Abstract
Specific protein glycoforms may be uniquely informative about the pathological state of a cyst and may serve as accurate biomarkers. Here we tested that hypothesis using antibody-lectin sandwich arrays in broad screens of protein glycoforms and in targeted studies of candidate markers. We profiled 16 different glycoforms of proteins captured by 72 different antibodies in cyst fluid from mucinous and nonmucinous cysts (n = 22), and we then tested a three-marker panel in 22 addition samples and 22 blinded samples. Glycan alterations were not widespread among the proteins and were mainly confined to MUC5AC and endorepellin. Specific glycoforms of these proteins, defined by reactivity with wheat germ agglutinin and a blood group H antibody, were significantly elevated in mucinous cysts, whereas the core protein levels were not significantly elevated. A three-marker panel based on these glycoforms distinguished mucinous from nonmucinous cysts with 93% accuracy (89% sensitivity, 100% specificity) in a prevalidation sample set (n = 44) and with 91% accuracy (87% sensitivity, 100% specificity) in independent, blinded samples (n = 22). Targeted lectin measurements and mass spectrometry analyses indicated that the higher wheat germ agglutinin and blood group H reactivity was due to oligosaccharides terminating in GlcNAc or N-acetyl-lactosamine with occasional α1,2-linked fucose. The results show that MUC5AC and endorepellin glycoforms may be highly specific and sensitive biomarkers for the differentiation of mucinous from nonmucinous pancreatic cysts.
Highlights
91% accuracy (87% sensitivity, 100% specificity) in independent, blinded samples (n ؍22)
Protein Glycoforms Associated with Mucinous Cysts—To test whether mucinous cysts (IPMNs and mucinous cystic neoplasms (MCNs)) and nonmucinous cysts (SCs and pseudocysts PCs) produce different levels of particular protein glycoforms, we used the antibodylectin sandwich array platform (23, 24) to survey multiple glycan levels on a variety of proteins captured from cyst fluid
The key to the accuracy of the biomarker panel was the detection of glycoforms of specific proteins, as opposed to total protein levels or total glycan levels
Summary
91% accuracy (87% sensitivity, 100% specificity) in independent, blinded samples (n ؍22). The results show that MUC5AC and endorepellin glycoforms may be highly specific and sensitive biomarkers for the differentiation of mucinous from nonmucinous pancreatic cysts. Two types of pancreatic cysts—intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), together termed “mucinous cysts”— have malignant potential, and other types of cysts, such as serous cystadenomas (SCs) and pseudocysts (PCs), are essentially benign. The most useful is CEA, which distinguishes mucinous cysts from nonmucinous cysts with 70% to 80% accuracy (2– 4). The abbreviations used are: CEA, carcinoembryonic antigen; BGH, blood group H; MCN, mucinous cystic neoplasm; IPMN, intraductal papillary mucinous neoplasm; PC, pseudocyst; PNET, pancreatic neuroendocrine tumor; SC, serous cystadenoma; WGA, wheat germ agglutinin. Specific Glycoforms of MUC5AC and Endorepellin Accurately Distinguish Mucinous from Nonmucinous Pancreatic Cysts to provide more accurate diagnoses and to help guide management. Proteomic, and glycomic profiling (13–15) have uncovered other candidate biomarkers that require further study and validation
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