Jin Seoub Kim, Hye Seon Kim, Kwon Yong Tak, Ji Won Han, Heechul Nam, Pil Soo Sung, Sung Won Lee, Jung Hyun Kwon, Si Hyun Bae, Jong Young Choi, Seung Kew Yoon, Jeong Won Jang
Clin Mol Hepatol 2025;31(2):509-524. Published online January 2, 2025
Background/Aims Hepatocellular carcinoma (HCC) exhibits significant sex disparities in incidence, yet its molecular mechanisms remain unclear. We explored the role of telomerase reverse transcriptase (TERT) genetic alterations and hepatitis B virus (HBV) integration, both known major contributors to HCC, in sex-specific risk for HBV-related HCC.
Methods We examined 310 HBV-related HCC tissues to investigate sex-specific TERT promoter (TERT-pro) mutations and HBV integration profiles, stratified by sex and age, and validated with single-cell RNA sequencing (scRNA-seq) data.
Results Tumors predominantly exhibited TERT-pro mutations (26.0% vs. 0%) and HBV-TERT integration (37.0% vs. 3.0%) compared to non-tumorous tissues. While TERT-pro mutations increased with age in both sexes, younger males (≤60 years) showed marked predominance compared to younger females. Males had significantly more HBV integrations at younger ages, while females initially had fewer integrations that gradually increased with age. Younger males' integrations showed significantly greater enrichment in the TERT locus compared to younger females, alongside a preference for promoters, PreS/S regions, and CpG islands. Overall, TERT genetic alterations were significantly sex-differential in younger individuals (75.3% in males vs. 23.1% in females) but not in older individuals (76.9% vs. 83.3%, respectively). These alterations were associated with increased TERT expression. The skewed TERT abnormalities in younger males were further corroborated by independent scRNA-seq data.
Conclusions Our findings highlight the critical role of TERT alterations and HBV integration patterns in the male predominance of HCC incidence among younger HBV carriers, offering insights for future exploration to optimize sex-specific patient care and HCC surveillance strategies.
Citations
Citations to this article as recorded by
Molecular biomarkers and nano-immunopharmacology in inflammatory carcinoma: Bridging mechanisms and therapeutic translation Kamlesh Sahu, Trilochan Satapathy, Poonam Sahu, Om Chandrakar Advances in Biomarker Sciences and Technology.2026; 8: 151. CrossRef
Mutational patterns and ancestry-linked profiles in a large hepatocellular carcinoma and combined hepatocellular–cholangiocarcinoma cohort C. Gerdes, S. Rengarajan, K. Murugesan, J.S. Ross, S. Bartels, A. Vogel, A. Saborowski ESMO Open.2026; 11(2): 106048. CrossRef
Shelterin Component TPP1 Drives Tumor Progression and Predicts Poor Prognosis in Hepatocellular Carcinoma Jung Eun Jang, Hye Seon Kim, Jin Seoub Kim, Jae Mo Han, Hee Sun Cho, Kwon Yong Tak, Ji Won Han, Pil Soo Sung, Si Hyun Bae, Jeong Won Jang Biomedicines.2026; 14(2): 364. CrossRef
Primary Liver Cancer Trends Worldwide and in China: Analysis of GLOBOCAN 2022 Data and Disease Management Implications Jiayan Yan, Jiayi Wang, Jian Fan, Xinyi Cui, Yuxi Zhang, Xinrong Yang, Qiang Gao, Zhenbin Ding, Zhaoyou Tang, Jia Fan, Dan G. Duda, Ao Huang, Jian Zhou Portal Hypertension & Cirrhosis.2026; 5(1): 65. CrossRef
Digital polymerase chain reaction detection of telomerase reverse transcriptase promoter mutations in hepatitis B virus related hepatocellular carcinoma Shuai Shao, Yu Xiong, Mo-Wei Kong, Yang Yu, Chun-Xiang Zhang World Journal of Gastrointestinal Oncology.2026;[Epub] CrossRef
