Pancreatic ductal adenocarcinoma (PDAC), already among the deadliest epithelial malignancies, is rising in both incidence and contribution to overall cancer deaths. Decades of research have improved our understanding of PDAC carcinogenesis, including characterizing germline predisposition, the cell of origin, precursor lesions, the sequence of genetic alterations, including simple and structural alterations, transcriptional changes and subtypes, tumour heterogeneity, metastatic progression and the tumour microenvironment. These fundamental advances inform contemporary translational efforts in primary prevention, screening and early detection, multidisciplinary management and survivorship, as prospective clinical trials begin to adopt molecular-based selection criteria to guide targeted therapies. Genomic and transcriptomic data on PDAC were also included in the international pan-cancer analysis of approximately 2,600 cancers, a milestone in cancer research that allows further insight through comparison with other tumour types. Thus, this is an ideal time to review our current knowledge of PDAC evolution and heterogeneity, gained from the study of preclinical models and patient biospecimens, and to propose a model of PDAC evolution that takes into consideration findings from varied sources, with a particular focus on the genomics of human PDAC.
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