title: Expression of novel markers of pancreatic ductal adenocarcinoma in pancreatic nonductal neoplasms: additional evidence of different genetic pathways.
abstract: Solid pseudopapillary tumor, pancreatoblastoma, undifferentiated carcinoma with osteoclastic-like giant cells, and acinar cell carcinomas are rare pancreatic nonductal neoplasms. Compared to the significant advances in our understanding of the pathogenesis of pancreatic ductal adenocarcinomas in the last decades, the molecular mechanisms underlying pancreatic nonductal neoplasms are poorly understood. In order to elucidate their molecular pathogenesis, we constructed tissue microarrays to study the expression of some novel pancreatic ductal adenocarcinoma-associated tumor markers in these nonductal pancreatic neoplasms. We analyzed nine markers including tumor suppressor gene (14-3-3 sigma), proliferation marker (topoisomerase II alpha), epithelial markers (prostate stem cell antigen, mesothelin and cytokeratin 19), stromal markers (fascin, hsp47 and fibronectin), and gamma-synuclein whose function is not delineated. In addition, we included tumor suppressor gene DPC4 and oncogene Beta-catenin to further confirm their expression in pancreatic nonductal tumors. Our results showed that in contrast to pancreatic ductal adenocarcinomas that show loss of Dpc4 protein in 55% of cases, loss of Dpc4 expression is absent in pancreatic nonductal neoplasms. Expression of 14-3-3 sigma is frequently seen in both pancreatic nonductal neoplasms (25-100%) and ductal adenocarcinomas (89%). Aberrant nuclear expression of beta-catenin is common in pancreatic nonductal neoplasms, specifically in solid pseudopapillary tumors (88%) and pancreatoblastomas (100%) but is rarely seen in pancreatic ductal adenocarcinomas (<5%). Expression of topoisomerase II alpha is not seen in solid pseudopapillary tumors and undifferentiated carcinomas with osteoclastic-like giant cells but is focally seen in pancreatoblastomas (50%) and acinar cell carcinomas (85%). Expression of PSCA and mesothelin was observed in pancreatic nonductal neoplasms but their expression was seen less frequently (0-50%) and weaker than that in pancreatic ductal adenocarcinomas (60-100%). CK19, a marker of pancreatic ductal adenocarcinomas, is not expressed in pancreatic nonductal neoplasms. Expression of gamma-synuclein as well as stromal markers (fascin, hsp47 and fibronectin) is frequently seen in both. Our findings indicate pancreatic nonductal neoplasms have distinctive patterns of protein expression relative to pancreatic ductal adenocarcinomas and suggest that pancreatic nonductal neoplasms have different genetic pathways from the more common pancreatic ductal adenocarcinomas.
authors.affiliation: Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21231-2410, USA.
authors.forename: Dengfeng
authors.initials: D
authors.lastname: Cao
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Jorge-Albores
authors.initials: JA
authors.lastname: Saavedra
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
authors.forename: N Volkan
authors.initials: NV
authors.lastname: Adsay
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
mesh_terms: D048948:14-3-3 Proteins; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor / Q000032:analysis*; D018267:Carcinoma, Acinar Cell / Q000378:metabolism / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000032:analysis; D003598:Cytoskeletal Proteins / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis; D005092:Exonucleases / Q000032:analysis; D005095:Exoribonucleases; D005353:Fibronectins / Q000032:analysis; D058851:GPI-Linked Proteins; D050958:HSP47 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D007633:Keratins / Q000032:analysis; D008562:Membrane Glycoproteins / Q000032:analysis; D000090204:Mesothelin; D008840:Microfilament Proteins / Q000032:analysis; D009363:Neoplasm Proteins / Q000032:analysis; D009419:Nerve Tissue Proteins / Q000032:analysis; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D015843:Serpins / Q000032:analysis; D051901:Smad4 Protein; D051843:Synucleins; D015534:Trans-Activators / Q000032:analysis; D051176:beta Catenin; D051845:gamma-Synuclein
chemical_list: D048948:14-3-3 Proteins; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D005353:Fibronectins; D058851:GPI-Linked Proteins; D050958:HSP47 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C110843:PSCA protein, human; C494660:SERPINH1 protein, human; C497796:SMAD4 protein, human; D015843:Serpins; D051901:Smad4 Protein; D051843:Synucleins; D015534:Trans-Activators; D051176:beta Catenin; D051845:gamma-Synuclein; C020324:fascin; D007633:Keratins; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human; D000090204:Mesothelin