New warning signs on the road: 5-hydroxymethylcytosine-based liquid biopsy for the early detection of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) ranks as the sixth most common neoplasm and the third leading cause of cancer-related death.1 As with many other cancers, HCC detected at an early stage has a better prognosis than the advanced-stage disease, in part due to the relative efficacy of local treatments compared with systemic therapies.1 At present, the serological determination of alpha-fetoprotein (AFP) levels is the only liquid biopsy test used for the detection and surveillance of HCC. However, it has demonstrated serious limitations and most patients are diagnosed in an advanced stage, when current treatments have little effectiveness. Moreover, although patients in early and intermediate stages might benefit from potentially curative treatments, there is a high rate of recurrence.2 Therefore, since the only chance to offer effective treatment is the early detection, there is an urgent need to develop non-invasive and precise methods for early HCC diagnosis and recurrence monitoring. In this regard, the focus of several recent studies has concentrated on the identification of specific genetic and epigenetic tumour alterations in plasma cell-free DNA (cfDNA). Among the circulating cfDNA, DNA released by the tumour to the peripheral blood has been shown not only to contain the same mutations as the primary tumour cells but also the same epigenetic patterns.3 The most extensively studied epigenetic feature for blood-based cancer biomarker development is DNA methylation, especially the 5-methylcytosine (5-mC) modification at the 5'-cytosine-phosphate-guanine-3' (CpG) dinucleotides. Importantly, DNA methylation patterns are usually tissue- and cancer-type specific. However, in spite …