Clonal evolutionary analysis reveals patterns of malignant transformation of Intraductal Papillary Mucinous Neoplasms of the pancreas.

Intraductal papillary mucinous neoplasms (IPMNs) are critical precursors to pancreatic ductal adenocarcinoma, a highly lethal cancer characterized by late detection and rapid progression. Here we integrate multi-region whole-genome and transcriptome sequencing to trace the evolution of IPMN, constructing detailed phylogenetic trees to provide insights into subclonal architectures and progression pathways. Our analysis identifies two distinct evolutionary trajectories: one driven by a single ancestral clone, and another involving multiple independent ancestral clones. We further explore the roles of mutational signatures and structural variants in promoting clonal evolution and the emergence of new subclones. Complementing these genomic findings, our transcriptomic analysis reveals unique gene expression profiles and variations in the immune landscape that correlate with different progression stages of IPMN. These insights reveal the complex molecular dynamics of IPMN heterogeneity and progression, highlighting the need to refine early detection and treatment strategies.