Figure 3.

A refined model of multistep tumorigenesis in premalignant pancreatic tumorigenesis. Low-grade IPMNs are characterized by multiple mutations in the initiating oncogene KRAS, suggesting polyclonal evolution of multiple genetically independent precancers. Selection of a clone leads to the development of a high-grade IPMN, which then undergoes ongoing evolution, at times with distinct alterations in the same gene arising in distinct subclones. Selection of an advanced clone that invades the basement membrane leads to the development of invasive PDAC. While this model has been validated in human IPMN samples, its applicability to microscopic human PanINs requires further investigation.