Genetics of Familial and Sporadic Pancreatic Cancer

In the previous decade, comprehensive genomic analyses have yielded important insights about the genetic alterations that underlie pancreatictumorigenesis. Whole- exomeand whole-genome sequencingof pancreaticductal adenocarcinomas have confirmed the critical driver genes altered in the majority of pancreatic cancers, as well as identified numerous less frequently altered driver genes, and have delineated cancer subgroups with unique biological and clinical features. It is now appreciated that pancreaticsusceptibility gene alterations are often identified in patients with pancreatic cancerwithout family histories suggestive of a familial cancer syndrome, prompting recent efforts to expand gene testing to all patients with pancreatic cancer. Studies of pancreatic cancerprecursor lesions have begun to elucidate the evolutionary history of pancreatictumorigenesis and to help us understand the utility of biomarkers for early detection and targets to develop new therapeutic strategies. In this review, we discuss the results of comprehensive genomic characterization of pancreaticductal adenocarcinoma and its precursor lesions, and we highlight translational applications in early detection and therapy.