Abstract
BackgroundDNA methylation changes occurring in cancer cells are featured with both promoter CpG island hypermethylation and diffuse genomic hypomethylation. Long interspersed element-1 (LINE-1) is repeated in an interspersed manner with an estimated 500,000 copies per genome. LINE-1 has its CpG sites of the 5′ untranslated region methylated heavily in normal cells and undergoes demethylation in association with cancerization. However, little information is available regarding LINE-1 hypomethylation and its prognostic implication in intrahepatic cholangiocarcinomas.MethodsA total of 172 cases of intrahepatic cholangiocarcinomas were analyzed for their methylation levels at four CpG sites of LINE-1 using bisulfite pyrosequencing. We examined the relation between tumoral LINE-1 methylation level and clinicopathological features, including survival.ResultsTumor 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. LINE-1 hypomethylation was significantly linked with lower cancer-specific survival in patients with intrahepatic cholangiocarcinoma and was found to be an independent prognostic parameter.ConclusionsOur findings suggest that tumoral LINE-1 hypomethylation could be a molecular biomarker heralding poor prognosis of patients with intrahepatic cholangiocarcinoma. Our findings need to be validated in further study.
Highlights
DNA methylation changes occurring in cancer cells are featured with both promoter CpG island hypermethylation and diffuse genomic hypomethylation
Four subsets of Intrahepatic cholangiocarcinoma (ICC) according to percentage of non-neoplastic cells (30%) were compared regarding the distribution of Long interspersed element-1 (LINE-1) methylation level and no significant difference was seen in LINE-1 methylation level between the subsets (p-value by Kruskal-Wallis method, 0.242; p-value by ANOVA test, 0.527)
In summary, we assessed LINE-1 methylation levels in a total of 172 cases of ICC using PCR pyrosequencing and elucidated whether LINE-1 methylation status was correlated with clinicopathological features of ICCs
Summary
DNA methylation changes occurring in cancer cells are featured with both promoter CpG island hypermethylation and diffuse genomic hypomethylation. LINE-1 has its CpG sites of the 5′ untranslated region methylated heavily in normal cells and undergoes demethylation in association with cancerization. DNA methylation changes occurring in cancer cells are featured with regional promoter CpG island hypermethylation and generalized genomic hypomethylation. Promoter CpG island hypermethylation contributes to inactivation of tumor suppressor genes or tumor-related genes, whereas diffuse genomic hypomethylation is associated with chromosomal instability [1]. Cancer staging and subsequent allocation to the optimal treatment approach is crucial for ICCs. none of the existing staging systems, including the 7th version of the American Joint Cancer Committee/Union for International Cancer Control (AJCC/UICC) staging system, fulfills the criteria for an optimal staging system [8]. More work should be done to optimize the existing staging systems, molecular biomarkers associated with clinical outcome can help to predict tumor behavior and clinical outcome and need to be developed
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