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Whole exome HBV DNA integration is independent of the intrahepatic HBV reservoir in HBeAg-negative chronic hepatitis B
Valentina Svicher # 1 , Romina Salpini # 1 , Lorenzo Piermatteo 1 , Luca Carioti 1 , Arianna Battisti 1 2 , Luna Colagrossi 1 3 , Rossana Scutari 1 , Matteo Surdo 4 , Valeria Cacciafesta 4 , Andrea Nuccitelli 4 , Navjyot Hansi 2 , Francesca Ceccherini Silberstein 1 , Carlo Federico Perno 5 , Upkar S Gill 2 , Patrick T F Kennedy 6
Affiliations
Affiliations
1
Department of Experimental Medicine, University of Rome Tor Vergata, Roma, Lazio, Italy.
2
Barts Liver Cente, Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK.
3
Department of Microbiology and Virology, University of Milan, Milano, Lombardia, Italy.
4
Molecular Genetics Laboratory, Eurofins GENOMA, Roma, Lazio, Italy.
5
Department of Oncology and Haematooncology, University of Milan, Milano, Lombardia, Italy.
6
Barts Liver Cente, Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK [email protected].
#
Contributed equally.
PMID: 33402415 DOI: 10.1136/gutjnl-2020-323300
Abstract
Objective: The involvement of HBV DNA integration in promoting hepatocarcinogenesis and the extent to which the intrahepatic HBV reservoir modulates liver disease progression remains poorly understood. We examined the intrahepatic HBV reservoir, the occurrence of HBV DNA integration and its impact on the hepatocyte transcriptome in hepatitis B 'e' antigen (HBeAg)-negative chronic hepatitis B (CHB).
Design: Liver tissue from 84 HBeAg-negative patients with CHB with low (n=12), moderate (n=25) and high (n=47) serum HBV DNA was analysed. Covalently closed circular DNA (cccDNA), pregenomic RNA (pgRNA) were evaluated by quantitative PCR, whole exome and transcriptome sequencing was performed by Illumina, and the burden of HBV DNA integrations was evaluated by digital droplet PCR.
Results: Patients with low and moderate serum HBV DNA displayed comparable intrahepatic cccDNA and pgRNA, significantly lower than in patients with high HBV DNA, while hepatitis B core-related antigen correlated strongly with the intrahepatic HBV reservoir, reflecting cccDNA quantity. Whole exome integration was detected in a significant number of patients (55.6%, 14.3% and 25% in high, moderate and low viraemic patients, respectively), at a frequency ranging from 0.5 to 157 integrations/1000 hepatocytes. Hepatitis B surface antigen >5000 IU/mL predicted integration within the exome and these integrations localised in genes involved in hepatocarcinogenesis, regulation of lipid/drug metabolism and antiviral/inflammatory responses. Transcript levels of specific genes, including the proto-oncogene hRAS, were higher in patients with HBV DNA integration, supporting an underlying oncogenic risk in patients with low-level to moderate-level viraemia.
Conclusions: HBV DNA integration occurs across all HBeAg-negative patients with CHB, including those with a limited HBV reservoir; localising in genes involved in carcinogenesis and altering the hepatocyte transcriptome.
Keywords: chronic viral hepatitis; hepatitis B; hepatocellular carcinoma; liver biopsy.
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. |
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发表于 2021-1-6 20:49