Combined Analysis of the Aberrant Epigenetic Alteration of Pancreatic Ductal Adenocarcinoma

Abstract

Background. Pancreatic ductal adenocarcinoma (PDAC) remains one of the most fatal malignancies due to its high morbidity and mortality. DNA methylation exerts a vital part in the development of PDAC. However, a mechanistic role of mutual interactions between DNA methylation and mRNA as epigenetic regulators on transcriptomic alterations and its correlation with clinical outcomes such as survival have remained largely uncovered in cancer. Therefore, elucidation of aberrant epigenetic alteration in the development of PDAC is an urgent problem to be solved. In this work, we conduct an integrative epigenetic analysis of PDAC to identify aberrant DNA methylation-driven cancer genes during the occurrence of cancer. Methods. DNA methylation matrix and mRNA profile were obtained from the TCGA database. The integration of methylation and gene expression datasets was analyzed using an R package MethylMix. The genes with hypomethylation/hypermethylation were further validated in the Kaplan–Meier analysis. The correlation analysis of gene expression and aberrant DNA methylation was also conducted. We performed a pathway analysis on aberrant DNG methylation genes identified by MethylMix criteria using ConsensusPathDB. Results. 188 patients with both methylation data and mRNA data were considered eligible. A mixture model was constructed, and differential methylation genes in normal and tumor groups using the Wilcoxon rank test was performed. With the inclusion criteria, 95 differential methylation genes were detected. Among these genes, 74 hypermethylation and 21 hypomethylation genes were found. The pathway analysis revealed an increase in hypermethylation of genes involved in ATP-sensitive potassium channels, Robo4, and VEGF signaling pathways crosstalk, and generic transcription pathway. Conclusion. Integrated analysis of the aberrant epigenetic alteration in pancreatic ductal adenocarcinoma indicated that differentially methylated genes could play a vital role in the occurrence of PDAC by bioinformatics analysis. The present work can help clinicians to elaborate on the function of differentially methylated expressed genes and pathways in PDAC. CDO1, GJD2, ID4, NOL4, PAX6, TRIM58, and ZNF382 might act as aberrantly DNA-methylated biomarkers for early screening and therapy of PDAC in the future.

Aberrantly DNA Methylated-Differentially Expressed Genes in Pancreatic Cancer Through an Integrated Bioinformatics Approach

“…Besides, a decrease in the expression of TRIM58 via hypermethylation has been strongly associated with cancer progression in patients with early stage lung adenocarcinoma ( Kajiura et al, 2017 ). Xu et al (2019) demonstrated that MeDEGs such as TRIM58 exerts great distinct influence on the development of pancreatic cancer via bioinformatics analysis.…”

NOL4 is Downregulated and Hyper-Methylated in Papillary Thyroid Carcinoma Suggesting Its Role as a Tumor Suppressor Gene

“…Meanwhile, Demokan et al (7) reported that aberrant methylation of CpG islands upstream of this gene was associated with head and neck squamous cell carcinoma (HNSCC). Furthermore, one study recently revealed that the NOL4 gene plays a role in glioblastoma multiform (GBM) (15). NOL4 intronic mutation has been detected in Indian families with Van der Woude syndrome (20).…”

“…In 1998, Ueki et al ( 13) identified novel nucleolar protein, termed NOLP (Nucleolar Localized Protein) which is now known as nucleolar protein 4 (NOL4). In spite of a number of different studies on the role of NOL4 as a tumor suppressor gene in different types of cancer like squamous cell carcinoma of head and cervical cancer, cervical cancer and Pancreatic ductal adenocarcinoma (7,14,15), there has been no study on the role of this gene in thyroid cancers to date.…”

Towards an updated view on the clinical management of pancreatic adenocarcinoma: Current and future perspectives (Review)

“…It must be added that all the genetic, metabolic and tissue changes produced in tumor cells cause patients to present a great variety of molecular alterations, mutations and aberrations in the expression of different antigens. These variations make it even more difficult to validate a single marker or battery of markers in the diagnosis of pancreatic cancer ( 69 ). The ideal scenario would be the combination of other markers that allows us to detect initial stages.…”