A Combination of MUC5AC and CA19-9 Improves the Diagnosis of Pancreatic Cancer: A Multicenter Study

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 expressi...

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Published in:	The American journal of gastroenterology Vol. 112; no. 1; pp. 172 - 183
Main Authors:	Kaur, Sukhwinder, Smith, Lynette M, Patel, Asish, Menning, Melanie, Watley, Duncan C, Malik, Saad S, Krishn, Shiv Ram, Mallya, Kavita, Aithal, Abhijit, Sasson, Aaron R, Johansson, Sonny L, Jain, Maneesh, Singh, Shailender, Guha, Sushovan, Are, Chandrakanth, Raimondo, Massimo, Hollingsworth, Michael A, Brand, Randall E, Batra, Surinder K
Format:	Journal Article
Language:	English
Published:	United States Wolters Kluwer Health Medical Research, Lippincott Williams & Wilkins 01-01-2017
Subjects:	Adenoma, Islet Cell - metabolism Biomarkers, Tumor - metabolism CA-19-9 Antigen - metabolism Carcinoma, Pancreatic Ductal - diagnosis Carcinoma, Pancreatic Ductal - metabolism Case-Control Studies Enzyme-Linked Immunosorbent Assay Gastroenterology Humans Immunohistochemistry Mucin 5AC - metabolism Multivariate Analysis Pancreatic cancer Pancreatic Neoplasms - diagnosis Pancreatic Neoplasms - metabolism Pancreatitis, Chronic - metabolism Radioimmunoassay Sensitivity and Specificity
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0002-9270 1572-0241
DOI:	10.1038/ajg.2016.482