The pancreatic cancer genome revisited

Pancreatic cancer is a genetic disease, and the recurrent genetic alterations characteristic of pancreatic cancer indicate the cellular processes that are targeted for malignant transformation. In addition to somatic alterations in the most common driver genes ( KRAS , CDKN2A , TP53 and SMAD4 ), large-scale studies have revealed major roles for genetic alterations of the SWI/SNF and COMPASS complexes, copy number alterations in GATA6 and MYC that partially define phenotypes of pancreatic cancer, and the role(s) of polyploidy and chromothripsis as factors contributing to pancreatic cancer biology and progression. Germline variants that increase the risk of pancreatic cancer continue to be discovered along with a greater appreciation of the features of pancreatic cancers with mismatch repair deficiencies and homologous recombination deficiencies that confer sensitivity to therapeutic targeting. Wild-type KRAS pancreatic cancers, some of which are driven by alternative oncogenic events affecting NRG1 or NTRK1 — for which targeted therapies exist — further underscore that pancreatic cancer is formally entering the era of precision medicine. Given the vast developments within this field, here we review the wide-ranging and most current information related to pancreatic cancer genomics with the goal of integrating this information into a unifying description of the life history of pancreatic cancer. Vast developments are being made within the field of pancreatic cancer genomics. This Review discusses the wide-ranging and most current research with the goal of integrating this information into a unifying description of the life history of pancreatic cancer. Key Points The natural history of pancreatic cancer is characterized by both genetic and epigenetic alterations that contribute to its formation, progression and resistance to therapy. Most pancreatic cancers arise due to the accumulation of somatic alterations in a recurrent set of genes; however, some patients might develop pancreatic cancer owing to a genetic predisposition. Rare subsets of pancreatic cancers arise in association with a genetic alteration that is targetable. The pancreatic cancer stroma, inclusive of the immune system, acts as a dynamic selective pressure to which the neoplasm continuously adapts. Distinct genomic events are associated with pancreatic cancer phenotypes that are differentially sensitive to currently available therapies.