d to be Kras whose activating mutations are found in more than 90% of PDAC and are present as early as PanIN grade I. Inactivation of Cdkn2a is also found in the early stages (95%) while inactivation of TP53 (75%) and SMAD4 (55%) are observed in the later stages. Large-scale genomic studies and approaches indicate that many important cellular pathways with major roles in cell growth and proliferation, survival and differentiation, gene regulatory networks or tumor suppression, are deregulated in PDAC. They include epidermal growth factor/neuregulin signaling, the SMAD-dependent transforming growth factor-beta, the extracellular signal-regulated Raf/Mek/Erk downstream of Kras and phosphatidylinositol 3-kinase-Akt, possibly also downstream of Kras. Raf/Mek/Erk may also contribute to inappropriate signaling of the hedgehog pathway. In addition to altered hedgehog, deregulation of the canonical Wnt, of scatter factor/hepatocyte growth factor and of integrin mediated signaling pathways are implicated in PDAC. Other pathways involved include p53 signaling, the G1/S transition of the mitotic cell cycle and the SWI/SNF family mediated chromatin remodeling. Of note is that Cdkn2a gives rise to two distinct transcripts resulting in two different proteins: p16/Ink4a and p14/Arf. P16/Ink4a is an inhibitor of cyclin-dependent kinases Cdk4 and Cdk6 involved in the G1/S transition pathway; p14/Arf binds to the Mdm2 negative regulator of p53 and antagonizes its function. Mutations in p16/Ink4a are associated with PDAC while mutant p14/Arf is implicated in other cancer types. The expression of many micro RNAs (miRNAs) has been shown to be both up- and down-regulated in pancreatic cancer tissues and cell lines as compared to normal ones. Consequently, unwanted expression or excessive down-regulation of targets can result from the aberrant expression of miRNAs. The early detection of pancreatic cancer has been rather challenging but the use of epigenetic markers may provide a solution. To see the ontology report for annotations, GViewer and download, click here. To see the Disease Ontology report for genes that in some fashion have been associated with pancreatic neoplasms or suspected to confer susceptibility, click here.
To link to the Cancer Disease Portal, click here. To see the associated KEGG map 05212, click here....(less)