Characterization of Modification Patterns, Biological Function, Clinical Implication, and Immune Microenvironment...

Objective: N⁶-methyladenosine (m⁶A) modification may modulate various biological processes. Nonetheless, clinical implications of m⁶A modification in pancreatic cancer are undefined. Herein, this study comprehensively characterized the m⁶A modification patterns in pancreatic cancer based on m⁶A regulators. Methods: Genetic mutation and expression pattern of 21 m⁶A regulators and their correlations were assessed in pancreatic cancer from TCGA dataset. m⁶A modification patterns were clustered using unsupervised clustering analysis in TCGA and ICGC datasets. Differences in survival, biological functions and immune cell infiltrations were assessed between modification patterns. A m⁶A scoring system was developed by principal component analysis. Genetic mutations and TIDE scores were compared between high and low m⁶A score groups. Results: ZC3H13 (11%), RBM15B (9%), YTHDF1 (8%), and YTHDC1 (6%) frequently occurred mutations among m⁶A regulators. Also, most of regulators were distinctly dysregulated in pancreatic cancer. There were tight crosslinks between regulators. Two m⁶A modification patterns were constructed, with distinct prognoses, immune cell infiltration and biological functions. Furthermore, we quantified m⁶A score in each sample. High m⁶A scores indicated undesirable clinical outcomes. There were more frequent mutations in high m⁶A score samples. Lower TIDE score was found in high m⁶A score group, with AUC = 0.61, indicating that m⁶A scores might be used for predicting the response to immunotherapy. Conclusion: Collectively, these data demonstrated that m⁶A modification participates pancreatic cancer progress and ornaments immune microenvironment, providing an insight into pancreatic cancer pathogenesis and facilitating precision medicine development.