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

Sukwinder Kaur, Lynette M Smith, Asish Patel, Melanie Menning, Duncan C. Watley, Saad S. Malik, Shiv Ram Krishn, Kavita Mallya, Abhijit Aithal, Aaron R. Sasson, Sonny L. Johansson, Maneesh Jain, Shailender Singh, Sushovan Guha, Chandrakanth Are, Massimo Raimondo, Michael A Hollingsworth, Randall E. Brand, Surinder Kumar Batra

Research output: Contribution to journalArticle

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Abstract

OBJECTIVES: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.METHODS: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).RESULTS: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.CONCLUSIONS:MUC5AC is a valuable diagnostic biomarker, either alone or in combination with CA19-9, to differentiate PC from CP and benign controls.

Original languageEnglish (US)
Pages (from-to)172-183
Number of pages12
JournalAmerican Journal of Gastroenterology
Volume112
Issue number1
DOIs
StatePublished - Jan 1 2017

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Pancreatic Neoplasms
Multicenter Studies
Chronic Pancreatitis
Mucins
Radioimmunoassay
Adenocarcinoma
Biomarkers
Enzyme-Linked Immunosorbent Assay
Immunohistochemistry
Pathology
Drug Therapy
Neoplasms

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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A Combination of MUC5AC and CA19-9 Improves the Diagnosis of Pancreatic Cancer : A Multicenter Study. / Kaur, Sukwinder; 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 Kumar.

In: American Journal of Gastroenterology, Vol. 112, No. 1, 01.01.2017, p. 172-183.

Research output: Contribution to journalArticle

Kaur, S, Smith, LM, Patel, A, Menning, M, Watley, DC, Malik, SS, Krishn, SR, Mallya, K, Aithal, A, Sasson, AR, Johansson, SL, Jain, M, Singh, S, Guha, S, Are, C, Raimondo, M, Hollingsworth, MA, Brand, RE & Batra, SK 2017, 'A Combination of MUC5AC and CA19-9 Improves the Diagnosis of Pancreatic Cancer: A Multicenter Study', American Journal of Gastroenterology, vol. 112, no. 1, pp. 172-183. https://doi.org/10.1038/ajg.2016.482
Kaur, Sukwinder ; 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 Kumar. / A Combination of MUC5AC and CA19-9 Improves the Diagnosis of Pancreatic Cancer : A Multicenter Study. In: American Journal of Gastroenterology. 2017 ; Vol. 112, No. 1. pp. 172-183.
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abstract = "OBJECTIVES: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.METHODS: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).RESULTS: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.CONCLUSIONS:MUC5AC is a valuable diagnostic biomarker, either alone or in combination with CA19-9, to differentiate PC from CP and benign controls.",
author = "Sukwinder Kaur and Smith, {Lynette M} and Asish Patel and Melanie Menning and Watley, {Duncan C.} and Malik, {Saad S.} and Krishn, {Shiv Ram} and Kavita Mallya and Abhijit Aithal and Sasson, {Aaron R.} and Johansson, {Sonny L.} and Maneesh Jain and Shailender Singh and Sushovan Guha and Chandrakanth Are and Massimo Raimondo and Hollingsworth, {Michael A} and Brand, {Randall E.} and Batra, {Surinder Kumar}",
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TY - JOUR

T1 - A Combination of MUC5AC and CA19-9 Improves the Diagnosis of Pancreatic Cancer

T2 - A Multicenter Study

AU - Kaur, Sukwinder

AU - Smith, Lynette M

AU - Patel, Asish

AU - Menning, Melanie

AU - Watley, Duncan C.

AU - Malik, Saad S.

AU - Krishn, Shiv Ram

AU - Mallya, Kavita

AU - Aithal, Abhijit

AU - Sasson, Aaron R.

AU - Johansson, Sonny L.

AU - Jain, Maneesh

AU - Singh, Shailender

AU - Guha, Sushovan

AU - Are, Chandrakanth

AU - Raimondo, Massimo

AU - Hollingsworth, Michael A

AU - Brand, Randall E.

AU - Batra, Surinder Kumar

PY - 2017/1/1

Y1 - 2017/1/1

N2 - OBJECTIVES: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.METHODS: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).RESULTS: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.CONCLUSIONS:MUC5AC is a valuable diagnostic biomarker, either alone or in combination with CA19-9, to differentiate PC from CP and benign controls.

AB - OBJECTIVES: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.METHODS: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).RESULTS: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.CONCLUSIONS:MUC5AC is a valuable diagnostic biomarker, either alone or in combination with CA19-9, to differentiate PC from CP and benign controls.

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