Early detection of cancer and precancerous conditions improves patient survival. This study will identify changes in protein associated glycans associated with the development of hepatocellular carcinoma. To achieve this goal, we developed mass spectrometric analysis of permethylated glycans enzymatically removed from serum proteins. This method allows an efficient and high-throughput comparison of glycans. We tested the method on a pilot set of hepatocellular carcinoma cases and controls from our unique study of hepatocellular carcinoma in Egypt, a country with an epidemic of hepatitis C viral infection. The pilot-study identified three glycans that predict hepatocellular carcinoma with 90% prediction accuracy compared to controls with chronic liver disease. In this study, we propose to expand the project and to include a comparison of hepatocellular carcinoma cases and chronic liver disease controls in the US population. As we continue to assess glycan changes in the progression of chronic viral infection to hepatocellular carcinoma, we will continue to improve the analytical methods for quantification and structural characterization of the glycans. It is expected that the quantification of glycans will improve the performance of currently available methods for early detection of hepatocellular carcinoma. Defining clinically applicable markers of early-stage cancer has potentially far-reaching consequences for disease management and patient health. The glycan markers could be used to screen high risk populations for early signs of disease;to design and test new chemoprevention strategies;and to follow disease progression after treatment. Identification of the changes in glycans associated with disease progression is expected to generate new hypotheses for carcinogenesis of the liver.

Public Health Relevance

Early detection of cancer and precancerous conditions improves patient survival. This study will identify changes in various protein-decorating sugars that accompany the development of liver cancer. To achieve this goal, we developed methods that allow high-throughput comparison of these sugars. The identified sugars could be used to screen high risk populations for early signs of liver cancer;to design and test new chemoprevention strategies;and to follow disease progression after treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA135069-04
Application #
8311564
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Zanetti, Krista A
Project Start
2009-09-04
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$392,840
Indirect Cost
$103,910
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Benicky, Julius; Sanda, Miloslav; Pompach, Petr et al. (2014) Quantification of fucosylated hemopexin and complement factor H in plasma of patients with liver disease. Anal Chem 86:10716-23
Chandler, Kevin Brown; Brnakova, Zuzana; Sanda, Miloslav et al. (2014) Site-specific glycan microheterogeneity of inter-alpha-trypsin inhibitor heavy chain H4. J Proteome Res 13:3314-29
Sanda, Miloslav; Pompach, Petr; Benicky, Julius et al. (2013) LC-MS3 quantification of O-glycopeptides in human serum. Electrophoresis 34:2342-9
Sanda, Miloslav; Pompach, Petr; Brnakova, Zuzana et al. (2013) Quantitative liquid chromatography-mass spectrometry-multiple reaction monitoring (LC-MS-MRM) analysis of site-specific glycoforms of haptoglobin in liver disease. Mol Cell Proteomics 12:1294-305
Lam, Phuc Vinh Nguyen; Goldman, Radoslav; Karagiannis, Konstantinos et al. (2013) Structure-based comparative analysis and prediction of N-linked glycosylation sites in evolutionarily distant eukaryotes. Genomics Proteomics Bioinformatics 11:96-104
Chandler, Kevin Brown; Pompach, Petr; Goldman, Radoslav et al. (2013) Exploring site-specific N-glycosylation microheterogeneity of haptoglobin using glycopeptide CID tandem mass spectra and glycan database search. J Proteome Res 12:3652-66
Chandler, Kevin; Goldman, Radoslav (2013) Glycoprotein disease markers and single protein-omics. Mol Cell Proteomics 12:836-45
Pompach, Petr; Brnakova, Zuzana; Sanda, Miloslav et al. (2013) Site-specific glycoforms of haptoglobin in liver cirrhosis and hepatocellular carcinoma. Mol Cell Proteomics 12:1281-93
Isailovic, Dragan; Plasencia, Manolo D; Gaye, Maissa M et al. (2012) Delineating diseases by IMS-MS profiling of serum N-linked glycans. J Proteome Res 11:576-85
Bekesova, S; Kosti, O; Chandler, K B et al. (2012) N-glycans in liver-secreted and immunoglogulin-derived protein fractions. J Proteomics 75:2216-24

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