Clinicopathological significance of Gli1 expression in hepatocellular carcinoma: a meta-analysis Sisi Li, Mengfan Chen, Shanshan Zhang, Zhong Xu, Hongling Wang Scientific Reports.2026;[Epub] CrossRef
Letter to the editor on “Male preference for TERT alterations and HBV integration in young-age HBV-related HCC: implications for sex disparity” Qicong Mai, Jianming Zheng, Meishi Tang, Yubin Liu Clinical and Molecular Hepatology.2026; 32(2): e134. CrossRef
Functional cure for chronic hepatitis B on hepatocellular carcinoma prevention: Evidence and clinical implications Wen Kang, Yu-Shen Liu, Tian-Ping Wang, Shu-Ming Zhang, Yu Li, Ye Zhang iLIVER.2026; 5(2): 100235. CrossRef
Association of TERT promoter mutations with early recurrence in hepatocellular carcinoma: a subgroup analysis in a Vietnamese cohort Hanh Thi Tuyet Ngo, Duy Duc Nguyen, Hoang Anh Vu, Thao Thi Phuong Doan, Minh-Xuan Dang, Phat Thi Hong Ho, Khoa Anh Luong BMC Cancer.2026;[Epub] CrossRef
Sex Hormone Receptors, HBV Integrations and Their Prognostic Predictive Value Among Hepatocellular Carcinoma Patients Die He, Xi Zeng, Lei Yin, Yang Liu, Weiping Zhou, Xing Liu, Linghao Zhao International Journal of Cancer.2026;[Epub] CrossRef
Transcriptional regulation of tumor suppressor gene RASSF1A by HBx Yanhong Kang, Wei Li, Junfeng Wei, Lin Yang, Yi Kang Molecular and Cellular Probes.2025; 82: 102034. CrossRef
Optimized digital polymerase chain reaction enables detection of telomerase reverse transcriptase C228T mutation for prognostic assessment in hepatocellular carcinoma Zulihumaer Aizimuaji, Nan Hu, Hai-Yang Li, Xi-Jun Wang, Sheng Ma, Ya-Ru Wang, Rui-Qi Zheng, Zhuo Li, Huan Zhao, Wei-Qi Rong, Ting Xiao World Journal of Gastrointestinal Oncology.2025;[Epub] CrossRef
Background/Aims The role of hepatitis B virus (HBV) integration into the host genome in hepatocarcinogenesis following hepatitis B surface antigen (HBsAg) seroclearance remains unknown. Our study aimed to investigate and characterize HBV integration events in chronic hepatitis B (CHB) patients who developed hepatocellular carcinoma (HCC) after HBsAg seroclearance.
Methods Using probe-based HBV capturing followed by next-generation sequencing technology, HBV integration was examined in 10 samples (seven tumors and three non-tumor tissues) from seven chronic carriers who developed HCC after HBsAg loss. Genomic locations and patterns of HBV integration were investigated.
Results HBV integration was observed in six patients (85.7%) and eight (80.0%) of 10 tested samples. HBV integration breakpoints were detected in all of the non-tumor (3/3, 100%) and five of the seven (71.4%) tumor samples, with an average number of breakpoints of 4.00 and 2.43, respectively. Despite the lower total number of tumoral integration breakpoints, HBV integration sites in the tumors were more enriched within the genic area. In contrast, non-tumor tissues more often showed intergenic integration. Regarding functions of the affected genes, tumoral genes with HBV integration were mostly associated with carcinogenesis. At enrollment, patients who did not remain under regular HCC surveillance after HBsAg seroclearance had a large HCC, while those on regular surveillance had a small HCC.
Conclusions The biological functions of HBV integration are almost comparable between HBsAg-positive and HBsAgserocleared HCCs, with continuing pro-oncogenic effects of HBV integration. Thus, ongoing HCC surveillance and clinical management should continue even after HBsAg seroclearance in patients with CHB.
