title: A Gastric Glycoform of MUC5AC Is a Biomarker of Mucinous Cysts of the Pancreas.
abstract: Molecular indicators to specify the risk posed by a pancreatic cyst would benefit patients. Previously we showed that most cancer-precursor cysts, termed mucinous cysts, produce abnormal glycoforms of the proteins MUC5AC and endorepellin. Here we sought to validate the glycoforms as a biomarker of mucinous cysts and to specify the oligosaccharide linkages that characterize MUC5AC. We hypothesized that mucinous cysts secrete MUC5AC displaying terminal N-acetylglucosamine (GlcNAc) in either alpha or beta linkage. We used antibody-lectin sandwich assays to detect glycoforms of MUC5AC and endorepellin in cyst fluid samples from three independent cohorts of 49, 32, and 66 patients, and we used monoclonal antibodies to test for terminal, alpha-linked GlcNAc and the enzyme that produces it. A biomarker panel comprising the previously-identified glycoforms of MUC5AC and endorepellin gave 96%, 96%, and 87% accuracy for identifying mucinous cysts in the three cohorts with an average sensitivity of 92% and an average specificity of 94%. Glycan analysis showed that MUC5AC produced by a subset of mucinous cysts displays terminal alpha-GlcNAc, a motif expressed in stomach glands. The alpha-linked glycoform of MUC5AC was unique to intraductal papillary mucinous neoplasms (IPMN), whereas terminal beta-linked GlcNAc was increased in both IPMNs and mucinous cystic neoplasms (MCN). The enzyme that synthesizes alpha-GlcNAc, A4GNT, was expressed in the epithelia of mucinous cysts that expressed alpha-GlcNAc, especially in regions with high-grade dysplasia. Thus IPMNs secrete a gastric glycoform of MUC5AC that displays terminal alpha-GlcNAc, and the combined alpha-GlcNAc and beta-GlcNAc glycoforms form an accurate biomarker of mucinous cysts.
authors.affiliation: Van Andel Research Institute, Grand Rapids, MI, United States of America.
authors.forename: Jessica
authors.initials: J
authors.lastname: Sinha
authors.affiliation: Van Andel Research Institute, Grand Rapids, MI, United States of America.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Cao
authors.affiliation: MD Anderson Cancer Center, Houston, TX, United States of America.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Dai
authors.affiliation: Van Andel Research Institute, Grand Rapids, MI, United States of America.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Tang
authors.affiliation: Van Andel Research Institute, Grand Rapids, MI, United States of America.
authors.forename: Katie
authors.initials: K
authors.lastname: Partyka
authors.affiliation: Van Andel Research Institute, Grand Rapids, MI, United States of America.
authors.forename: Galen
authors.initials: G
authors.lastname: Hostetter
authors.affiliation: University of Michigan School of Medicine, Ann Arbor, MI, United States of America.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Simeone
authors.affiliation: MD Anderson Cancer Center, Houston, TX, United States of America.
authors.forename: Ziding
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, United States of America.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Allen
authors.affiliation: University of Pittsburgh Medical Center, Pittsburgh, PA, United States of America.
authors.forename: Randall E
authors.initials: RE
authors.lastname: Brand
authors.affiliation: Van Andel Research Institute, Grand Rapids, MI, United States of America.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Haab
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism; D002288:Adenocarcinoma, Mucinous / Q000175:diagnosis / Q000378:metabolism*; D015415:Biomarkers / Q000737:chemistry / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000175:diagnosis / Q000378:metabolism*; D002291:Carcinoma, Papillary / Q000175:diagnosis / Q000378:metabolism*; D015331:Cohort Studies; D006031:Glycosylation; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D055271:Mucin 5AC / Q000737:chemistry* / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D010181:Pancreatic Cyst / Q000175:diagnosis / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism
chemical_list: D015415:Biomarkers; D019812:Heparan Sulfate Proteoglycans; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D010446:Peptide Fragments; C071927:perlecan; D017351:N-Acetylglucosaminyltransferases; D000117:Acetylglucosamine