Clin Mol Hepatol.
2025 Apr;31(2):509-524. 10.3350/cmh.2024.0545.
Male preference for TERT alterations and HBV integration in young-age HBV-related HCC: implications for sex disparity
- Kim JS1,2,3
- Kim HS1,2,3
- Tak KY4
- Han JW1,4
- Nam H1,4
- Sung PS1,4
- Lee SW1,4
- Kwon JH1,4
- Bae SH1,4
- Choi JY1,4
- Yoon SK1,4
- Jang JW
1,3,4
- Affiliations
-
- 1The Catholic University Liver Research Center, The Catholic University of Korea
- 2Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea
- 3Department of Medical Informatics, Cancer Research Institute, College of Medicine, The Catholic University of Korea
- 4Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- KMID: 2566973
- DOI: http://doi.org/10.3350/cmh.2024.0545
Abstract
- 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.
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