Dataset Information

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

ABSTRACT: 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 prognostic biomarker in tumors. However, the correlation of LINE-1 hypomethylation with clinicopathological 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 performed 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 methylation only in HCC. It correlated significantly with poor survival (log rank test, p = 0.007). An inverse 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.

SUBMITTER: Anwar SL

PROVIDER: S-EPMC6502450 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Anwar Sumadi Lukman SL Hasemeier Britta B Schipper Elisa E Vogel Arndt A Kreipe Hans H Lehmann Ulrich U

PloS one 20190506 5

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 prognostic biomarker in tumors. However, the correlation of LINE-1 hypomethylation with clinicopathological parameters and the CpG island methylator phenotype (CIMP) in patients with liver tumors is not yet well defined, particularl ...[more]

PMID: 31059558

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Project description:Interim analysis of the DOSISPHERE-01 study demonstrated a strong improvement in response and overall survival (OS) on using 90Y-loaded glass microspheres with personalized dosimetry compared with standard dosimetry in patients with nonoperable locally advanced hepatocellular carcinoma. This report sought to provide a long-term analysis of OS. Methods: In this phase II study (ClinicalTrials.gov identifier NCT02582034), treatment was randomly assigned (1:1) with the goal to deliver either at least 205 Gy (if possible >250-300 Gy) to the index lesion in the personalized dosimetry approach (PDA) or 120 ± 20 Gy to the treated volume in the standard dosimetry approach (SDA). The 3-mo response of the index lesion was the primary endpoint, with OS being one of the secondary endpoints. This report is a post hoc long-term analysis of OS. Results: Overall, 60 hepatocellular carcinoma patients with at least 1 lesion larger than 7 cm and more than 30% of hepatic reserve were randomized (intent-to-treat population: PDA, n = 31; SDA, n = 29), with 56 actually treated (modified intent-to-treat population: n = 28 in each arm). The median follow-up for long-term analysis was 65.8 mo (range, 2.1-73.1 mo). Median OS was 24.8 mo and 10.7 mo (hazard ratio [HR], 0.51; 95% CI, 0.29-0.9; P = 0.02) for PDA and SDA, respectively, in the modified intent-to-treat population. Median OS was 22.9 mo for patients with a tumor dose of at least 205 Gy, versus 10.3 mo for those with a tumor dose of less than 205 Gy (HR, 0.42; 95% CI, 0.22-0.81; P = 0.0095), and was 22.9 mo for patients with a perfused liver dose of 150 Gy or higher, versus 10.3 mo for those with a perfused liver dose of less than 150 Gy (HR, 0.42; 95% CI, 0.23-0.75; P = 0.0033). Lastly, median OS was not reached in patients who were secondarily resected (n = 11, 10 in the PDA group and 1 in the SDA group), versus 10.8 mo in those without secondary resection (n = 45) (HR, 0.17; 95% CI, 0.065-0.43; P = 0.0002). Only resected patients displayed favorable long-term OS rates, meaning an OS of more than 50% at 5 y. Conclusion: After longer follow-up, personalized dosimetry sustained a meaningful improvement in OS, which was dramatically improved for patients who were accurately downstaged toward resection, including most portal vein thrombosis patients.

Dataset Information

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

Publications

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

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