HBV DNA Integration and Somatic Mutations in HCC Patients with HBV-HCV Dual Infection Reveals Profiles Intermediate Between HBV- and HCV-related HCC

Overview

Journal J Biomed Sci

Publisher Biomed Central

Specialty Biology

Date 2025 Jan 1

PMID 39743539

Authors

Chiao-Ling Li

Chia-Lang Hsu

You-Yu Lin

Ming-Chih Ho

Rey-Heng Hu

Sheng-Tai Tzeng

Ya-Chun Wang

Yasuhito Tanaka

Pei-Jer Chen

Shiou-Hwei Yeh

Affiliations

Soon will be listed here.

Abstract

Background: In regions with a high prevalence of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, coinfected patients face a heightened risk of developing hepatocellular carcinoma (HCC), termed HBV/HCV-related HCC (HBCV-HCC). We aimed to investigate the contribution of preexisting chronic hepatitis B (CHB) and subsequent chronic hepatitis C (CHC) to the development of HBCV-HCC.

Methods: We examined HBV's involvement in 93 HBCV-HCC cases by analyzing HBV DNA integration as an indicator of HCC originating from HBV-infected hepatocytes, compared with 164 HBV-HCCs and 56 HCV-HCCs as controls.

Results: Next generation sequencing revealed that 55% of HBCV-HCCs exhibited clonal HBV integration, which falls between the rates observed in HBV-HCCs (88%) and HCV-HCCs (7%), with similar integration patterns to HBV-HCCs. Common HCC somatic mutation analysis indicated HCV superinfection in HBCV-HCCs correlated with increased mutation rates in the telomerase reverse transcriptase (TERT) promoter and beta-catenin genes. Transcriptome analysis showed a prevalence of replicating HCV over HBV in HBCV-HCCs, with preexisting HBV exerting a proliferative role. The comparison of clinical characteristics revealed similarities between HBCV-HCC and HCV-HCC patients, including later onset for HBCV-HCC, possibly due to HCV superinfection slowing carcinogenesis. Notably, HBCV-HCCs with the same driver mutation, HBV integration at the TERT promoter, tended to develop later and showed a better prognosis post-tumor resection than HBV-HCCs.

Conclusions: Our findings shed light on the interplay between preexisting CHB and subsequent CHC in elevating the risk of HBCV-HCC. These insights are crucial for understanding viral etiology-specific carcinogenesis and guiding surveillance policies for HBCV-HCC post-antiviral therapy.

References

Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z . clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021; 2(3):100141. PMC: 8454663. DOI: 10.1016/j.xinn.2021.100141. View

Waziry R, Hajarizadeh B, Grebely J, Amin J, Law M, Danta M . Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: A systematic review, meta-analyses, and meta-regression. J Hepatol. 2017; 67(6):1204-1212. DOI: 10.1016/j.jhep.2017.07.025. View

Kim C, Hwang S, Keam B, Yu Y, Kim J, Kim D . Gene Signature for Sorafenib Susceptibility in Hepatocellular Carcinoma: Different Approach with a Predictive Biomarker. Liver Cancer. 2020; 9(2):182-192. PMC: 7206603. DOI: 10.1159/000504548. View

Danaher P, Warren S, Dennis L, DAmico L, White A, Disis M . Gene expression markers of Tumor Infiltrating Leukocytes. J Immunother Cancer. 2017; 5:18. PMC: 5319024. DOI: 10.1186/s40425-017-0215-8. View

Huang Y, Jen C, Yang H, Lee M, Su J, Lu S . Lifetime risk and sex difference of hepatocellular carcinoma among patients with chronic hepatitis B and C. J Clin Oncol. 2011; 29(27):3643-50. PMC: 4874144. DOI: 10.1200/JCO.2011.36.2335. View

Yeh M, Hung C, Tseng K, Lai H, Chen C, Kuo H . Long-term outcome of liver complications in patients with chronic HBV/HCV co-infection after antiviral therapy: a real-world nationwide study on Taiwanese Chronic Hepatitis C Cohort (T-COACH). Hepatol Int. 2021; 15(5):1109-1121. DOI: 10.1007/s12072-021-10220-8. View

