Molecular Pathogenesis of Pancreatic Cancer

Pancreatic cancers arise predominantly from ductal epithelial cells of the exocrine pancreas and are of the ductal adenocarcinoma histological subtype (PDAC). PDAC is an aggressive disease associated with a poor clinical prognosis, weakly effective therapeutic options, and a lack of early detection methods. Furthermore, the genetic and phenotypic heterogeneity of PDAC complicates efforts to identify universally efficacious therapies. PDACs commonly harbor activating mutations in the KRAS oncogene, which is a potent driver of tumor initiation and maintenance. Inactivating mutations in tumor suppressor genes such as CDKN2A/p16, TP53, and SMAD4 cooperate with KRAS mutations to cause aggressive PDAC tumor growth. PDAC can be classified into 3-4 molecular subtypes by global gene expression profiling. These subtypes can be distinguished by distinct molecular and phenotypic characteristics. This chapter will provide an overview of the current knowledge of PDAC pathogenesis at the genetic and molecular level as well as novel therapeutic opportunities to treat this highly aggressive disease.