m6A/m1A/m5C-related genes identify two pancreatic cancer subtypes and predict prognosis

Pancreatic cancer is a highly aggressive malignancy with an exceptionally poor prognosis, largely due to late diagnosis and limited effective therapeutic options. Current prognostic markers often lack the precision needed for personalized treatment strategies. Understanding the underlying molecular mechanisms, particularly in epigenetic regulation, offers a promising avenue for identifying novel biomarkers. RNA methylation, including N6-methyladenosine (m6A), N1-methyladenosine (m1A), and 5-methylcytosine (m5C), plays crucial roles in gene expression and various cellular processes, and its dysregulation is increasingly implicated in carcinogenesis and tumor progression.

Researchers analyzed gene expression data from the TCGA-PAAD cohort (n=178) for pancreatic cancer patients and GTEx normal pancreatic tissues (n=332). They identified 43 genes associated with m6A/m1A/m5C methylation pathways. Consensus clustering was applied to stratify patients into distinct molecular subtypes based on these genes. A prognostic risk-scoring model was then developed using nine key m6A/m1A/m5C-related genes. To enhance predictive accuracy, a nomogram integrating clinical variables with the risk score was constructed. Furthermore, immunohistochemistry and multicolor immunofluorescence were employed to investigate TRMT61B expression in tumor tissues.

Significant expression differences were observed in 43 m6A/m1A/m5C-related genes between neoplastic and non-neoplastic pancreatic tissues, correlating with multiple biological pathways. Consensus clustering successfully divided pancreatic cancer patients into two distinct molecular subtypes, which exhibited pronounced survival differences. The developed prognostic risk-scoring model, based on nine m6A/m1A/m5C-related genes, demonstrated efficacy in predicting patient outcomes. This model was further refined by a nomogram that integrated clinical variables, improving prognostic precision.

A comprehensive investigation revealed that higher TRMT61B expression in tumor tissues was significantly associated with higher pancreatic cancer stage, and might relate to an immunosuppressive and dysfunctional tumor immune microenvironment. These findings highlight the critical role of m6A/m1A/m5C-associated genes, particularly TRMT61B, in the epigenetic regulation of pancreatic cancer progression.