Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common and among the deadliest of pancreatic cancers. Its 5-year survival is only ∼8%. Pancreatic cancers are a heterogeneous group of diseases, of which PDAC is particularly aggressive. Like many other cancers, PDAC also starts as a pre-invasive precursor lesion (known as pancreatic intraepithelial neoplasia, PanIN), which offers an opportunity for both early detection and early treatment. Even advanced PDAC can benefit from prognostic biomarkers. However, reliable biomarkers for early diagnosis or those for prognosis of therapy remain an unfulfilled goal for PDAC. In this study, we selected 153 PDAC patients from the TCGA database and used their clinical, DNA methylation, gene expression, and micro-RNA (miRNA) and long non-coding RNA (lncRNA) expression data for multi-omics analysis. Differential methylations at about 12,000 CpG sites were observed in PDAC tumor genomes, with about 61% of them hypermethylated, predominantly in the promoter regions and in CpG-islands. We correlated promoter methylation and gene expression for mRNAs and identified 17 genes that were previously recognized as PDAC biomarkers. Similarly, several genes (B3GNT3, DMBT1, DEPDC1B) and lncRNAs (PVT1, and GATA6-AS) are strongly correlated with survival, which have not been reported in PDAC before. Other genes such as EFR3B, whose biological roles are not well known in mammals are also found to strongly associated with survival. We further identified 406 promoter methylation target loci associated with patients survival, including known esophageal squamous cell carcinoma biomarkers, cg03234186 (ZNF154), and cg02587316, cg18630667, and cg05020604 (ZNF382). Overall, this is one of the first studies that identified survival associated genes using multi-omics data from PDAC patients.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) originates from the ductal epithelial cells of the pancreas and it is the most common malignancy of the pancreas
Our analyses revealed that CpG segments close to transcription start site (TSS) and the islands themselves have, in general, a higher level of DNA methylation in tumor samples (Figure S2)
Our study is more comprehensive, since we scoped for differential methylation, differential gene expression, differential miRNA, differential long non-coding RNA (lncRNA) in a genome-wide manner, and we correlated these results with patient survival
Summary
Pancreatic ductal adenocarcinoma (PDAC) originates from the ductal epithelial cells of the pancreas and it is the most common malignancy of the pancreas. We are beginning to gather information about the early-onset and PDAC-specific epigenetic alterations that alter gene expression (Neureiter et al, 2014), especially those that induce metastatic changes such as genome structure reorganization and affect tumor grade, stage, and patient survival (Thompson et al, 2015). Such studies are helping in identifying targets for designing epigenetic inhibitors to treat PDAC. These targets belong to growth signaling and tumor suppressor-silencing pathways, and those that affect cell cycle checkpoints (Paradise et al, 2018)
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