Multiomics integrative analysis for gene signatures and prognostic values of m⁶A regulators in pancreatic adenocarcinoma: a retrospective study in The Cancer Genome Atlas project

N6-methyladenosine(m 6 A) is the most abundant post-transcriptional RNA modification in eukaryotes. However, little is known about its role in pancreatic adenocarcinoma (PAAD). The aim of our study was to identify gene signatures and prognostic values of m 6 A regulators in PAAD. Patients from 3 different datasets with complete genomic and transcriptomic sequencing data were enrolled. Survival analysis for different gene alterations was performed using log-rank tests and Cox regression model. The association between alteration of m 6 A regulators and clinicopathological characteristics was examined using chi-square test. Results showed a high frequency of copy number alterations (CNAs) of m 6 A regulatory genes in PAAD patients, but somatic mutations were rarely happened. CNAs and mutations of m 6 A regulatory genes was associated with patient's gender, pathologic stage and resected tumor size. Patients with "gain of function" for m 6 A "reader" genes combined with copy number loss of "writers" or "erasers" had worse overall survival (OS) compared with other patterns. Moreover, copy number gain of m 6 A "reader" gene insulin growth factor 2 binding protein 2 ( IGF2BP2) was an independent risk factor for OS (HR = 2.392, 95%CI: 1.392-4.112, p<0.001) and disease-free survival (DFS) (HR = 2.400, 95%CI: 1.236-4.659, p=0.010). Gene Set Enrichment Analysis (GSEA) indicated that IGF2BP2 was correlated with multiple biological processes associated with cancer, of which the most significant processes were relevant to cancer cell cycle, cell immortalization and tumor immunity. To sum up, a significant relationship was found between m 6 A genomic alterations and worse clinical outcomes. These innovative findings are expected to guide further research on the mechanism of m 6 A in PAAD.