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Detection of Hepatitis B Virus–Host Junction Sequences in Urine of Infected Patients
Selena Y. Lin, Yih-Ping Su, Evan R. Trauger, Benjamin P. Song, Emilie G.C. Thompson, Malcolm C. Hoffman, Ting-Tsung Chang, Yih-Jyh Lin, Yu-Lan Kao, Yixiao Cui, Hie-Won Hann, Grace Park … See all authors
First published: 25 August 2021
https://doi.org/10.1002/hep4.1783
Supported by the National Cancer Institute (R43-CA165312, R43-CA192507, and R44-CA165312).
Potential conflict of interest: Dr. Selena Lin owns stock in, is employed by, and received grants from JBS Science. Dr. Wei Song owns stock in and is the CEO of JBS Science. Dr. Ying-Hsiu Su owns stock and equity in and advises JBS Science. Her spouse is CEO of JBS Science.
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Abstract
Integrated hepatitis B virus (HBV) DNA, found in more than 85% of HBV-associated hepatocellular carcinomas (HBV-HCCs), can play a significant role in HBV-related liver disease progression. HBV-host junction sequences (HBV-JSs), created through integration events, have been used to determine HBV-HCC clonality. Here, we investigate the feasibility of analyzing HBV integration in a noninvasive urine liquid biopsy. Using an HBV-targeted next-generation sequencing (NGS) assay, we first identified HBV-JSs in eight HBV-HCC tissues and designed short-amplicon junction-specific polymerase chain reaction assays to detect HBV-JSs in matched urine. We detected and validated tissue-derived junctions in five of eight matched urine samples. Next, we screened 32 urine samples collected from 25 patients infected with HBV (5 with hepatitis, 10 with cirrhosis, 4 with HCC, and 6 post-HCC). Encouragingly, all 32 urine samples contained HBV-JSs detectable by HBV-targeted NGS. Of the 712 total HBV-JSs detected in urine, 351 were in gene-coding regions, 11 of which, including TERT (telomerase reverse transcriptase), had previously been reported as recurrent integration sites in HCC tissue and were found only in the urine patients with cirrhosis or HCC. The integration breakpoints of HBV DNA detected in urine were found predominantly (~70%) at a previously identified integration hotspot, HBV DR1-2 (down-regulator of transcription 1-2). Conclusion: HBV viral–host junction DNA can be detected in urine of patients infected with HBV. This study demonstrates the potential for a noninvasive urine liquid biopsy of integrated HBV DNA to monitor patients infected with HBV for HBV-associated liver diseases and the efficacy of antiviral therapy.
Abbreviations
bp
base pair
cfDNA
cell-free DNA
DR1-2
down-regulator of transcription 1-2
dsDNA
double-stranded DNA
FOCAD
focadhesin
HBV
hepatitis B virus
HBV-HCC
HBV-infected hepatocellular carcinoma
HBV-JS
HBV–host junction sequence
HCC
hepatocellular carcinoma
NGS
next-generation sequencing
PCR
polymerase chain reaction
PPP2R2C
protein phosphatase 2 regulatory subunit Bgamma
RE
restriction endonuclease
SR
supporting read
TERT
telomerase reverse transcriptase
UMT
unique molecular tag
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发表于 2022-7-16 13:10