Identification of m6A-related genes and m6A RNA methylation regulators in pancreatic cancer and their association with survival

Background: N6-methyladenosine (m6A) modification holds an important position in tumorigenesis and metastasis because it can change gene expression and even function in multiple levels including RNA splicing, stability, translocation and translation. In present study, we aim to conducted comprehensive investigation on m6A RNA methylation regulators and m6A-related genes in pancreatic cancer and their association with survival time. Methods: Based on Univariate Cox regression analysis, protein-protein interaction analysis, LASSO Cox regression, a risk prognostic model, STRING, Spearman and consensus clustering analysis, data from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) database was used to analyze 15 m6A RNA methylation regulators that were widely reported and 1,393 m6A-related genes in m6Avar. Results: We found that 283 candidate m6A RNA methylation-related genes and 4 m6A RNA methylation regulatory factors, including RNA binding motif protein 15 (RBM15), methyltransferase like 14 (METTL14), fat mass and obesity-associated protein (FTO), and alpha-ketoglutarate-dependent dioxygenase AIkB homolog 5 (ALKBH5), differed significantly among different stages of the American Joint Committee on Cancer (AJCC) staging system. Protein-protein interaction analysis indicated epidermal growth factor receptor (EGFR), plectin-1 (PLEC), BLM RecQ like helicase (BLM), and polo like kinase 1 (PLK1) were closely related to other genes and could be considered as hub genes in the network. The results of LASSO Cox regression and the risk prognostic model indicated that AJCC stage, stage 'I' and N, KRAS mutation status and x8q23.3 CNV fragment mutation differed significantly between the high-risk and the low-risk subgroups. The AUCs of 1 to 5 years after surgery were all more than 0.7 and increased year by year. Finally, we found KRAS mutation status and AJCC stage differed significantly among these groups after TCGA samples divided into subgroups with k=7. Moreover, we identified four m6A RNA methylation related genes expressed significantly differently among these seven subgroups, including collagen type VII alpha 1 chain (COL7A1), branched chain amino acid transaminase 1 (BCAT1), zinc finger protein 596 (ZNF596), and PLK1. Conclusions: Our study systematically analyzed the m6A RNA methylation related genes, including expression, protein-protein interaction, potential function, and prognostic value and provides important clues to further research on the function of RNA m6A methylation and its related genes in pancreatic cancer.