Abstract
BACKGROUND: RNA methylation refers to a form of methyl modification in RNA that modulates various epigenetic alterations. Mounting studies have focused on its potential mechanisms in cancer initiation and progression. However, the prognostic value and potential role of RNA methylation in the immune microenvironment of pancreatic cancer remain unclear. METHODS: Comprehensive bioinformatics analysis was performed to illuminate the expression profiles of RNA methylation modulators. In addition, the ConsensusClusterPlus algorithm was utilized to identify two remarkably different subtypes, and a feasible risk stratification method was established to accurately estimate prognosis. In addition, we validated our signature at the cytology and histology levels and conducted functional experiments to explore the biological functions of our key genes. RESULTS: Two subtypes with remarkable survival differences were identified by the consensus clustering algorithm. Cluster 2 tended to have higher expression levels of RNA methylation regulators and to be the high RNA methylation group. In addition, cluster 1 exhibited a significantly higher abundance of almost all immune cells and increased immune checkpoint expression compared to cluster 2. Chemotherapeutic sensitivity analysis indicated that there were significant differences in the sensitivity of four of the six drugs between different subgroups. Mutation investigation revealed a higher mutation burden and a higher number of mutations in cluster 2. An accurate and feasible risk stratification method was established based on the expression of key genes of each subtype. Patients with low risk scores exhibited longer survival times in one training (TCGA) and two validation cohorts (ICGC, GSE57495), with p values of 0.001, 0.0081, and 0.0042, respectively. In addition, our signature was further validated in a cohort from Fudan University Shanghai Cancer Center. The low-risk group exhibited higher immune cell abundance and immune checkpoint levels than the high-risk group. The characteristics of the low-risk group were consistent with those of cluster 1: higher stromal score, estimate score, and immune score and lower tumor purity. Additionally, cell function investigations suggested that knockdown of CDKN3 remarkably inhibited the proliferation and migration of pancreatic cancer cells. CONCLUSIONS: RNA methylation has a close correlation with prognosis, immune infiltration and therapy in pancreatic cancer. Our subtypes and risk stratification method can accurately predict prognosis and the efficacy of immune therapy and chemotherapy.