Pancreatic adenocarcinoma is the 4th leading cause of cancer-related death in the United States (1) and is associated with a 4% five-year survival rate. Most patients have unresectable disease at presentation although a small minority of patients (10-20%) is found to have early resectable pancreatic cancer. A method for early-stage detection of pancreatic cancer would provide a prospect of long-term survival and even curability. A highly specific noninvasive test that can differentiate early pancreatic adenocarcinoma from unresectable disease, as well as chronic pancreatitis and other non-pancreatic cancers and inflammatory conditions may provide a valuable clinical tool. Many types of malignancies have been shown to possess unique glycan moieties on specific glycoproteins in comparison to the same proteins found in normal states or other diseases that can be detected in the serum. In the proposed work, we will use a mass spec based assay to enhance the analytical specificity for detecting changes in glycan structures between disease states. We will use a platform involving an antibody capture of selected proteins from serum followed by deglycosylation and collection of the glycans from these proteins. The glycans will then be analyzed by an ion mobility/tandem mass spectrometry method which is sensitive to even subtle changes in glycan structure. The ion mobility method can provide a rapid separation of the glycans including glycoforms and the use of tandem mass spec detection can readily observe changes in the glycan structure at the sugar level as a function of disease. The method can be multiplexed to analyze several glycoprotein changes simultaneously where it can be used for high-throughput analysis of a large number of samples using the combined separation capabilities of the ion mobility method and mass spec techniques. The proposed work will involve studying fifteen antibody/protein combinations which were selected based on our preliminary glycoarray studies. We hypothesize that unique glycosylation patterns can be observed in proteins from serum samples of patients with benign pancreatic mucinous cystic neoplasms (MCNs) and intraductal papillary mucinous neoplasms (IPMNs), patients with long-term type II diabetes, patients with chronic pancreatitis, and patients with pancreatic cancer. To address this hypothesis, we will use 50 serum samples from each of the five disease groups to calculate sensitivity and specificity, to identify markers that should be advanced to a blinded test set and to define cut- points for decision making. We will also screen for comparison 50 samples each of other cancers that are archived including esophageal, colorectal, hepatocellular, and ovarian cancers. We hypothesize that the glycosylation patterns of pancreatic cancer are unique and do not overlap with other cancers.

Public Health Relevance

If this work is successful then it will lead to potential markers that can be used for future pre-validation studies for the early detection of pancreatic cancer based upon an antibody/ion mobility/tandem mass spectrometry assay that will reveal unique changes that can be detected in patient serum.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA154455-02
Application #
8210825
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Wagner, Paul D
Project Start
2011-01-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$313,429
Indirect Cost
$105,929
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Yin, Haidi; Zhu, Jianhui; Wu, Jing et al. (2016) A procedure for the analysis of site-specific and structure-specific fucosylation in alpha-1-antitrypsin. Electrophoresis 37:2624-2632
Zhu, Jianhui; Wu, Jing; Yin, Haidi et al. (2015) Mass Spectrometric N-Glycan Analysis of Haptoglobin from Patient Serum Samples Using a 96-Well Plate Format. J Proteome Res 14:4932-9
Tan, Zhijing; Yin, Haidi; Nie, Song et al. (2015) Large-scale identification of core-fucosylated glycopeptide sites in pancreatic cancer serum using mass spectrometry. J Proteome Res 14:1968-78
Yin, Haidi; Tan, Zhijing; Wu, Jing et al. (2015) Mass-Selected Site-Specific Core-Fucosylation of Serum Proteins in Hepatocellular Carcinoma. J Proteome Res 14:4876-84
Nie, Song; Yin, Haidi; Tan, Zhijing et al. (2014) Quantitative analysis of single amino acid variant peptides associated with pancreatic cancer in serum by an isobaric labeling quantitative method. J Proteome Res 13:6058-66
Zhu, Jianhui; Lin, Zhenxin; Wu, Jing et al. (2014) Analysis of serum haptoglobin fucosylation in hepatocellular carcinoma and liver cirrhosis of different etiologies. J Proteome Res 13:2986-97
Zhu, Jianhui; Thakolwiboon, Smathorn; Liu, Xinhua et al. (2014) Overexpression of CD90 (Thy-1) in pancreatic adenocarcinoma present in the tumor microenvironment. PLoS One 9:e115507
Lin, Zhenxin; Yin, Haidi; Lo, Andy et al. (2014) Label-free relative quantification of alpha-2-macroglobulin site-specific core-fucosylation in pancreatic cancer by LC-MS/MS. Electrophoresis 35:2108-15
Nie, Song; Lo, Andy; Wu, Jing et al. (2014) Glycoprotein biomarker panel for pancreatic cancer discovered by quantitative proteomics analysis. J Proteome Res 13:1873-84
Yin, Haidi; Lin, Zhenxin; Nie, Song et al. (2014) Mass-selected site-specific core-fucosylation of ceruloplasmin in alcohol-related hepatocellular carcinoma. J Proteome Res 13:2887-96

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