Citations
Citations to this article as recorded by
Landscape of Somatic and Age‐Related Pathogenic Structural Variations in Hepatocellular Carcinoma Revealed by Long‐Read Sequencing Zhewen Wei, Yinghao Cao, Hongchao Liu, Mei Liu, Bolun Zhang, Jianming Ying, Jianqiang Cai, Xinyu Bi, Jianjun Zhao, Jianguo Zhou, Zhiyu Li, Zhen Huang, Jianmei Liu, Xueyan Lv, Zhiwen Luo, Zhicheng Wei, Xiaoshi Zhang, Yi Yang, Yiqiao Deng, Yanjiang Yin, Jin MedComm.2026;[Epub] CrossRef
KASL clinical practice guidelines for management of chronic hepatitis B Endorsed by the East Asia Liver Alliance (EALA) Won-Mook Choi, Ji Won Han, Tae Hyung Kim, Miyoung Choi, Moon Haeng Hur, Hyo Young Lee, Han Ah Lee, Byeong Geun Song, Heechul Nam, Jeong-Ju Yoo, Chang Hun Lee, Gi-Ae Kim, Hye Won Lee, Gwang Hyeon Choi, Young Eun Chon, Yun Bin Lee, Dong Hyun Sinn, Bo Hyun K Clinical and Molecular Hepatology.2026; 32(3): 1029. CrossRef
Evaluation of Truenat results for viral hepatitis Vandana Sharma, Mahima Mahima, Sanjay Mankotia Journal of Laboratory Physicians.2026; 0: 1. CrossRef
Statistical Cure After Hepatectomy for Hepatitis B Virus-Associated Hepatocellular Carcinoma: A Risk-Stratification Model Yi-Fan Li, Lan-Qing Yao, Chao Li, Hong Ren, Jin-Bo Gong, Han Wu, Li-Hui Gu, Ying-Jian Liang, Yu-Ze Yang, Kong-Ying Lin, Zi-Qiang Li, Qi-Xuan Zheng, Ting-Hao Chen, Ya-Hao Zhou, Hong Wang, Hong-Wei Guo, Jia-Hao Xu, Zhong Chen, Feng Shen, Ming-Da Wang, Tian Annals of Surgical Oncology.2025; 32(6): 4396. CrossRef
Update on the treatment navigation for functional cure of chronic hepatitis B: Expert consensus 2.0 Di Wu, Jia-Horng Kao, Teerha Piratvisuth, Xiaojing Wang, Patrick T.F. Kennedy, Motoyuki Otsuka, Sang Hoon Ahn, Yasuhito Tanaka, Guiqiang Wang, Zhenghong Yuan, Wenhui Li, Young-Suk Lim, Junqi Niu, Fengmin Lu, Wenhong Zhang, Zhiliang Gao, Apichat Kaewdech, Clinical and Molecular Hepatology.2025; 31(Suppl): S134. CrossRef
Prediction of long-term HBsAg seroclearance in patients with HBeAg-negative chronic hepatitis B Hae Lim Lee, Soon Kyu Lee, Ji Won Han, Hyun Yang, Heechul Nam, Pil Soo Sung, Hee Yeon Kim, Sung Won Lee, Do Seon Song, Jung Hyun Kwon, Chang Wook Kim, Si Hyun Bae, Jong Young Choi, Seung Kew Yoon, Jeong Won Jang JHEP Reports.2025; 7(7): 101391. CrossRef
Male preference for TERT alterations and HBV integration in young-age HBV-related HCC: implications for sex disparity Jin Seoub Kim, Hye Seon Kim, Kwon Yong Tak, Ji Won Han, Heechul Nam, Pil Soo Sung, Sung Won Lee, Jung Hyun Kwon, Si Hyun Bae, Jong Young Choi, Seung Kew Yoon, Jeong Won Jang Clinical and Molecular Hepatology.2025; 31(2): 509. CrossRef
Risk of Hepatocellular Carcinoma Decreases After Antiviral Therapy–Induced HBsAg Seroclearance Han Ah. Lee, Hyun Woong Lee, Yeon Seok Seo, Dong Hyun Sinn, Sang Hoon Ahn, Beom Kyung Kim, Seung Up Kim Journal of Gastroenterology and Hepatology.2025; 40(7): 1675. CrossRef
Distinguishing True Immune Tolerant Hepatitis B Patients: Insights From Long‐Term Clinical Outcomes Jung Hyun Kwon, Sung Won Lee, Hee‐Yeon Kim, Do Seon Song, Soon Kyu Lee, Heechul Nam, Soon Woo Nam, Si Hyun Bae, Jong Young Choi, Seung Kew Yoon, Jeong Won Jang Journal of Viral Hepatitis.2025;[Epub] CrossRef
Functional cure of chronic hepatitis B virus infection: current therapeutic regimens Yi-Wei Shi, Rui Pu, Yi-Bo Ding, Wen-Bin Liu, Zi-Shuai Li, Jia-Yi Zhao, Yi-Fan Chen, Guang-Wen Cao Hepatoma Research.2025;[Epub] CrossRef
