APASL, Istambul, Turkey - Day 1

Hepatocellular carcinoma (HCC) is driven not only by genetic mutations but also by epigenetic alterations, which regulate gene expression without changing the DNA sequence. These changes are reversible and dynamic, making them important in both carcinogenesis and therapeutic targeting.

One major mechanism is DNA methylation, particularly hypermethylation of tumor suppressor gene promoters, leading to gene silencing. Conversely, global hypomethylation can activate oncogenes and promote genomic instability.

Histone modifications—including acetylation and methylation—alter chromatin structure and gene accessibility. Dysregulation of histone-modifying enzymes leads to abnormal activation of pathways involved in cell proliferation, survival, and metastasis.

Another key layer involves non-coding RNAs, especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). These molecules regulate gene expression post-transcriptionally and are frequently dysregulated in HCC, contributing to tumor growth, angiogenesis, and immune evasion.

Epigenetic changes are influenced by chronic liver injury, such as viral hepatitis, MAFLD, and alcohol, linking environmental factors to cancer development.

Clinically, epigenetic alterations have potential as biomarkers for early detection, prognosis, and treatment response. Therapeutically, epigenetic drugs (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors) are being explored, often in combination with immunotherapy.

Key Message:
Epigenetic dysregulation is central to HCC pathogenesis—offering promising avenues for early diagnosis, risk stratification, and targeted therapy, with the advantage of being potentially reversible.