Calvaruso V, Ferraro D, Licata A, Bavetta M, Petta S, Bronte F . HBV reactivation in patients with HCV/HBV cirrhosis on treatment with direct-acting antivirals. J Viral Hepat. 2017; 25(1):72-79. DOI: 10.1111/jvh.12754. View

Cong Y, Wen J, Bacchetti S . The human telomerase catalytic subunit hTERT: organization of the gene and characterization of the promoter. Hum Mol Genet. 1999; 8(1):137-42. DOI: 10.1093/hmg/8.1.137. View

Scotto J, Hadchouel M, Hery C, Alvarez F, Yvart J, Tiollais P . Hepatitis B virus DNA in children's liver diseases: detection by blot hybridisation in liver and serum. Gut. 1983; 24(7):618-24. PMC: 1420040. DOI: 10.1136/gut.24.7.618. View

10.

Chen C, Yang P, Huang G, Lee H, Sung J, Sheu J . Estimation of seroprevalence of hepatitis B virus and hepatitis C virus in Taiwan from a large-scale survey of free hepatitis screening participants. J Formos Med Assoc. 2007; 106(2):148-55. DOI: 10.1016/S0929-6646(09)60231-X. View

11.

Fitzgerald K, Diaz M . MLL2: A new mammalian member of the trx/MLL family of genes. Genomics. 1999; 59(2):187-92. DOI: 10.1006/geno.1999.5860. View

12.

Liaw Y, Chen Y, Sheen I, Chien R, Yeh C, Chu C . Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection. Gastroenterology. 2004; 126(4):1024-9. DOI: 10.1053/j.gastro.2004.01.011. View

13.

Hino O, Kitagawa T, Koike K, Kobayashi M, Hara M, Mori W . Detection of hepatitis B virus DNA in hepatocellular carcinomas in Japan. Hepatology. 1984; 4(1):90-5. DOI: 10.1002/hep.1840040116. View

14.

Yeh M, Huang C, Huang C, Holmes J, Hsieh M, Tsai Y . Hepatitis B-related outcomes following direct-acting antiviral therapy in Taiwanese patients with chronic HBV/HCV co-infection. J Hepatol. 2020; 73(1):62-71. DOI: 10.1016/j.jhep.2020.01.027. View

15.

Chen D, SUNG J . Hepatitis B virus infection and chronic liver disease in Taiwan. Acta Hepatogastroenterol (Stuttg). 1978; 25(6):423-30. View

16.

Wang H, Chien M, Huang H, Chang H, Wu C, Chen P . Distinct hepatitis B virus dynamics in the immunotolerant and early immunoclearance phases. J Virol. 2010; 84(7):3454-63. PMC: 2838120. DOI: 10.1128/JVI.02164-09. View

17.

Lin Y, Hsieh C, Chen J, Lu X, Kao J, Chen P . De novo assembly of highly polymorphic metagenomic data using in situ generated reference sequences and a novel BLAST-based assembly pipeline. BMC Bioinformatics. 2017; 18(1):223. PMC: 5406902. DOI: 10.1186/s12859-017-1630-z. View

18.

Galibert F, Mandart E, Fitoussi F, Tiollais P, Charnay P . Nucleotide sequence of the hepatitis B virus genome (subtype ayw) cloned in E. coli. Nature. 1979; 281(5733):646-50. DOI: 10.1038/281646a0. View

19.

Liu C, Chuang W, Lee C, Yu M, Lu S, Wu S . Peginterferon alfa-2a plus ribavirin for the treatment of dual chronic infection with hepatitis B and C viruses. Gastroenterology. 2008; 136(2):496-504.e3. DOI: 10.1053/j.gastro.2008.10.049. View

20.

Li C, Li C, Lin Y, Ho M, Chen D, Chen P . Androgen Receptor Enhances Hepatic Telomerase Reverse Transcriptase Gene Transcription After Hepatitis B Virus Integration or Point Mutation in Promoter Region. Hepatology. 2018; 69(2):498-512. DOI: 10.1002/hep.30201. View