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.