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Whole exome HBV DNA integration is independent of the intrahepatic HBV reservoir in HBeAg-negative chronic hepatitis B
Valentina Svicher1, Romina Salpini1, Lorenzo Piermatteo1, Luca Carioti1, Arianna Battisti1,2, Luna Colagrossi1,3, Rossana Scutari1, Matteo Surdo4, Valeria Cacciafesta4, Andrea Nuccitelli4, Navjyot Hansi2, Francesca Ceccherini Silberstein1, Carlo Federico Perno5, Upkar S Gill2, http://orcid.org/0000-0001-9201-0094Patrick T F Kennedy2
Correspondence to Dr Patrick T F Kennedy, Barts Liver Centre, Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, Newark Street, London, E1 2AT, UK; [email protected]
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.
Data availability statement
Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All clinical data have been collected in an anonymous database available at The Blizard Institute, Barts and The London SMD, QMUL. Responsible: PTFK
http://creativecommons.org/licenses/by-nc/4.0/
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
http://dx.doi.org/10.1136/gutjnl-2020-323300
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发表于 2021-11-9 08:39
