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Dissertation
Analysis of the complexity of HBV-host junction sequences in patients with HBV-related hepatocellular carcinoma
Doctor of Philosophy (Ph.D.), Drexel University
Jan 2016
DOI:
https://doi.org/10.17918/etd-7162
Abstract
Hepatocellular carcinoma (HCC) suffers from poor prognosis due to late detection and lack of effective therapies. Chronic hepatitis B virus (HBV) infection is the major etiology of HCC. Over 85% of HBV related HCCs contain integrated HBV DNA with various HBV-host junction sequences (HBV-JSs) generated by integration. We hypothesize that it is feasible to detect uncontrolled clonally-expanded (major) HBV-JSs or a reduced complexity of HBV-JSs in urine to investigate the dynamic of HBV-JSs during hepatocarcinogenesis and the detection of major HBV-JSs can be one approach to probe for HCC-driver mutations for HCC characterization. To test this hypothesis, three aims were proposed. Aim 1 is to develop an HBV-enriched next generation sequencing (NGS) assay for detecting cell-free HBV-JSs and was successfully completed. Aim 2 is to perform a meta-analysis of HBV-JSs for characterization of HCC. Using the developed assay from Aim 1, we identified 34 integration sites from 22 HCC tumor DNA. Together with previously reported sites, 1,554 sites were complied to investigate the associations of HCC-derived sites with clinical features to probe for potential HCC-drivers for HCC characterization. We found the most frequently identified site, TERT, was associated with old age (n=19) and cirrhosis (n=47), and integration in CCNE1 seems to be associated with non-cirrhotic HCCs, thus accomplishing Aim 2. Aim 3 is to analyze the complexity of HBV-JSs in the urine of HBV-HCC patients. Urine DNA from HBV-infected hepatitis (n=21), cirrhosis (n=19), and HCC (n=20) patients were analyzed and found that significantly more HCC urine samples contained detectable HBV-JSs compared to non-HCC urine samples (p < 0.0001), as well as an increase HBV-JS load (p < 0.0001). Although, the complexity of HBV-JSs in HCC urine samples was not significantly reduced as compared to non-HCC urine due to the small sample size. In conclusion, this study supports the hypothesis that HCC-derived clonally-expanded HBV-JSs and the complexity of HBV-JSs can be detected and analyzed in urine, Our study also supports that identification of major HBV-JSs can be one approach to detect HCC-drivers of hepatocarcinogenesis, and further our understanding of the role HBV integration plays in carcinogenesis.
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Details
- Title
- Analysis of the complexity of HBV-host junction sequences in patients with HBV-related hepatocellular carcinoma
- Creators
- Selena Lin - DU
- Contributors
- Ying-Hsiu Su (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 7162; 991014632193004721