Abstract
BACKGROUND: Hepatocellular carcinoma (HCC) incidence and mortality are rising. Liver transplantation (LT) offers the best outcomes, but current tumor size- and number-based selection criteria restrict access. Molecular profiling may better reflect tumor biology and guide precision-based selection strategies. METHODS: This prospective single-center study included patients with HCC who had undergone LT between 11 November 2016 and 4 April 2023 with sufficient tumor cellularity in explanted livers. Tumor DNA was subjected to targeted sequencing for 38 genes, with the results returned to clinicians. Altered genes were grouped into HCC-relevant signaling pathways. Outcomes included post-LT overall survival (OS), recurrence-free survival (RFS), and recurrence sites. The Cancer Genome Atlas (TCGA) HCC cohort was used for validation. RESULTS: Among 1,103 LT recipients, 261 were for HCC and 91 underwent sequencing. Most patients were male (n = 68), white (n = 56), and hepatitis C positive (n = 34). The median tumor size was 3 cm (IQR 1.8-4.5), the number was 1 (IQR 1-3), and the follow-up time was 1,982 days. Of the 36 unique mutations found across 11 genes, six were potentially actionable. Cell cycle pathway alterations (n = 14) were prognostic for worse OS (3-year 90.9% without vs. 62.5% with alterations) and RFS in uni- and multivariable models. Recurrences were more common in the liver and lungs with cell cycle alterations (p < 0.05). CONCLUSION: Post-LT molecular profiling of HCC reveals tumor-specific alterations associated with outcomes, supporting the incorporation of tumor biology into future LT selection criteria.