Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and has limited therapeutic options. Epigenetic dysregulation plays a crucial role in hepatocarcinogenesis; however, its impact on cis-regulatory elements (CREs) and retrotransposons remains underexplored. Here, we investigated the epigenetic changes underlying the aberrant CRE and retrotransposon activity in HCC. We show that focal DNA hypomethylation of these elements is associated with transcriptional reprogramming. Notably, we uncover a dual regulatory mechanism for GPC3, a key diagnostic biomarker and immunotherapeutic target in HCC. This requires the concomitant reactivation of a fetal liver super-enhancer (SE) and DNA hypomethylation of CpG islands. Furthermore, DNA methylation loss drives cryptic activation of retrotransposons, some of which exhibit prognostic potential. Intriguingly, we identify a HERVE-int-derived long non-coding RNA that shows higher expression in patients with more aggressive tumors, poorer disease outcomes, and is correlated with molecular signatures associated with improved response to immunotherapy. Collectively, our findings reveal widespread epigenomic dysregulation of CREs and retrotransposons in HCC, highlighting new potential therapeutic strategies and biomarkers.