The pancreas is a glandular organ with both endocrine and exocrine function. Its overall purpose is to maintain metabolic homeostasis by producing hormones that regulate blood glucose levels as well as enzymes that aid in digestion. 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.
However, myriad additional genes are mutated in subsets of tumors, typically at a very low frequency(≤10%), with many of these mutations not occurring in a recurrent manner. Further analysis of these infrequent alterations has revealed that they converge on a relatively small number of pathways and cellular processes including KRAS, TGF-β, WNT, NOTCH, and Hedgehog signaling as well as S-phase entry, axonal guidance, chromatin remodeling, DNA repair, and RNA processing.

References

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