LINE-1 hypomethylation in human hepatocellular carcinomas correlates with shorter overall survival and CIMP phenotype

Anwar, Sumadi Lukman; Hasemeier, Britta; Schipper, Elisa; Vogel, Arndt; Kreipe, Hans; Lehmann, Ulrich ORCID

Reactivation of interspersed repetitive sequences due to loss of methylation is associated with genomic instability, one of the hallmarks of cancer cells. LINE-1 hypomethylation is a surrogate marker for global methylation loss and is potentially a new diagnostic and prog-nostic biomarker in tumors. However, the correlation of LINE-1 hypomethylation with clinico-pathological parameters and the CpG island methylator phenotype (CIMP) in patients with liver tumors is not yet well defined, particularly in Caucasians who show quite low rates of HCV/HBV infection and a higher incidence of liver steatosis. Therefore, quantitative DNA methylation analysis of LINE-1, RASSF1A, and CCND2 using pyrosequencing was per-formed in human hepatocellular carcinomas (HCC, n = 40), hepatocellular adenoma (HCA, n = 10), focal nodular hyperplasia (FNH, n = 5), and corresponding peritumoral liver tissues as well as healthy liver tissues (n = 5) from Caucasian patients. Methylation results were correlated with histopathological findings and clinical data. We found loss of LINE-1 DNA meth- ylation only in HCC. It correlated significantly with poor survival (log rank test, p = 0.007). Aninverse correlation was found for LINE-1 and RASSF1A DNA methylation levels (r2 = -0.47,p = 0.002). LINE-1 hypomethylation correlated with concurrent RASSF1/CCND2 hypermethylation (Fisher’s exact test, p = 0.02). Both LINE-1 hypomethylation and RASSF1A/CCND2 hypermethylation were not found in benign hepatocellular tumors (HCA and FNH). Our results show that LINE-1 hypomethylation and RASSF1A/CCND2 hypermethylation are epigenetic aberrations specific for the process of malignant liver transformation. In addition, LINE-1 hypomethylation might serve as a future predictive biomarker to identify HCC patients with unfavorable overall survival.

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Anwar, Sumadi / Hasemeier, Britta / Schipper, Elisa / et al: LINE-1 hypomethylation in human hepatocellular carcinomas correlates with shorter overall survival and CIMP phenotype. 2019.

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