Circulating-Free DNA Analysis in Hepatocellular Carcinoma: A Promising Strategy to Improve Patients' Management and Therapy Outcomes.

Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide, representing the third leading cause of cancer-related deaths. HCC genetic characterization at the tumor level has been recently completed, highlighting how a number of genes are frequently mutated in this pathology. Actionable somatic mutations found in a HCC tumor may represent targets for innovative drugs as well as prognostic/predictive markers. Nonetheless, surgical or bioptic tissue is hardly accessible in HCC and a single tumor sample is poorly representative of the tumor genetic heterogeneity. In this context, analyzing the circulating cell-free DNA (ccfDNA) and its tumor-derived fraction (ctDNA) could represent a promising strategy of liquid biopsy. Recent data suggested that the fluctuation of the ccfDNA quantity in the plasma of HCC patients could anticipate the detection of tumor progression. The presence of somatic mutations in p53 signaling, Wnt/β-catenin, chromatin remodeling, response to oxidative stress and telomerase maintenance pathways can also be studied in ccfDNA bypassing the need to perform a tumor biopsy. The profiling of ccfDNA fragmentation and the methylation pattern could further improve the clinical management of HCC patients. Performing a dynamic monitoring in the course of systemic treatment with sorafenib or regorafenib is a possible way to provide insights into the resistance mechanism, and to identify predictive and prognostic genetic alterations, helping the clinicians in terms of treatment decision making. This review will discuss the most recent literature data about the use of ccfDNA to monitor and improve the treatment of HCC.