Genetics of Pancreatic Cystic Tumors

Pancreatic cystic tumors (PCTs) are a heterogeneous group of pancreatic neoplasms with variable malignant potential. Advances in imaging and molecular genetics have improved their detection and characterization. This chapter explores the genetic and molecular mechanisms underlying major PCTs, including intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), serous cystic neoplasms (SCNs), and solid pseudopapillary neoplasms (SPENs). Each form of PCT is characterized by specific genetic mutations that drive its development and determine its clinical course such as KRAS and GNAS in IPMNs, KRAS, RNF43, TP53, and SMAD4 in MCNs, VHL in SCNs, and CTNNB1 in SPENs. Familial syndromes such as Von Hippel–Lindau (VHL), Peutz-Jeghers (PJS), Lynch, FAMMM, and BRCA1/2-related syndromes contribute to inherited susceptibility to PCTs. The molecular pathogenesis of these tumors involves sequential genetic events-early oncogenic activation, intermediate tumor suppressor loss, and late-stage invasive transformation. Genetic testing using next-generation sequencing (NGS) and liquid biopsy of cyst fluid enhances diagnostic precision, enabling differentiation between benign and malignant cysts. Biomarkers such as KRAS, GNAS, TP53, and SMAD4 have diagnostic and prognostic significance. Emerging multi-omics and AI-based approaches are transforming early detection and targeted therapy strategies. Integrating molecular genetics into clinical management promises improved outcomes through personalized medicine and early intervention in malignant progression of pancreatic cystic neoplasms.