Global Level of Plasma DNA Methylation is Associated with Overall Survival in Patients with Hepatocellular Carcinoma

Background The impact of folate deficiency on global DNA methylation is uncertain. It also is unclear whether global DNA methylation is associated with outcome in HCC. LINE-1 methylation levels, as a surrogate marker of global methylation, may be influenced by folate deficiency. However, the interaction between LINE-1 methylation and folate level on overall survival (OS) in hepatocellular carcinoma (HCC) patients is unknown. We evaluated whether LINE-1 hypomethylation and folate deficiency are associated with HCC prognosis. Methods We prospectively recruited 172 HCC patients between 2008 and 2012. LINE-1 methylation levels in plasma and white blood cells (WBC) were measured by pyrosequencing, and plasma folate levels by a radioprotein-binding assay. Results Patients with plasma LINE-1 methylation <70.0% (hypomethylation) had significantly worse OS compared with those with ≥70.0% methylation (hypermethylation) [hazard ratio (HR) = 1.77; 95% confidence interval (CI) 1.12–2.79; P = 0.015]. HCC patients with lower plasma folate levels also had worse survival (<27.7 vs. ≥27.7 nmol/L; HR = 1.96; 95% CI, 1.24–3.09; P = 0.004). Furthermore, survival was poor in patients in whom both plasma LINE-1 methylation and folate levels were low compared with those patients in whom both levels were high (HR = 3.36; 95%CI, 1.77-6.40; P < 0.001). This interaction neared statistical significance ( P = 0.057). No significant association was found between WBC LINE-1 methylation levels and survival. Conclusions These findings suggest that both lower plasma levels of LINE-1 methylation and folate are associated with worse survival in HCC patients.