Cell-Free Virus-Host Chimera DNA From Hepatitis B Virus Integration Sites as a Circulating Biomarker of Hepatocellular Cancer
Journal
Hepatology
Journal Volume
72
Journal Issue
6
Pages
2063-2076
Date Issued
2020
Author(s)
Li C.-L.
Lin Y.-Y.
Tzeng S.-T.
Chen Y.-J.
Pai H.-Y.
Wang Y.-C.
Lee Y.-H.
Chen D.-S.
Abstract
Background and Aims: Early recurrence of hepatocellular carcinoma (HCC) after surgical resection compromises patient survival. Timely detection of HCC recurrence and its clonality is required to implement salvage therapies appropriately. This study examined the feasibility of virus-host chimera DNA (vh-DNA), generated from junctions of hepatitis B virus (HBV) integration in the HCC chromosome, as a circulating biomarker for this clinical setting. Approach and Results: HBV integration in 50 patients with HBV-related HCC was determined by the Hybridization capture-based next-generation sequencing (NGS) platform. For individual HCC, the vh-DNA was quantified by specific droplet digital PCR (ddPCR) assay in plasma samples collected before and 2 months after surgery. HBV integrations were identified in 44 out of 50 patients with HBV-related HCC. Tumor-specific ddPCR was developed to measure the corresponding vh-DNA copy number in baseline plasma from each patient immediately before surgery. vh-DNA was detected in 43 patients (97.7%), and the levels correlated with the tumor sizes (detection limit at 1.5 cm). Among the plasma collected at 2 months after surgery, 10 cases (23.3%) still contained the same signature vh-DNA detected at baseline, indicating the presence of residual tumor cells. Nine of them (90%) experienced HCC recurrence within 1 year, supporting vh-DNA as an independent risk factor in predicting early recurrence. Analysis of circulating vh-DNA at recurrence further helped identify the clonal origin. A total of 81.8% of recurrences came from original HCC clones sharing the same plasma vh-DNA, whereas 18.2% were from de novo HCC. Conclusions: vh-DNA was shown to be a circulating biomarker for detecting the tumor load in majority of patients with HBV-related HCC and aided in monitoring residual tumor and recurrence clonality after tumor resection. ? 2020 by the American Association for the Study of Liver Diseases.
SDGs
Other Subjects
DNA; tumor marker; unclassified drug; virus host chimera DNA; cell free nucleic acid; tumor marker; virus DNA; adult; Article; blood sampling; cancer recurrence; cancer surgery; cell free system; clinical article; droplet digital polymerase chain reaction; early cancer diagnosis; feasibility study; female; gene dosage; Hepatitis B virus; high throughput sequencing; human; liver cell carcinoma; male; middle aged; patient identification; priority journal; risk factor; tumor volume; virus DNA cell DNA interaction; aged; blood; diagnosis; follow up; genetics; Hepatitis B virus; liver cell carcinoma; liver resection; liver tumor; minimal residual disease; polymerase chain reaction; prospective study; tumor recurrence; virology; virus DNA cell DNA interaction; Aged; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell-Free Nucleic Acids; DNA, Viral; Feasibility Studies; Female; Follow-Up Studies; Gene Dosage; Hepatectomy; Hepatitis B virus; Host Microbial Interactions; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm, Residual; Polymerase Chain Reaction; Prospective Studies; Virus Integration
Publisher
John Wiley and Sons Inc
Type
journal article