Plasma cell-free DNA methylation: a liquid biomarker of hepatic fibrosis

We recently reported dynamic epigenetic markers of fibrosis detectable in patients’ plasma that may have utility in non-invasive diagnosis and staging of fibrosis in patients with chronic liver disease.1 Specifically, we uncovered DNA methylation markers at the human PPARγ promoter detectable in circulating cell-free DNA (ccfDNA) that display differential methylation densities. Remarkably, PPARγ hypermethylation correlated with progression to cirrhosis in alcoholic liver disease (ALD) and with specific stages of liver fibrosis in non-alcoholic fatty liver disease (NAFLD). Furthermore, ccfDNA signatures were traced back to the molecular pathology in fibrotic liver tissue, providing a biomarker of the underlying pathological process and defining hepatocytes as the source of hypermethylated DNA found in plasma.1 The original study posed several important outstanding questions: (1) Can ccfDNA methylation be used as a biomarker of fibrosis in liver diseases of other aetiologies? (2) Does the presence of hepatocellular carcinoma (HCC) alter the biomarker in plasma? (3) Does presence of fibrosis in other organs generate similar biomarker profiles? In the present letter, we answer these questions and demonstrate the broader utility of DNA methylation at three CpG dinucleotides within PPARγ promoter in several new patient cohorts (figure 1A and table …