title: A structured proteomic approach identifies 14-3-3Sigma as a novel and reliable protein biomarker in panel based differential diagnostics of liver tumors.
abstract: Hepatocellular carcinoma (HCC) is a major lethal cancer worldwide. Despite sophisticated diagnostic algorithms, the differential diagnosis of small liver nodules still is difficult. While imaging techniques have advanced, adjuvant protein-biomarkers as glypican3 (GPC3), glutamine-synthetase (GS) and heat-shock protein 70 (HSP70) have enhanced diagnostic accuracy. The aim was to further detect useful protein-biomarkers of HCC with a structured systematic approach using differential proteome techniques, bring the results to practical application and compare the diagnostic accuracy of the candidates with the established biomarkers. After label-free and gel-based proteomics (n=18 HCC/corresponding non-tumorous liver tissue (NTLT)) biomarker candidates were tested for diagnostic accuracy in immunohistochemical analyses (n=14 HCC/NTLT). Suitable candidates were further tested for consistency in comparison to known protein-biomarkers in HCC (n=78), hepatocellular adenoma (n=25; HCA), focal nodular hyperplasia (n=28; FNH) and cirrhosis (n=28). Of all protein-biomarkers, 14-3-3Sigma (14-3-3S) exhibited the most pronounced up-regulation (58.8×) in proteomics and superior diagnostic accuracy (73.0%) in the differentiation of HCC from non-tumorous hepatocytes also compared to established biomarkers as GPC3 (64.7%) and GS (45.4%). 14-3-3S was part of the best diagnostic three-biomarker panel (GPC3, HSP70, 14-3-3S) for the differentiation of HCC and HCA which is of most important significance. Exclusion of GS and inclusion of 14-3-3S in the panel (>1 marker positive) resulted in a profound increase in specificity (+44.0%) and accuracy (+11.0%) while sensitivity remained stable (96.0%). 14-3-3S is an interesting protein biomarker with the potential to further improve the accuracy of differential diagnostic process of hepatocellular tumors. This article is part of a Special Issue entitled: Medical Proteomics.
authors.affiliation: Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany. Electronic address: henning.reis@uk-essen.de.
authors.forename: Henning
authors.initials: H
authors.lastname: Reis
authors.affiliation: Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany. Electronic address: carolin.puetter@uk-essen.de.
authors.forename: Carolin
authors.initials: C
authors.lastname: Pütter
authors.affiliation: Medizinisches Proteom-Center, Ruhr-Universität Bochum, Universitätsstr. 150, 44780 Bochum, Germany. Electronic address: dominik.megger@rub.de.
authors.forename: Dominik A
authors.initials: DA
authors.lastname: Megger
authors.affiliation: Medizinisches Proteom-Center, Ruhr-Universität Bochum, Universitätsstr. 150, 44780 Bochum, Germany. Electronic address: thilo.bracht@rub.de.
authors.forename: Thilo
authors.initials: T
authors.lastname: Bracht
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany. Electronic address: frank.weber@uk-essen.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Weber
authors.affiliation: West German Cancer Centre Essen, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany. Electronic address: andreas-claudius.hoffmann@uk-essen.de.
authors.forename: Andreas-C
authors.initials: AC
authors.lastname: Hoffmann
authors.affiliation: Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany. Electronic address: stefanie.bertram@uk-essen.de.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bertram
authors.affiliation: Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany. Electronic address: jeremias.wohlschlaeger@uk-essen.de.
authors.forename: Jeremias
authors.initials: J
authors.lastname: Wohlschläger
authors.affiliation: Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany. Electronic address: sascha.hagemann@uk-essen.de.
authors.forename: Sascha
authors.initials: S
authors.lastname: Hagemann
authors.affiliation: Medizinisches Proteom-Center, Ruhr-Universität Bochum, Universitätsstr. 150, 44780 Bochum, Germany. Electronic address: martin.eisenacher@rub.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Eisenacher
authors.affiliation: Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany; Clinical Epidemiology, Integrated Research and Treatment Centre, Centre for Sepsis Control and Care (CSCC), Jena University Hospital, Erlanger Allee 101, 07747 Jena, Germany. Electronic address: andre.scherag@uk-essen.de.
authors.forename: André
authors.initials: A
authors.lastname: Scherag
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany. Electronic address: joerg-friedrich.schlaak@uk-essen.de.
authors.forename: Jörg F
authors.initials: JF
authors.lastname: Schlaak
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany. Electronic address: ali.canbay@uk-essen.de.
authors.forename: Ali
authors.initials: A
authors.lastname: Canbay
authors.affiliation: Medizinisches Proteom-Center, Ruhr-Universität Bochum, Universitätsstr. 150, 44780 Bochum, Germany; Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Bunsen-Kirchhoff-Straße 11, 44139 Dortmund, Germany. Electronic address: helmut.meyer@rub.de.
authors.forename: Helmut E
authors.initials: HE
authors.lastname: Meyer
authors.affiliation: Medizinisches Proteom-Center, Ruhr-Universität Bochum, Universitätsstr. 150, 44780 Bochum, Germany. Electronic address: barbara.sitek@rub.de.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sitek
authors.affiliation: Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany. Electronic address: hideo.baba@uk-essen.de.
authors.forename: Hideo A
authors.initials: HA
authors.lastname: Baba
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000378:metabolism; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D012680:Sensitivity and Specificity
chemical_list: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins
keywords: 14-3-3Sigma; Biomarker panel; Hepatocellular carcinoma; Immunohistochemistry; Label free proteomics; Stratifin