome cohort, N78) and is associated with distinctive immunogenomic features. CONCLUSIONS: A non-genetic state recapitulating the transcriptional footprint associated with CTNNB1 mutation identifies wild-type HCCs characterized by unfavorable survival outcomes and immune-excluded tumor immune microenvironment.
Authors
- Gian Luca Grazi (ORCID: https://orcid.org/0000-0002-3279-0313)
- Giulia Schiavoni (ORCID: https://orcid.org/0009-0005-9975-0606)
- Emanuela Dell’Aquila (ORCID: https://orcid.org/0000-0002-7258-1364)
- Federico Cappuzzo (ORCID: https://orcid.org/0000-0002-6295-6767)
- Elisa Melucci (ORCID: https://orcid.org/0000-0003-4908-5271)
- Giulia Bon (ORCID: https://orcid.org/0000-0002-5409-5864)
- Ludovica Ciuffreda (ORCID: https://orcid.org/0000-0002-7964-7119)
- Pasquale Perri (ORCID: https://orcid.org/0000-0002-2416-3299)
- Massimo Zeuli
- Frauke Goeman (ORCID: https://orcid.org/0000-0002-7803-8821)
- Chiara Manai (ORCID: https://orcid.org/0000-0003-2716-0429)
- G Paoletti
- Stefano Scalera (ORCID: https://orcid.org/0000-0001-5192-5917)
- Eriseld Krasniqi (ORCID: https://orcid.org/0000-0002-6702-0087)
- Gennaro Ciliberto (ORCID: https://orcid.org/0000-0003-2851-8605)
- Maurizio Fanciulli (ORCID: https://orcid.org/0000-0002-5281-4191)
- Francesca De Nicola (ORCID: https://orcid.org/0000-0002-2187-7544)
- Maddalena Barba (ORCID: https://orcid.org/0000-0001-9050-2917)
- Enzo Gallo (ORCID: https://orcid.org/0000-0002-4938-4071)
- Laura Pizzuti
- Mariagrazia Diodoro
- Patrizia Vici
- Laura Cipriani
- Edoardo Pescarmona
- Marcello Maugeri-Saccà
- Andrea Scarinci
Institutions
- Azienda Ospedaliera Sant'Andrea (IT)
- National Cancer Institute (MY)
- Cellular Therapeutics (United Kingdom) (GB)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- University of Florence (IT)
Publication Details
- Journal
- Experimental and Molecular Pathology
- Published
- 2026-05-11
- DOI
- https://doi.org/10.1016/j.yexmp.2026.105049
- Primary Topic
- Wnt/β-catenin signaling in development and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Fondazione AIRC per la ricerca sul cancro ETS
- Ministero dell'Istruzione e del Merito