title: Changes in the Glycosylation of Kininogen and the Development of a Kininogen-Based Algorithm for the Early Detection of HCC.
abstract: Background:Hepatocellular carcinoma (HCC) has the greatest increase in mortality among all solids tumors in the United States related to low rates of early tumor detection. Development of noninvasive biomarkers for the early detection of HCC may reduce HCC-related mortality.Methods:We have developed an algorithm that combines routinely observed clinical values into a single equation that in a study of >3,000 patients from 5 independent sites improved detection of HCC as compared with the currently used biomarker, alpha-fetoprotein (AFP), by 4% to 20%. However, this algorithm had limited benefit in those with AFP <20 ng/mL. To that end, we have developed a secondary algorithm that incorporates a marker, fucosylated kininogen, to improve the detection of HCC, especially in those with AFP <20 ng/mL and early-stage disease.Results:The ability to detect early-stage AFP-negative (AFP <20 ng/mL) HCC increased from 0% (AFP alone) to 89% (for the new algorithm). Glycan analysis revealed that kininogen has several glycan modifications that have been associated with HCC, but often not with specific proteins, including increased levels of core and outer-arm fucosylation and increased branching.Conclusions:An algorithm combining fucosylated kininogen, AFP, and clinical characteristics is highly accurate for early HCC detection.Impact:Our biomarker algorithm could significantly improve early HCC detection and curative treatment eligibility in patients with cirrhosis.Cancer Epidemiol Biomarkers Prev; 26(5); 795-803. ©2017 AACR.
authors.affiliation: Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Mengjun
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Miloslav
authors.initials: M
authors.lastname: Sanda
authors.affiliation: Department of Microbiology and Immunology, Drexel University, Philadelphia, Pennsylvania.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Comunale
authors.affiliation: Department of Microbiology and Immunology, Drexel University, Philadelphia, Pennsylvania.
authors.forename: Harmin
authors.initials: H
authors.lastname: Herrera
authors.affiliation: Glycotest, Inc, New York, New York.
authors.forename: Charles
authors.initials: C
authors.lastname: Swindell
authors.affiliation: Division of Gastroenterology and Hepatology, University of California, San Diego, California.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kono
authors.affiliation: Division of Digestive and Liver Diseases, University of Texas Southwestern, Dallas, Texas.
authors.forename: Amit G
authors.initials: AG
authors.lastname: Singal
authors.affiliation: Division of Digestive and Liver Diseases, University of Texas Southwestern, Dallas, Texas.
authors.forename: Jorge
authors.initials: J
authors.lastname: Marrero
authors.affiliation: The Baruch S. Blumberg Institute, Doylestown, Pennsylvania.
authors.forename: Timothy
authors.initials: T
authors.lastname: Block
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Radoslav
authors.initials: R
authors.lastname: Goldman
authors.affiliation: Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Medical University of South Carolina, Charleston, South Carolina. mehtaa@musc.edu.
authors.forename: Anand
authors.initials: A
authors.lastname: Mehta
mesh_terms: D000368:Aged; D000465:Algorithms; D014408:Biomarkers, Tumor / Q000032:analysis*; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000378:metabolism; D055088:Early Detection of Cancer / Q000379:methods*; D005260:Female; D006801:Humans; D007704:Kininogens / Q000032:analysis*; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012680:Sensitivity and Specificity; D014481:United States; D000509:alpha-Fetoproteins / Q000032:analysis
chemical_list: D014408:Biomarkers, Tumor; C000591034:KNG1 protein, human; D007704:Kininogens; D000509:alpha-Fetoproteins