Date of Award

2022-12-01

Degree Name

Doctor of Philosophy

Department

Biological Sciences

Advisor(s)

Jianying J. Zhang

Second Advisor

Renato R. Aguilera

Abstract

Liver cancer is one of the most prevalent malignancies, in which hepatocellular carcinoma (HCC) takes up more than 80% of liver cancer cases. Early diagnosis and treatment are practical approaches to impede HCC progression. Identifying and classifying autoantibodies against tumor-associated antigens (TAAs) have long been interested in cancer diagnosis, especially for HCC. Circulating anti-TAA autoantibodies amplify the antigen expression and are more stable in blood, guaranteeing anti-TAA autoantibodies as valid diagnostic biomarkers in clinical application. Nonetheless, very few studies had focused on the Hispanic HCC group, which might retain distinct etiological risk factors compared to other ethnicities. The high incidence rate of metabolic disorders correlated liver diseases and increased consumption of alcohol in the Hispanic population have favored the development of HCC. In this study, we identified 9 potential TAA targets using the immunoproteomic approach serological proteome analysis (SERPA) and 10 potential TAA targets by the differentially expressed driver genes from Hispanic patients. 9 TAA targets were detected by SERPA, including HSPA5, HSP60, TPI, P4HB, ACTG1, HSP70, ENO1, TPM3, CALR. Using the IntoGen driver gene database together with Oncomine and TCGA cancer genome databases, 10 driver genes were investigated as potential targets with significantly different mRNA expression between HCC and normal liver tissues, which are CDKN2A, SETDB1, DHX9, SMARCA4, GNAS, NF2, DNMT3A, NRAS, GMPS, and MAPK1. Among all the identified targets, anti- DNMT3A, p16, Hsp60, and HSPA5 autoantibodies were defined as diagnostic biomarkers with a significantly higher frequency in the Hispanic HCC group compared to the NHS group. The area under the receiver operating characteristic curve (AUC) value of the single TAA varies from 0.7505 to 0.8885, showing the great diagnostic value of these biomarkers. After combining all the TAAs, the sensitivity of the anti-TAA autoantibody panel increased to 75%, while the highest sensitivity of the single TAA was 45.8%. Next, to explore the exclusiveness of the 4 autoantibodies for Hispanic HCC diagnosis, we established a multi-ethnicity study with a separate Asian sera cohort. It is shown that anti-p16 and anti-HSPA5 autoantibody titers or frequencies are significantly higher than the normal sera group, suggesting DNMT3A and HSP60 are exclusive diagnostic biomarkers for Hispanic HCC. The present research shows the 4 protein targets TAAs including DNMT3A, p16, HSPA5, and HSP60 as diagnostic biomarkers that elicit remarkable autoimmune responses in sera from Hispanic HCC patients. Also, DNMT3A and HSP60 could be potential biomarkers exclusive to Hispanic HCC diagnosis, while HSPA5 and HSP60 might be effective biomarkers in both Hispanic and Asian HCC populations.

Language

en

Provenance

Received from ProQuest

File Size

85 p.

File Format

application/pdf

Rights Holder

Yangcheng Ma

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