Detection of HBV DNA integration in plasma cell-free DNA of different HBV diseases utilizing DNA capture strategy Zerui Yang, Jingyan Zeng, Yueyue Chen, Mengchun Wang, Hongchun Luo, Ai-Long Huang, Haijun Deng, Yuan Hu Virologica Sinica.2024; 39(4): 655. CrossRef
Core protein inhibitors: Opportunities and challenges at the forefront of hepatitis B cure: Editorial on “Phase 1 trial of the safety, pharmacokinetics, and antiviral activity of EDP-514 in untreated viremic chronic hepatitis B patients” Hae Lim Lee, Jeong Won Jang Clinical and Molecular Hepatology.2024; 30(4): 692. CrossRef
The impact of integrated hepatitis B virus DNA on oncogenesis and antiviral therapy Mingming Zhang, Han Chen, Huan Liu, Hong Tang Biomarker Research.2024;[Epub] CrossRef
Hepatocellular carcinoma in HBsAg seroclearance: clinical features, recurrence, and prognosis following curative hepatectomy Wei Xu, Huai Gong, Bolun Li, Xinmin Yin Therapeutic Advances in Medical Oncology.2024;[Epub] CrossRef
Surveillance Following Hepatitis B Surface Antigen Loss: An Issue Requiring Attention Shuai-Wen Huang, Hong Long, Jia-Quan Huang Pathogens.2024; 14(1): 8. CrossRef
Post-operative recurrence of liver cancer according to antiviral therapy for detectable hepatitis B viremia: A nationwide study Byungyoon Yun, Sang Hoon Ahn, Juyeon Oh, Jin-Ha Yoon, Beom Kyung Kim European Journal of Internal Medicine.2023; 107: 66. CrossRef
Comparable Mortality Between Asian Patients with Chronic Hepatitis B Under Long-Term Antiviral Therapy vs Matched Control: A Population-Based Study Byungyoon Yun, Juyeon Oh, Sang Hoon Ahn, Jin-Ha Yoon, Beom Kyung Kim American Journal of Gastroenterology.2023; 118(6): 1001. CrossRef
Statin use is associated with better post‐operative prognosis among patients with hepatitis B virus‐related hepatocellular carcinoma Byungyoon Yun, Sang Hoon Ahn, Juyeon Oh, Jin‐Ha Yoon, Beom Kyung Kim European Journal of Clinical Investigation.2023;[Epub] CrossRef
A longitudinal study to detect hepatitis B surface and core-related antigens in chronic hepatitis B patients with hepatitis B surface antigen seroclearance using highly sensitive assays Danny Ka-Ho Wong, Takako Inoue, Lung-Yi Mak, Rex Wan-Hin Hui, James Fung, Ka-Shing Cheung, Wai-Kay Seto, Yasuhito Tanaka, Man-Fung Yuen Journal of Clinical Virology.2023; 160: 105375. CrossRef
Comparable outcomes between immune-tolerant and active phases in noncirrhotic chronic hepatitis B: a meta-analysis Han Ah Lee, Seung Up Kim, Yeon Seok Seo, Sang Hoon Ahn, Chai Hong Rim Hepatology Communications.2023; 7(2): e0011. CrossRef
Effects of hepatitis B virus infection and strategies for preventing mother-to-child transmission on maternal and fetal T-cell immunity Huihui Lu, Weihua Cao, Luxue Zhang, Liu Yang, Xiaoyue Bi, Yanjie Lin, Wen Deng, Tingting Jiang, Fangfang Sun, Zhan Zeng, Yao Lu, Lu Zhang, Ruyu Liu, Yuanjiao Gao, Shuling Wu, Hongxiao Hao, Xiaoxue Chen, Leiping Hu, Mengjiao Xu, Qiqiu Xiong, Jianping Dong, Frontiers in Immunology.2023;[Epub] CrossRef
The role of different viral biomarkers on the management of chronic hepatitis B Lung-Yi Mak, Rex Wan-Hin Hui, James Fung, Wai Kay Seto, Man-Fung Yuen Clinical and Molecular Hepatology.2023; 29(2): 263. CrossRef
Outcome of untreated low-level viremia versus antiviral therapy-induced or spontaneous undetectable HBV-DNA in compensated cirrhosis Daniel Q. Huang, Nobuharu Tamaki, Hyung Woong Lee, Soo Young Park, Yu Rim Lee, Hye Won Lee, Seng Gee Lim, Tae Seop Lim, Masayuki Kurosaki, Hiroyuki Marusawa, Toshie Mashiba, Masahiko Kondo, Yasushi Uchida, Haruhiko Kobashi, Koichiro Furuta, Namiki Izumi, Hepatology.2023; 77(5): 1746. CrossRef
