Abstract
BackgroundThe two most common repetitive elements (REs) in humans, long interspersed nuclear element-1 (LINE-1) and Alu element (Alu), have been linked to various cancers. Hepatitis C virus (HCV) may cause hepatocellular carcinoma (HCC) by suppressing host defenses, through DNA methylation that controls the mobilization of REs. We aimed to investigate the role of RE methylation in HCV-induced HCC (HCV-HCC).ResultsWe studied methylation of over 30,000 locus-specific REs across the genome in HCC, cirrhotic, and healthy liver tissues obtained by surgical resection. Relative to normal liver tissue, we observed the largest number of differentially methylated REs in HCV-HCC followed by alcohol-induced HCC (EtOH-HCC). After excluding EtOH-HCC-associated RE methylation (FDR < 0.001) and those unable to be validated in The Cancer Genome Atlas (TCGA), we identified 13 hypomethylated REs (11 LINE-1 and 2 Alu) and 2 hypermethylated REs (1 LINE-1 and 1 Alu) in HCV-HCC (FDR < 0.001). A majority of these REs were located in non-coding regions, preferentially enriched with chromatin repressive marks H3K27me3, and positively associated with gene expression (median correlation r = 0.32 across REs). We further constructed an HCV-HCC RE methylation score that distinguished HCV-HCC (lowest score), HCV-cirrhosis, and normal liver (highest score) in a dose-responsive manner (p for trend < 0.001). HCV-cirrhosis had a lower score than EtOH-cirrhosis (p = 0.038) and HCV-HCC had a lower score than EtOH-HCC in TCGA (p = 0.024).ConclusionsOur findings indicate that HCV infection is associated with loss of DNA methylation in specific REs, which could implicate molecular mechanisms in liver cancer development. If our findings are validated in larger sample sizes, methylation of these REs may be useful as an early detection biomarker for HCV-HCC and/or a target for prevention of HCC in HCV-positive individuals.
Highlights
Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy and a leading cause of cancer-related death, with 746,000 deaths worldwide in 2012 [1, 2]
We examined 32,439 Repetitive element (RE) (3813 long interspersed nuclear element-1 (LINE-1) and 28,626 Alu element (Alu)) using University of Florida Shands Hospital (UFSH) data and 21,257 REs (2812 LINE-1 and 18,445 Alu) using The Cancer Genome Atlas (TCGA) data
We identified LINE-1 and Alu elements associated with HCVHCC located mainly in intronic and intergenic regions, preferentially enriched in H3K27me3 marks, and positively correlated with proximal gene expression
Summary
Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy and a leading cause of cancer-related death, with 746,000 deaths worldwide in 2012 [1, 2]. Repetitive elements (REs), including long interspersed element-1 (LINE-1) and Alu element (Alu), activate oncogenic pathways in HCC [8]. LINE-1 and Alu represent the two most abundant types of RE sequences that can mobilize in the human genome [9]. Their unfettered mobility can cause genetic instability as they copy and paste. The two most common repetitive elements (REs) in humans, long interspersed nuclear element-1 (LINE-1) and Alu element (Alu), have been linked to various cancers. Hepatitis C virus (HCV) may cause hepatocellular carcinoma (HCC) by suppressing host defenses, through DNA methylation that controls the mobilization of REs. We aimed to investigate the role of RE methylation in HCV-induced HCC (HCV-HCC)
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