Abstract
Abnormal DNA methylation, an epigenetic modification, has increasingly been linked to the pathogenesis of many human cancers. However, there has been little focus on the DNA methylation patterns of genes encoding long noncoding RNAs (lncRNAs) in gastric cancer (GC). This study comprehensively determined DNA methylation and lncRNA expression profiles in GC through genome-wide analysis. Differentially methylated loci and lncRNAs were identified by integrating multi-omics data. In total, 548 differentially methylated CpG sites in lncRNA promoters and 2,399 differentially expressed lncRNAs were screened that were capable of distinguishing GC from normal tissues. Among them, 22 differentially methylation sites in 17 lncRNAs were inversely related to expression levels. Further analysis of DNA methylation status and gene expression level in GC revealed that three CpG sites (cg01550148, cg22497867, and cg20001829) and two lncRNAs (RP11-366F6.2 and RP5-881L22.5) were significantly associated with GC patient overall survival. Molecular function analysis showed that these abnormally methylated lncRNAs were mainly involved in transcriptional activator activity. Our study identified several lncRNAs regulated by aberrant DNA methylation that have clinical utility as novel prognostic biomarkers in GC. These findings help improve the understanding of methylated patterns of lncRNAs and further our knowledge of the role of epigenetics in cancer development.
Highlights
Gastric carcinoma (GC) is the fourth most prevalent malignancy and third leading cause of cancer death worldwide (Torre et al, 2015)
The methylation distribution in long noncoding RNAs (lncRNAs) showed a V-shaped curve around the transcription start site (TSS), indicating a relative reduction of the methylation density at the TSS (Figure 1A)
We characterized DNA methylation in the promoters of lncRNA-encoding genes and inferred the potential lncRNAs regulated by aberrant DNA methylation in gastric cancer (GC)
Summary
Gastric carcinoma (GC) is the fourth most prevalent malignancy and third leading cause of cancer death worldwide (Torre et al, 2015). The lncRNA C5orf66-AS1 functions as a tumor suppressor gene in GC, and aberrant hypermethylation of the regions around its transcription start site (TSS) is associated with its expression and is cancer-specific (Guo et al, 2018). This study indicated that hypermethylation of the C5orf66-AS1 promoter may serve as a potential prognostic marker in predicting GC patient survival. Shahabi et al identified an epigenetically deregulated lncRNA linc00261, whose expression was lost in lung adenocarcinoma through DNA methylation silencing. LncRNAs showing aberrant DNA methylation may serve as potential epigenetically-based diagnostic factors. Elucidating the relationship between DNA methylation and lncRNA expression is essential for understanding GC development and potentially identifying new prognostic or diagnostic markers
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