title: Identification of a novel serum biomarker for pancreatic cancer, C4b-binding protein α-chain (C4BPA) by quantitative proteomic analysis using tandem mass tags.
abstract: Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease due to the lack of specific early diagnostic markers. To improve the outcomes, proteomic approaches are being developed for the discovery of novel biomarkers of PDAC.
  
  
  
  Using tandem mass tag labelling and LC-MS/MS, we performed comparative analyses of pre- and postoperative sera from PDAC patients to identify specific serum biomarkers for PDAC. In validation studies, we evaluated the discriminatory power of candidate proteins.
  
  
  
  Among the 302 proteins analysed, 20 were identified as potential biomarkers, with C4b-binding protein α-chain (C4BPA) and polymeric immunoglobulin receptor (PIGR) being selected for further analysis. The sera levels of C4BPA and PIGR were significantly higher in the preoperative PDAC patients than in the postoperative ones (P<0.008, P<0.036, respectively). In addition, serum C4BPA levels, but not PIGR, in patients with PDAC were significantly higher than those in healthy controls as well as in patients with pancreatitis and other malignancies including biliary tract cancers (BTC) (P<0.001). The respective area under the receiver operator characteristics (ROC) curve (AUC) was 0.860 for C4BPA, 0.846 for CA19-9 and 0.930 for the combination of C4BPA and CA19-9 in PDAC vs non-cancer individuals. The respective AUC was 0.912 for C4BPA, 0.737 for CA19-9 in Stages I and II of PDAC, 0.854 for C4BPA and 0.264 for CA19-9 in PDAC vs BTC.
  
  
  
  We have demonstrated that C4BPA is a novel serum biomarker for detecting early stage PDAC, as well as for distinguishing PDAC from other gastroenterological cancers. Further analysis in large cohort studies will warrant C4BPA as a promising biomarker of PDAC in clinical use.
authors.affiliation: Department of Biochemistry, School of Life and Environmental Science, Azabu University, Kanagawa 252-0206, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sogawa
authors.affiliation: Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Shigetsugu
authors.initials: S
authors.lastname: Takano
authors.affiliation: Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Fumie
authors.initials: F
authors.lastname: Iida
authors.affiliation: Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.|Divisions of Clinical Mass Spectrometry and Clinical Genetics, Chiba University Hospital, Chiba 260-8670, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Satoh
authors.affiliation: Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Sachio
authors.initials: S
authors.lastname: Tsuchida
authors.affiliation: Center for Disease Proteomics, School of Science, Kitasato University, Kanagawa 252-0373, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kawashima
authors.affiliation: Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yoshitomi
authors.affiliation: Department of Biochemistry, School of Life and Environmental Science, Azabu University, Kanagawa 252-0206, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sanda
authors.affiliation: Center for Disease Proteomics, School of Science, Kitasato University, Kanagawa 252-0373, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kodera
authors.affiliation: Kashiwado Clinic in Port-Square, Kashiwado Memorial Foundation, Chiba 260-0025, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Takizawa
authors.affiliation: Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Rintaro
authors.initials: R
authors.lastname: Mikata
authors.affiliation: Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ohtsuka
authors.affiliation: Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Miyazaki
authors.affiliation: Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Yokosuka
authors.affiliation: Divisions of Clinical Mass Spectrometry and Clinical Genetics, Chiba University Hospital, Chiba 260-8670, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Nomura
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000097:blood*; D021441:Carcinoma, Pancreatic Ductal / Q000097:blood* / Q000601:surgery; D016022:Case-Control Studies; D050716:Complement C4b-Binding Protein / Q000032:analysis*; D003937:Diagnosis, Differential; D004067:Digestive System Neoplasms / Q000097:blood; D005260:Female; D006801:Humans; D018189:Immunomagnetic Separation; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000097:blood*; D010190:Pancreatic Neoplasms / Q000097:blood* / Q000601:surgery; D010195:Pancreatitis / Q000097:blood; D011184:Postoperative Period; D012372:ROC Curve; D019056:Receptors, Polymeric Immunoglobulin / Q000097:blood; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry
chemical_list: D014408:Biomarkers, Tumor; C055609:C4BPA protein, human; D050716:Complement C4b-Binding Protein; D009363:Neoplasm Proteins; D019056:Receptors, Polymeric Immunoglobulin