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.