Date of Award

2020

Embargo Period

8-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell and Molecular Pharmacology and Experimental Therapeutics

College

College of Graduate Studies

First Advisor

Anand Mehta

Second Advisor

Richard Drake

Third Advisor

Peggi Angel

Fourth Advisor

Stephen Duncan

Fifth Advisor

David Long

Abstract

The vast majority of biomarkers used in the detection of cancer are glycoproteins, and numerous studies have indicated that the N-glycosylation of serum glycoproteins changes with the development of hepatocellular carcinoma (HCC). However, current biomarkers for HCC are lacking in sensitivity and specificity, and there is a need for higher throughput techniques to discover more powerful biomarkers. The majority of methods that do analyze N-glycans and their protein carriers generally require large amounts of sample preparation and/or look at only one protein at a time, which is a barrier for translating discoveries to the clinic. In response to this need for multiplexed biomarker analysis of protein-specific N-glycan changes, we developed a novel platform for the simultaneous analysis of potentially 100s of N-linked glycoproteins from biofluids with the goal of discovering new clinically-relevant cancer biomarkers. This new mass spectrometry imaging platform for multiplexed N-glycoprotein biomarker was applied to multiple cohorts of cirrhotic and HCC patient serum samples. An antibody panel encompassing antibodies for seven glycoproteins was used in the analysis of two cohorts consisting of 100 patients. These data were used to create biomarker algorithms incorporating protein-specific glycan signatures and clinical information. These models produced AUROCs of 0.9289 and 0.9278 for differentiating HCC from cirrhosis, which were significant improvements on the currently used biomarker AFP. We also expect that this platform can be expanded for biomarker discovery of other types of cancers and diseases from numerous types of biofluids.

Rights

All rights reserved. Copyright is held by the author.

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