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Glycosylation Variants of Mucins and CEACAMs As Candidate Biomarkers for the Diagnosis of Pancreatic Cystic Neoplasms

Haab, Brian B. PhD*; Porter, Andrew MD*; Yue, Tingting BS*; Li, Lin PhD; Scheiman, James MD; Anderson, Michelle A. MD, PhD; Barnes, Dawn MD§; Schmidt, C. Max MD; Feng, Ziding PhD; Simeone, Diane M. MD§∥

doi: 10.1097/SLA.0b013e3181d7738d
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Background and Aims: Cystic lesions of the pancreas are increasingly being recognized due to the widespread use of high resolution abdominal imaging. Since certain cyst types are precursors to invasive cancer, this situation presents an opportunity to intervene prior to malignant progression. Effective implementation of that strategy has been hampered by difficulties in clearly distinguishing cystic lesions with no malignant potential from those with malignant potential. Here we explored whether glycosylation variants on specific proteins in cyst fluid samples could serve as biomarkers to aid in this diagnosis.

Methods: We used a novel antibody-lectin sandwich microarray method to measure the protein expression and glycosylation of mucin (MUC)1, MUC5AC, MUC16, carcinoembryonic antigen, and other proteins implicated in pancreatic neoplasia in cyst fluid samples. Fifty-three cyst fluid samples were obtained from patients with mucinous cystic neoplasms (n = 17), intraductal papillary mucinous neoplasms (n = 15), serous cystadenomas (n = 12), or pseudocysts (n = 9), with confirmation of histologic diagnosis at surgical resection.

Results: The detection of a glycan variant on MUC5AC using the lectin wheat-germ agglutinin discriminated mucin-producing cystic tumors (mucinous cystic neoplasms + intraductal papillary mucinous neoplasms) from benign cystic lesions (serous cystadenomas + pseudocysts) with a 78% sensitivity at 80% specificity, and when used in combination with cyst fluid CA 19-9 gave a sensitivity of 87% at 86% specificity. These biomarkers performed better than cyst fluid carcinoembryonic antigen (37%/80% sensitivity/specificity).

Conclusions: These results demonstrate the value of glycan variants for biomarker discovery and suggest that these biomarkers could greatly enhance the accuracy of differentiating pancreatic cystic tumors. Validation studies will be required to determine the clinical value of these markers.

Our objective was to determine if measurement of glycosylation variants of specific proteins would identify useful biomarkers to define pancreatic cystic lesions with malignant potential. We found that detection of a glycan variant on MUC5AC, used in combination with cyst fluid CA 19–9, performed significantly better than cyst fluid carcinoembryonic antigen, the biomarker most commonly used currently in the clinical setting. SUPPLEMENTAL DIGITAL CONTENT IS AVAILABLE IN THE TEXT.

From the *Van Andel Research Institute, Grand Rapids, MI; †Fred Hutchinson Cancer Research Center, Seattle, WA; ‡Departments of Internal Medicine, and §Surgery, University of Michigan, Ann Arbor, MI; ¶Department of Surgery, Biochemistry, and Molecular Biology, Indiana University, Indianapolis, IN; and ∥Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI.

Supported by NCI (R21 CA122890 and R33 CA122890) (to B.B.H. and T.Y.); National Institutes of Health (NCI R21 CA122890 and R33 CA122890 (to B.B.H.); 1 R03 CA 112629–01A1 (to C.M.S.); UO1 1CA117452), the Van Andel Research Institute, and University of Michigan Comprehensive Cancer Center.

Contribution of individual authors to the submitted work—conception and design, analysis and interpretation of data: B.B.H and D.M.S.; acquisition and analysis of data: A.P., T.Y., L.L., M.A.A., D.B., C.M.S., D.M.S., J.S., and Z.F.; drafting of article: J.S.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.annalsofsurgery.com).

Reprints: Diane M. Simeone, MD, Departments of Surgery and Molecular and Integrative Physiology, TC 2210B, Box 5343, University of Michigan Medical Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109. E-mail: simeone@umich.edu.

© 2010 Lippincott Williams & Wilkins, Inc.