Identification Of CDKN2A Somatic Mutations in HCC Patients: Insights from NGS in An Egyptian Cohort

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, most often arising in the setting of cirrhosis associated with chronic hepatitis B or C virus infection. While curative treatment is possible at early stages, advanced disease is marked by high recurrence rates and poor prognosis. A deeper understanding of the molecular mechanisms underlying HCC is essential for improving therapeutic outcomes. Cyclin-dependent kinase inhibitor 2A (CDKN2A) is a tumor suppressor gene central to cell cycle regulation, and its alterations have been linked to several malignancies. In this study, circulating cell-free DNA from 21 Egyptian HCC patients was analyzed using targeted next-generation sequencing (NGS) with full CDKN2A coverage. Mutations were detected in 6 patients (28.6%), with 10 somatic variants identified: 40% were single-nucleotide variants (SNVs), 50% copy number variants (CNVs), and 10% multi-nucleotide variants (MNVs). Among SNVs, half were synonymous, while the remainder included non-synonymous and splice-site variants. Predicted functional impacts ranged from deleterious to uncertain or likely tolerated. No significant association was observed between CDKN2A mutation status and clinicopathological features. These findings highlight CDKN2A as a potential contributor to hepatocarcinogenesis and underscore the need for larger studies to clarify its prognostic and therapeutic relevance.