Model of pancreatic carcinogenesis and progression based on clonal evolution studies. Carcinogenesis begins with an initiating alteration in a normal epithelial cell progenitor that provides a selective advantage. Over time, waves of clonal expansion take place in association with the acquisition of mutations in genes such as CDKN2A, TP53, or SMAD4, corresponding to the genetic progression model of pancreatic intraepithelial neoplasia (PanIN). This clonal expansion is expected to generate more than one subclone within a PanIN, one of which will give rise to the founder cell that will eventually become the parental clone (P) of cells that initiate the infiltrating carcinoma. The time taken for a cell with an initiating alteration to accumulate all mutations eventually present in the founder cell that forms the parental clone of the neoplasm is estimated to be at least 12 years . Additional waves of clonal expansion and accumulation of mutations continue to occur in cell lineages derived from the parental clone leading to the formation of numerous subclones and a genetically heterogeneous primary carcinoma.