Efficacy of Antiviral Prophylaxis up to 6 or 12 Months From Completion of Rituximab in Resolved Hepatitis B Patients: A Multicenter, Randomized Study Heejoon Jang, Su Jong Yu, Hong Ghi Lee, Tae Min Kim, Yun Bin Lee, Eun Ju Cho, Jeong-Hoon Lee, Jung-Hwan Yoon, Yoon Jun Kim Journal of Korean Medical Science.2023;[Epub] CrossRef
Prediction model of hepatitis B virus-related hepatocellular carcinoma in patients receiving antiviral therapy Beom Kyung Kim, Sang Hoon Ahn Journal of the Formosan Medical Association.2023; 122(12): 1238. CrossRef
Reply to: ‘A risk prediction model for hepatocellular carcinoma after hepatitis B surface antigen seroclearance: Has the correct patient cohort been targeted?’ Hyun Yang, Ji Hoon Kim, Ji Won Han, Soon Kyu Lee, Jeong Won Jang Journal of Hepatology.2023; 79(4): e155. CrossRef
A risk prediction model for hepatocellular carcinoma after hepatitis B surface antigen seroclearance Hyun Yang, Si Hyun Bae, Heechul Nam, Hae Lim Lee, Sung Won Lee, Sun Hong Yoo, Myeong Jun Song, Jung Hyun Kwon, Soon Woo Nam, Jong Young Choi, Seung Kew Yoon, Jeong Won Jang Journal of Hepatology.2022; 77(3): 632. CrossRef
KASL clinical practice guidelines for management of chronic hepatitis B
Clinical and Molecular Hepatology.2022; 28(2): 276. CrossRef
The Investigation of Hepatitis B Vaccine Immune Responses in Occult Hepatitis B Virus-Infected Patients Jing Peng, Xueying Yao, Chunyan Yuan, Xiaoli Liu, Renxiang Xia, Jian He, Rui Li, Yunqing Yao Frontiers in Immunology.2022;[Epub] CrossRef
Prognostic Impact of MAFLD Following Surgical Resection of Hepatitis B Virus-Related Hepatocellular Carcinoma: A Nationwide Cohort Study Byungyoon Yun, Sang Hoon Ahn, Juyeon Oh, Jin-Ha Yoon, Beom Kyung Kim Cancers.2022; 14(20): 5002. CrossRef
Hepatitis B virus DNA integration as a novel biomarker of hepatitis B virus-mediated pathogenetic properties and a barrier to the current strategies for hepatitis B virus cure Romina Salpini, Stefano D’Anna, Livia Benedetti, Lorenzo Piermatteo, Upkar Gill, Valentina Svicher, Patrick T. F. Kennedy Frontiers in Microbiology.2022;[Epub] CrossRef
Suboptimal Performance of Hepatocellular Carcinoma Prediction Models in Patients with Hepatitis B Virus-Related Cirrhosis Jae Lee, Tae Lim, Hye Lee, Seung Kim, Jun Park, Do Kim, Sang Ahn, Hyun Lee, Jung Lee, Ja Kim, In Min, Beom Kim Diagnostics.2022; 13(1): 3. CrossRef
Comprehensive investigation of HBV-related hepatocellular carcinoma and choice of anti-HBV therapy Huihui Lu, Wei Yi, Fangfang Sun, Zhan Zeng, Lu Zhang, Minghui Li, Yao Xie Biosafety and Health.2021; 3(4): 190. CrossRef
Viral Biomarkers for Hepatitis B Virus-Related Hepatocellular Carcinoma Occurrence and Recurrence Yuanyuan Liu, Vaishnavi Veeraraghavan, Monica Pinkerton, Jianjun Fu, Mark W. Douglas, Jacob George, Thomas Tu Frontiers in Microbiology.2021;[Epub] CrossRef
Association between HBs Ag quantification and the risk of hepatocellular carcinoma in patients treated with tenofovir disoproxil fumarate or entecavir Jung Hyun Lim, Jung Hwan Yu, Young Ju Suh, Jin-Woo Lee, Young-Joo Jin Medicine.2021; 100(39): e27417. CrossRef
Distinct Patterns of HBV Integration and TERT Alterations between in Tumor and Non-Tumor Tissue in Patients with Hepatocellular Carcinoma Jeong-Won Jang, Hye-Seon Kim, Jin-Seoub Kim, Soon-Kyu Lee, Ji-Won Han, Pil-Soo Sung, Si-Hyun Bae, Jong-Young Choi, Seung-Kew Yoon, Dong-Jin Han, Tae-Min Kim, Lewis R. Roberts International Journal of Molecular Sciences.2021; 22(13): 7056. CrossRef
First
Prev
