| Male preference for TERT alterations and HBV integration in young-age HBV-related HCC: implications for sex disparity |
| Jin Seoub Kim2,3,4, Hye Seon Kim2,3,4, Kwon Yong Tak5, Ji Won Han1,2, Heechul Nam1,2, Pil Soo Sung1,2, Sung Won Lee1,2, Jung Hyun Kwon1,2, Si Hyun Bae1,2, Jong Young Choi1,2, Seung Kew Yoon1,2, Jeong Won Jang1,2,4 |
1Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
2The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Republic of Korea
3Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul, Republic of Korea
4Department of Medical Informatics, Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
5Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea |
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Received: July 10, 2024 Revised: December 24, 2024 Accepted: December 30, 2024 |
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| ABSTRACT |
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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. |
| KeyWords:
Hepatocellular carcinoma, Telomere, Mutation, Virus integration, Sex |
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