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Hepatol Int. 2020 Feb 25. doi: 10.1007/s12072-020-10016-2. [Epub ahead of print]
Noninvasive chimeric DNA profiling identifies tumor-originated HBV integrants contributing to viral antigen expression in liver cancer.
Chen W1,2, Zhang K3,4, Dong P5, Fanning G4, Tao C1, Zhang H1, Guo S6, Wang Z5, Hong Y1,7, Yang X8, Lai S1, Ding H5, Zhao H8, Zeng C9, Protzer U10,11, Zhang D12,13.
Author information
1
Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, NO.1 Beichen West Road, Chaoyang, Beijing, 100101, China.
2
Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China.
3
Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Trogerstrasse 30, 81675, Munich, Germany.
4
Janssen China Research and Development Center, Shanghai, 201210, China.
5
Department of Hepatology, Beijing You'an Hospital Affiliated with Capital Medical University, Beijing, 100069, China.
6
Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI, USA.
7
Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
8
Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
9
Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, NO.1 Beichen West Road, Chaoyang, Beijing, 100101, China. [email protected].
10
Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Trogerstrasse 30, 81675, Munich, Germany. [email protected].
11
German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany. [email protected].
12
Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, NO.1 Beichen West Road, Chaoyang, Beijing, 100101, China. [email protected].
13
Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China. [email protected].
Abstract
BACKGROUND:
Host genome integration of HBV sequence is considered to be significant in HBV antigen expression and the development of hepatocellular carcinoma (HCC).
METHOD:
We developed a probe-based capture strategy to enrich integrated HBV DNA for deep-sequencing analysis of integration sites in paired patient samples derived from tumor, liver tissue adjacent to tumor, saliva and plasma, as a platform for exploring the correlation, significance and utility of detecting integrations in these sample types.
RESULTS:
Most significantly, alpha fetoprotein levels significantly correlated to the amounts of integrations detected in tumor. Viral-host chimeric DNA fragments were successfully detected at high sequencing coverage in plasma rather than saliva samples from HCC patients, and each fragment of this type was only seen once in plasma from chronic hepatitis B patients. Almost all plasma chimeric fragments were derived from integrations in tumor rather than in adjacent liver tissues. Over 50% of them may produce viral-host chimeric transcripts according to deep RNA sequencing in paired tissue samples. Particularly, in patients with low HBV DNA level (< 250 UI/ml), the seemingly normal HBsAg titers may be explained by larger amounts of integrations detected. Meanwhile, we developed a strategy to predict integrants by pairing breakpoints for each integration event. Among four resolved viral patterns, the majority of Pattern I events (81.2%) retained the complete opening reading frame for HBV surface proteins.
CONCLUSION:
We achieve the efficient enrichment of plasma cell-free chimeric DNA from integration site, and demonstrate that chimeric DNA profiling in plasma is a promising noninvasive approach to monitor HBV integration in liver cancer development and to determine the ability of integrated sequences to express viral proteins that can be targeted, e.g. by immunotherapies.
KEYWORDS:
Alpha fetoprotein; Circulating cell-free DNA; DNA capture; HBsAg; Hepatocellular carcinoma; Immune therapy; Liquid biopsy; Neoantigen; Repeat elements; Saliva; Viral integration
PMID:
32100258
DOI:
10.1007/s12072-020-10016-2
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发表于 2020-2-28 13:08
