Genome-wide identification of differential methylation between primary and recurrent hepatocellular carcinomas

A biomarker capable of clinically predicting hepatocellular carcinoma (HCC) recurrence has not previously been established. Here genome‐wide differential methylation between primary and recurrent HCC cell lines (Hep‐11 and Hep‐12) from the same patient was characterized. The HCC samples from two independent cohorts, complete with follow‐up data, were used to validate the feasibility of the selected methylation biomarkers in predicting HCC prognosis. A methylation array assay identified 30 candidate genes or intergenic‐fragments with an absolute methylation fold‐change >2.0 between these cell lines; 22 candidates were hypomethylated in Hep‐12 cells relative to Hep‐11 cells. Bisulfite sequencing confirmed these results. Most importantly, classification of tumors by LINE‐2 methylation level was significantly associated with HCC recurrence in both cohorts (P