A Combination of MUC5AC and CA19-9 Improves the Diagnosis of Pancreatic Cancer: A Multicenter Study.
A Combination of MUC5AC and CA19-9 Improves the Diagnosis of Pancreatic Cancer: A Multicenter Study.
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DOI：
10.1038/ajg.2016.482
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发表时间：
2017-01
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影响因子：
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通讯作者：
Batra SK
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作者：
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
胰腺癌是一种缺乏特异性诊断标志物的致死性恶性肿瘤。本研究利用多中心训练和验证集，探讨了最差异过表达的分泌黏液蛋白MUC5AC单独和与CA19-9联合的诊断潜力。免疫组化法检测MUC5AC在胰腺良性病变、PC前体病变、原发性PC组织及转移灶中的表达。循环MUC5AC水平采用自主研发的夹心ELISA法测定，CA19-9水平采用放射免疫法测定。采用联合训练集（n =346）评估MUC5AC的诊断意义（n =241）和预测意义（n =105，来自术前、术后和化疗组的总样本201）。使用来自梅奥诊所（n =94）和匹兹堡大学医学中心（n =321）的独立集，通过预先定义的临界值进一步验证结果。组织表达分析显示MUC5AC在胰腺上皮内前体病变1A （PanIN1A）中从头表达；在浸润性腺癌进展的所有阶段均保持表达。可切除早期PC （EPC）患者（1/2期；67.2 ng/ml, IQR: 23.9-382.1）和不可切除晚期PC （LPC）患者（3/4期；389.7 ng/ml, IQR: 87.7-948.6）的中位循环MUC5AC水平显著高于良性对照（BC） （7.2 ng/ml, IQR: 0.4-26.5）和慢性胰腺炎（CP）对照（p值≤0.0001）（8.4 ng/ml, IQR: 1.5-19.2）。在诊断训练集中（n =241）， MUC5AC能有效区分EPC与健康对照（HC）(83%/80%敏感（SN)/特异性（SP））、BC （67%/87% SN/SP）和CP （83%/77% SN/SP）。来自梅奥诊所和UPMC的独立验证集证实了MUC5AC区分EPC和BC（68%/73%; 65%/83%）和CP（68%/79%; 65%/72%）的诊断潜力。此外，MUC5AC和CA19-9联合使用显著提高了区分可切除病例与对照组的诊断准确性（p值< 0.001）。MUC5AC是一种有价值的诊断性生物标志物，可单独使用或与CA19-9联合使用，用于区分PC与CP和良性对照。
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.