Tumoral LINE-1 hypomethylation is associated with poor survival of patients with intrahepatic cholangiocarcinoma

Abstract

DNA methylation changes occurring in cancer cells are characterized by both promoter CpG island hypermethylation and diffuse genomic hypomethylation. LINE-1 is half-million times repeated in the human genome in an interspersed manner and CpG sites located in 5 untranslated region of LINE-1 are heavily methylated in normal cells and undergo demethylation in association with cancerization. However, little information is available regarding LINE-1 hypomethylation and its prognostic implication in intrahepatic cholangiocarcinomas. We analyzed 172 cases of intrahepatic cholangiocarcinomas for their methylation status at four CpG sites of LINE-1 using pyrosequencing and correlated LINE-1 methylation level with clinicopathological features. Tumor differentiation, lymphatic invasion, and T stage were associated with a low average methylation level of LINE-1 at the four CpG sites

LINE-1 methylation level tended to be lower in high grade differentiation, lymphatic emboli, and higher T stage. Lower methylation status of LINE-1 was significantly associated with lower overall survival in patients with intrahepatic cholangiocarcinoma and found to be an independent prognostic parameter. Our findings suggest that tumoral LINE-1 hypomethylation could be a molecular biomarker heralding poor prognosis of patients with intrahepatic cholangiocarcinoma. A further study is required to validate our findings.