Distinct Patterns of HBV Integration and <i>TERT</i> Alterations between in Tumor and Non-Tumor Tissue in Patients with Hepatocellular Carcinoma
Although hepatitis B virus (HBV) integration into the cellular genome is well known in HCC (hepatocellular carcinoma) patients, its biological role still remains uncertain. This study investigated the patterns of HBV integration and correlated them with <i>TERT</i> (telomerase reverse tr...
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| Format: | Article |
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MDPI AG
2021-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/13/7056 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jeong-Won Jang |
| collection | DOAJ |
| description | Although hepatitis B virus (HBV) integration into the cellular genome is well known in HCC (hepatocellular carcinoma) patients, its biological role still remains uncertain. This study investigated the patterns of HBV integration and correlated them with <i>TERT</i> (telomerase reverse transcriptase) alterations in paired tumor and non-tumor tissues. Compared to those in non-tumors, tumoral integrations occurred less frequently but with higher read counts and were more preferentially observed in genic regions with significant enrichment of integration into promoters. In HBV-related tumors, <i>TERT</i> promoter was identified as the most frequent site (38.5% (10/26)) of HBV integration. <i>TERT</i> promoter mutation was observed only in tumors (24.2% (8/33)), but not in non-tumors. Only 3.00% (34/1133) of HBV integration sites were shared between tumors and non-tumors. Within the HBV genome, HBV breakpoints were distributed preferentially in the 3’ end of HBx, with more tumoral integrations detected in the preS/S region. The major genes that were recurrently affected by HBV integration included <i>TERT</i> and <i>MLL4</i> for tumors and <i>FN1</i> for non-tumors. Functional enrichment analysis of tumoral genes with integrations showed enrichment of cancer-associated genes. The patterns and functions of HBV integration are distinct between tumors and non-tumors. Tumoral integration is often enriched into both human-virus regions with oncogenic regulatory function. The characteristic genomic features of HBV integration together with <i>TERT</i> alteration may dysregulate the affected gene function, thereby contributing to hepatocarcinogenesis. |
| first_indexed | 2024-03-10T09:54:58Z |
| format | Article |
| id | doaj.art-a1e1cb71cbbd49179f543e62f5dd0e29 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T09:54:58Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a1e1cb71cbbd49179f543e62f5dd0e292023-11-22T02:24:20ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-06-012213705610.3390/ijms22137056Distinct Patterns of HBV Integration and <i>TERT</i> Alterations between in Tumor and Non-Tumor Tissue in Patients with Hepatocellular CarcinomaJeong-Won Jang0Hye-Seon Kim1Jin-Seoub Kim2Soon-Kyu Lee3Ji-Won Han4Pil-Soo Sung5Si-Hyun Bae6Jong-Young Choi7Seung-Kew Yoon8Dong-Jin Han9Tae-Min Kim10Lewis R. Roberts11Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaThe Catholic University Liver Research Center, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaThe Catholic University Liver Research Center, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaDivision of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaDivision of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaDivision of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaDivision of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaDivision of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaDivision of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaDepartment of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul 06591, KoreaDepartment of Medical Informatics, Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaDivision of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55902, USAAlthough hepatitis B virus (HBV) integration into the cellular genome is well known in HCC (hepatocellular carcinoma) patients, its biological role still remains uncertain. This study investigated the patterns of HBV integration and correlated them with <i>TERT</i> (telomerase reverse transcriptase) alterations in paired tumor and non-tumor tissues. Compared to those in non-tumors, tumoral integrations occurred less frequently but with higher read counts and were more preferentially observed in genic regions with significant enrichment of integration into promoters. In HBV-related tumors, <i>TERT</i> promoter was identified as the most frequent site (38.5% (10/26)) of HBV integration. <i>TERT</i> promoter mutation was observed only in tumors (24.2% (8/33)), but not in non-tumors. Only 3.00% (34/1133) of HBV integration sites were shared between tumors and non-tumors. Within the HBV genome, HBV breakpoints were distributed preferentially in the 3’ end of HBx, with more tumoral integrations detected in the preS/S region. The major genes that were recurrently affected by HBV integration included <i>TERT</i> and <i>MLL4</i> for tumors and <i>FN1</i> for non-tumors. Functional enrichment analysis of tumoral genes with integrations showed enrichment of cancer-associated genes. The patterns and functions of HBV integration are distinct between tumors and non-tumors. Tumoral integration is often enriched into both human-virus regions with oncogenic regulatory function. The characteristic genomic features of HBV integration together with <i>TERT</i> alteration may dysregulate the affected gene function, thereby contributing to hepatocarcinogenesis.https://www.mdpi.com/1422-0067/22/13/7056hepatitis B virusvirus integrationliver cancertelomerasepoint mutation |
| spellingShingle | 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 Distinct Patterns of HBV Integration and <i>TERT</i> Alterations between in Tumor and Non-Tumor Tissue in Patients with Hepatocellular Carcinoma International Journal of Molecular Sciences hepatitis B virus virus integration liver cancer telomerase point mutation |
| title | Distinct Patterns of HBV Integration and <i>TERT</i> Alterations between in Tumor and Non-Tumor Tissue in Patients with Hepatocellular Carcinoma |
| title_full | Distinct Patterns of HBV Integration and <i>TERT</i> Alterations between in Tumor and Non-Tumor Tissue in Patients with Hepatocellular Carcinoma |
| title_fullStr | Distinct Patterns of HBV Integration and <i>TERT</i> Alterations between in Tumor and Non-Tumor Tissue in Patients with Hepatocellular Carcinoma |
| title_full_unstemmed | Distinct Patterns of HBV Integration and <i>TERT</i> Alterations between in Tumor and Non-Tumor Tissue in Patients with Hepatocellular Carcinoma |
| title_short | Distinct Patterns of HBV Integration and <i>TERT</i> Alterations between in Tumor and Non-Tumor Tissue in Patients with Hepatocellular Carcinoma |
| title_sort | distinct patterns of hbv integration and i tert i alterations between in tumor and non tumor tissue in patients with hepatocellular carcinoma |
| topic | hepatitis B virus virus integration liver cancer telomerase point mutation |
| url | https://www.mdpi.com/1422-0067/22/13/7056 |
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