Abstract
Pancreatic adenocarcinoma (PAAD) is the most malignant digestive tumor. The global incidence of pancreatic cancer has been rapidly trending upwards, necessitating an exploration of potential prognostic biomarkers and mechanisms of disease development. One of the most prevalent RNA modifications is 5-methylcytosine (m5C); however, its contribution to PAAD remains unclear. Data from The Cancer Genome Atlas (TCGA) database, including genes, copy number variations (CNVs), and simple nucleotide variations (SNVs), were obtained in the present study to identify gene signatures and prognostic values for m5C regulators in PAAD. Regulatory gene m5C changes were significantly correlated with TP53, BRCA1, CDKN2A, and ATM genes, which play important roles in PAAD pathogenesis. In particular, there was a significant relationship between m5C regulatory gene CNVs, especially in genes encoding epigenetic “writers”. According to m5C-regulated gene expression in clinically graded cases, one m5C-regulated genes, DNMT3A, showed both a strong effect on CNVs and a significant correlation between expression level and clinical grade (P < 0.05). Furthermore, low DNMT3A expression was not only associated with poor PAAD patient prognosis but also with the ribosomal processing. The relationship between low DNMT3A expression and poor prognosis was confirmed in an International Cancer Genome Consortium (ICGC) validation dataset.
Highlights
Pancreatic adenocarcinoma (PAAD) is the most malignant digestive tumor
With the application of high-throughput sequencing techniques for detecting m5C RNA modifications, a whole-transcriptome map of m5C sites has become available in which m5C mainly appears in the anticodon loop and variable region of tRNAs and rRNAs and the coding sequences of mRNAs20–24. m5C deposition occurs through a methyltransferase complex involving three homologous factors, including methyltransferases (“writers”), demethylases (“erasers”), and m5C binding proteins (“readers”). m5C affects RNA structural stability and translational efficiency like other nucleobase modifications, and research has revealed a potential role in promoting mRNA export and regulating tissue differentiation[25,26]
The results illustrated that low DNMT3A expression significantly correlated with poor prognosis (Fig. 5C). These results suggested that DNMT3A gene expression could be a clinically significant biomarker for PAAD patients
Summary
Pancreatic adenocarcinoma (PAAD) is the most malignant digestive tumor. The global incidence of pancreatic cancer has been rapidly trending upwards, necessitating an exploration of potential prognostic biomarkers and mechanisms of disease development. Data from The Cancer Genome Atlas (TCGA) database, including genes, copy number variations (CNVs), and simple nucleotide variations (SNVs), were obtained in the present study to identify gene signatures and prognostic values for m5C regulators in PAAD. Based on The Cancer Genome Atlas (TCGA) database, researchers can access the gene expression, copy number variations (CNVs), and simple nucleotide variations (SNVs) data of human cancers. Both CNVs and SNVs can play crucial roles in cancer progression, but how the CNVs and SNVs of m5C-related genes contribute are poorly understood[31]. These findings enabled the discovery of genetic alterations to m5C regulatory genes that contribute to PAAD patient outcomes and enhance our understanding of m5C epigenetic regulation in PAAD
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