title: A Combination of MUC5AC and CA19-9 Improves the Diagnosis of Pancreatic Cancer: A Multicenter Study.
abstract: Pancreatic cancer (PC) is a lethal malignancy that lacks specific diagnostic markers. The present study explores the diagnostic potential of the most differentially overexpressed secretory mucin MUC5AC alone and in combination with CA19-9 using multi-center training and validation sets.
  
  
  
  The expression of MUC5AC in benign pancreatic pathologies, PC precursor lesions, primary PC tissues and metastatic lesions was evaluated by immunohistochemistry. Circulating MUC5AC levels were measured using sandwich ELISA assay developed in-house, and CA19-9 was measured using radioimmunoassay. A combined training set (n=346) was used to evaluate the diagnostic (n=241) and predictive (n=105, total samples 201 from pre- and post-surgical and chemotherapy set) significance of MUC5AC. Results were further validated with a pre-defined cut-off value using independent sets from the Mayo Clinic (n=94) and the University of Pittsburgh Medical Center (n=321).
  
  
  
  Tissue expression analyses indicated the de novo expression of MUC5AC in pancreatic intraepithelial precursor lesions 1A (PanIN1A); the expression was maintained through all stages of progression to invasive adenocarcinoma. The median circulating MUC5AC levels in patients with resectable early-stage PC (EPC) (stage 1/2; 67.2 ng/ml, IQR: 23.9-382.1) and unresectable late-stage PC (LPC) (stage 3/4; 389.7 ng/ml, IQR: 87.7-948.6) were significantly higher compared with (P-value ≤0.0001) benign controls (BC) (7.2 ng/ml, IQR: 0.4-26.5) and (P-value ≤0.0001) chronic pancreatitis (CP) controls (8.4 ng/ml, IQR: 1.5-19.2). In the diagnostic training set (n=241), MUC5AC efficiently differentiated EPC from healthy controls (HC) (83%/80% sensitive (SN)/specific (SP)), BC (67%/87% SN/SP), and CP (83%/77% SN/SP). Independent validation sets from the Mayo Clinic and UPMC confirmed the diagnostic potential of MUC5AC to differentiate EPC from BC (68%/73%; 65%/83%) and CP (68%/79%; 65%/72%). Furthermore, MUC5AC and CA19-9 combination significantly improved (p-value < 0.001) the diagnostic accuracy for differentiating resectable cases from controls.
  
  
  
  MUC5AC is a valuable diagnostic biomarker, either alone or in combination with CA19-9, to differentiate PC from CP and benign controls.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Sukhwinder
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Department of Biostatistics, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Smith
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Asish
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Menning
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Duncan C
authors.initials: DC
authors.lastname: Watley
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Saad S
authors.initials: SS
authors.lastname: Malik
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Shiv Ram
authors.initials: SR
authors.lastname: Krishn
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Kavita
authors.initials: K
authors.lastname: Mallya
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Aithal
authors.affiliation: Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Sasson
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Sonny L
authors.initials: SL
authors.lastname: Johansson
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Maneesh
authors.initials: M
authors.lastname: Jain
authors.affiliation: Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Shailender
authors.initials: S
authors.lastname: Singh
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The University of Texas Medical School and Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Sushovan
authors.initials: S
authors.lastname: Guha
authors.affiliation: Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Chandrakanth
authors.initials: C
authors.lastname: Are
authors.affiliation: Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Raimondo
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hollingsworth
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Randall E
authors.initials: RE
authors.lastname: Brand
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.|Fred and Pamela Buffett Cancer Center, Omaha, Nebraska, USA.
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Batra
mesh_terms: D007516:Adenoma, Islet Cell / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018395:CA-19-9 Antigen / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000175:diagnosis / Q000378:metabolism*; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D055271:Mucin 5AC / Q000378:metabolism*; D015999:Multivariate Analysis; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D050500:Pancreatitis, Chronic / Q000378:metabolism; D011863:Radioimmunoassay; D012680:Sensitivity and Specificity
chemical_list: D014408:Biomarkers, Tumor; D018395:CA-19-9 Antigen; C524678:MUC5AC protein, human; D055271:Mucin 5AC