review of literature on clinical pancreatology - The Pancreapedia

considered for women with Lynch syndrome who are past childbearing age, especially duringsurgery for colorectal cancer. No data show efficacy <strong>of</strong> chemopreventive drugs in reducingthe risk <strong>of</strong> extracolonic cancers for patients with Lynch syndrome [358].Molecular biologyAs with many human malignancies, pancreatic cancer is a complex genetic disorder. Severalthousand disease-associated alterations on the DNA, mRNA, miRNA and protein levels havebeen reported to date. Some <strong>of</strong> these alterations, including a number <strong>of</strong> gatekeepermutations, which are <strong>of</strong> pre-eminent importance for the onset and progression <strong>of</strong> the disease,have been extensively studied in primary tissues, in vitro experiments and transgenic mousemodels. For the vast majority <strong>of</strong> alterations, however, data about the functional significanceare lacking. The situation is complicated by the fact that no certainty exists concerning theidentity <strong>of</strong> the cells that originally undergo malignant transformation nor about the precisenature and fate <strong>of</strong> premalignant lesions that are observed in pancreatic tissues [359].Most cases <strong>of</strong> pancreatic cancer are diagnosed at an advanced stage when the disease isbeyond surgical intervention. Molecular studies during the past decade have contributedgreatly to our understanding <strong>of</strong> this disease. Various germ-line and somatic mutationsassociated with pancreatic cancers have been characterized, along with abnormal variationsin the gene expression patterns. A thorough characterization <strong>of</strong> molecular alterations such asgenetic and epigenetic changes, alterations in the expression <strong>of</strong> genes and changes inproteins, and posttranslational modifications in pancreatic cancer could lead to a betterunderstanding <strong>of</strong> its pathogenesis. The available data from pancreatic cancer suggests thatthere are a large number <strong>of</strong> molecular alterations at genomic, epigenetic, transcriptomic, andproteomic levels. It is now possible to initiate a systems approach to studying pancreaticcancer especially in light <strong>of</strong> newer initiatives to dissect the pancreatic cancer genome [360].MethodologyGenomic analysis using tissue samples is an essential approach in cancer genetics.However, technical and biological limits exist in this approach. Microsatellite instability (MSI)is frequently observed in human tumors. MSI assays are now prevalent and regarded ascommonplace. However, several technical problems have been left unsolved in theconventional assay technique. Indeed, the reported frequencies <strong>of</strong> MSI differ widely in eachmalignancy. An example is pancreatic cancer. Using a unique fluorescent technique, it wasfound that MSI is extremely infrequent in this malignancy, despite the relatively highfrequencies in some reports. In a series <strong>of</strong> simulations, we have demonstrated that theextremely low frequency was derived neither from less sensitive assays nor from a scarcity<strong>of</strong> cancer cells in tissue samples. Furthermore, analyzing laser-capture microdissection(LCM)-processed cell populations <strong>of</strong> a microsatellite-unstable colorectal cancer cell line,HCT116, it was shown that MSI can be detected only when comparing two cell populationsthat have grown independently to a sufficiently large size. When MSI is not detected inanalyses using tissue samples, LCM is not advisable. It was concluded that microsatellitesequence alterations are not detectable in human pancreatic cancer [361].ACLAMALCAM (activated leucocyte cell adhesion molecule, synonym CD166) is a cell adhesionmolecule, which belongs to the Ig superfamily. Disruption <strong>of</strong> the ALCAM-mediatedadhesiveness by proteolytic sheddases such as ADAM17 has been suggested to have arelevant impact on tumor invasion. Although the expression <strong>of</strong> ALCAM is a valuableprognostic and predictive marker in several types <strong>of</strong> epithelial tumors, its role as a prognostic