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
Sanda, Miloslav; Zhang, Lihua; Edwards, Nathan J et al. (2017) Site-specific analysis of changes in the glycosylation of proteins in liver cirrhosis using data-independent workflow with soft fragmentation. Anal Bioanal Chem 409:619-627
Wang, Mengjun; Sanda, Miloslav; Comunale, Mary Ann et al. (2017) Changes in the Glycosylation of Kininogen and the Development of a Kininogen-Based Algorithm for the Early Detection of HCC. Cancer Epidemiol Biomarkers Prev 26:795-803
Darebna, Petra; Novak, Petr; Kucera, Radek et al. (2017) Changes in the expression of N- and O-glycopeptides in patients with colorectal cancer and hepatocellular carcinoma quantified by full-MS scan FT-ICR and multiple reaction monitoring. J Proteomics 153:44-52
Kozlik, Petr; Goldman, Radoslav; Sanda, Miloslav (2017) Study of structure-dependent chromatographic behavior of glycopeptides using reversed phase nanoLC. Electrophoresis 38:2193-2199
Sanda, Miloslav; Goldman, Radoslav (2016) Data Independent Analysis of IgG Glycoforms in Samples of Unfractionated Human Plasma. Anal Chem 88:10118-10125
Sanda, Miloslav; Benicky, Julius; Wu, Jing et al. (2016) Increased sialylation of site specific O-glycoforms of hemopexin in liver disease. Clin Proteomics 13:24
Goldman, Radoslav; Sanda, Miloslav (2015) Targeted methods for quantitative analysis of protein glycosylation. Proteomics Clin Appl 9:17-32
Yuan, Wei; Sanda, Miloslav; Wu, Jing et al. (2015) Quantitative analysis of immunoglobulin subclasses and subclass specific glycosylation by LC-MS-MRM in liver disease. J Proteomics 116:24-33
Nayak, Aparajita; Pattabiraman, Nagarajan; Fadra, Numrah et al. (2015) Structure-function analysis of hepatitis C virus envelope glycoproteins E1 and E2. J Biomol Struct Dyn 33:1682-94
Fu, Ying; Mi, Lixin; Sanda, Miloslav et al. (2014) A Click Chemistry Approach to Identify Protein Targets of Cancer Chemopreventive Phenethyl Isothiocyanate. RSC Adv 4:3920-3923

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