title: Novel prognostic markers revealed by a proteomic approach separating benign from malignant insulinomas.
abstract: The prognosis of pancreatic neuroendocrine tumors is related to size, histology and proliferation rate. However, this stratification needs to be refined further. We conducted a proteome study on insulinomas, a well-defined pancreatic neuroendocrine tumor entity, in order to identify proteins that can be used as biomarkers for malignancy. Based on a long follow-up, insulinomas were divided into those with metastases (malignant) and those without (benign). Microdissected cells from six benign and six malignant insulinomas were subjected to a procedure combining fluorescence dye saturation labeling with high-resolution two-dimensional gel electrophoresis. Differentially expressed proteins were identified using nano liquid chromatography-electrospray ionization/multi-stage mass spectrometry and validated by immunohistochemistry on tissue microarrays containing 62 insulinomas. Sixteen differentially regulated proteins were identified among 3000 protein spots. Immunohistochemical validation revealed that aldehyde dehydrogenase 1A1 and voltage-dependent anion-selective channel protein 1 showed significantly stronger expression in malignant insulinomas than in benign insulinomas, whereas tumor protein D52 (TPD52) binding protein was expressed less strongly in malignant insulinomas than in benign insulinomas. Using multivariate analysis, low TPD52 expression was identified as a strong independent prognostic factor for both recurrence-free and overall disease-related survival.
authors.affiliation: Clinic of Gynecology and Obstetrics, University Hospitals Schleswig-Holstein, Kiel, Germany.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Alkatout
authors.affiliation: Institute of Pathology, University of Zurich, Zurich, Switzerland.
authors.forename: Juliane
authors.initials: J
authors.lastname: Friemel
authors.affiliation: Medizinisches Proteom-Center, Ruhr-University Bochum, Bochum,Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sitek
authors.affiliation: Section Neuroendocrine Neoplasms, Institute of Pathology, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Anlauf
authors.affiliation: Department of Molecular Medicine, Max-Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Eisenach
authors.affiliation: Molecular Proteomics Laboratory, Biologisch-Medizinisches Forschungszentrum, Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Stühler
authors.affiliation: ARC-NET Research Center and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Aurel
authors.initials: A
authors.lastname: Perren
authors.affiliation: 1] Medizinisches Proteom-Center, Ruhr-University Bochum, Bochum,Germany [2] Institute of Pathology, University of Tübingen, Tübingen, Germany.
authors.forename: Helmut E
authors.initials: HE
authors.lastname: Meyer
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Hospital, Düsseldorf, Germany.
authors.forename: Wolfram T
authors.initials: WT
authors.lastname: Knoefel
authors.affiliation: Institute of Pathology, Technical University of Munich, Munich, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Klöppel
authors.affiliation: Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany.
authors.forename: Bence
authors.identifier: 0000000273113343
authors.initials: B
authors.lastname: Sipos
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D002853:Chromatography, Liquid; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007340:Insulinoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D053208:Kaplan-Meier Estimate; D008297:Male; D042282:Microdissection; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D016016:Proportional Hazards Models; D040901:Proteomics / Q000379:methods*; D021241:Spectrometry, Mass, Electrospray Ionization; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; C114751:TPD52 protein, human