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Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide and despite improvement in therapeutic approaches, prognosis remains poor. This can be partly attributed to the fact that the majority of HCCs are diagnosed at intermediate or advanced stages. Availability of circulating biomarkers able to detect HCC at early stages could improve patients’ prognosis. At present, however, alpha fetoprotein or desg-carboxyprothrombin are unable to reliably detect HCC at early stages and better circulating biomarkers are needed. Circulating tumor DNA (ctDNA) and non-coding RNAs (ncRNAs) are emerging as promising biomarkers to achieve the goal. Genetic and epigenetic alterations in ctDNA allow to pinpoint tumor-specific biomarkers, reveal tumor heterogeneity, help monitor tumor evolution over time and assess therapy efficacy. It remains to be fully evaluated the possibility of detecting these biomarkers at early tumor stages. Circulating ncRNAs are quantitative biomarkers with potential use in diagnostic, prognostic and predictive clinical settings. They may help to reveal HCC at early stages. However, because of heterogeneous and sometimes conflicting reported results, they still require validation and standardization of pre-analytical and analytical approaches before clinical applications could be envisaged.

Circulating tumor DNAs and non-coding RNAs as potential biomarkers for hepatocellular carcinoma diagnosis, prognosis and response to therapy