Genomic alterations in pancreatic cystic neoplasms: from molecular characterization to precision clinical management

Pancreatic cystic neoplasms (PCNs) are a heterogeneous group of pancreatic lesions with the potential for malignant transformation. Next-generation sequencing has revealed subtype-specific driver mutations and pathways that govern the initiation and progression of PCN. Evidence suggests that subtype-specific genetic trajectories and temporal sequences of genetic and molecular events are pivotal in determining disease progression and malignant transformation. Novel methodologies in genetic testing, particularly through minimally invasive cyst fluid analysis and advanced tissue-based sequencing, have profoundly enhanced diagnostic accuracy and the molecular classification of PCNs. Furthermore, these genetic insights guide risk stratification, clinical decision-making, and personalized therapeutic interventions. This review systematically summarizes current genomic insights into the molecular landscape of PCNs, critically evaluates the comparative diagnostic performance of cyst fluid versus tissue-based genetic testing, and integrates these findings into a practical framework for clinical management.