Distinct Patterns of HBV Integration and TERT 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 TERT (telomerase reverse transcriptase) altera...
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| Veröffentlicht in: | International journal of molecular sciences 2021-07, Vol.22 (13), p.7056 |
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| creator | Jang, Jeong-Won Kim, Hye-Seon Kim, Jin-Seoub Lee, Soon-Kyu Han, Ji-Won Sung, Pil-Soo Bae, Si-Hyun Choi, Jong-Young Yoon, Seung-Kew Han, Dong-Jin Kim, Tae-Min Roberts, Lewis R. |
| 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 TERT (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, TERT promoter was identified as the most frequent site (38.5% (10/26)) of HBV integration. TERT 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 TERT and MLL4 for tumors and FN1 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 TERT alteration may dysregulate the affected gene function, thereby contributing to hepatocarcinogenesis. |
| doi_str_mv | 10.3390/ijms22137056 |
| format | Article |
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This study investigated the patterns of HBV integration and correlated them with TERT (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, TERT promoter was identified as the most frequent site (38.5% (10/26)) of HBV integration. TERT 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 TERT and MLL4 for tumors and FN1 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 TERT alteration may dysregulate the affected gene function, thereby contributing to hepatocarcinogenesis.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms22137056</identifier><identifier>PMID: 34209079</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Breakpoints ; Chromosomes ; Enrichment ; Genes ; Genomes ; Hepatitis B ; Hepatocellular carcinoma ; Infections ; Integration ; Liver cancer ; Mutation ; RNA-directed DNA polymerase ; Senescence ; Telomerase ; Telomerase reverse transcriptase ; Tumors</subject><ispartof>International journal of molecular sciences, 2021-07, Vol.22 (13), p.7056</ispartof><rights>2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 by the authors. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c389t-c6fe2344197b7960ae068dd74937670e9e5993a013de47d487088abe36a9f3f23</citedby><cites>FETCH-LOGICAL-c389t-c6fe2344197b7960ae068dd74937670e9e5993a013de47d487088abe36a9f3f23</cites><orcidid>0000-0003-1456-1450 ; 0000-0002-4476-4868 ; 0000-0003-3255-8474 ; 0000-0001-7885-8574 ; 0000-0002-5780-9607 ; 0000-0003-1865-8225</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268258/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268258/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27923,27924,53790,53792</link.rule.ids></links><search><creatorcontrib>Jang, Jeong-Won</creatorcontrib><creatorcontrib>Kim, Hye-Seon</creatorcontrib><creatorcontrib>Kim, Jin-Seoub</creatorcontrib><creatorcontrib>Lee, Soon-Kyu</creatorcontrib><creatorcontrib>Han, Ji-Won</creatorcontrib><creatorcontrib>Sung, Pil-Soo</creatorcontrib><creatorcontrib>Bae, Si-Hyun</creatorcontrib><creatorcontrib>Choi, Jong-Young</creatorcontrib><creatorcontrib>Yoon, Seung-Kew</creatorcontrib><creatorcontrib>Han, Dong-Jin</creatorcontrib><creatorcontrib>Kim, Tae-Min</creatorcontrib><creatorcontrib>Roberts, Lewis R.</creatorcontrib><title>Distinct Patterns of HBV Integration and TERT Alterations between in Tumor and Non-Tumor Tissue in Patients with Hepatocellular Carcinoma</title><title>International journal of molecular sciences</title><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 TERT (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, TERT promoter was identified as the most frequent site (38.5% (10/26)) of HBV integration. TERT 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 TERT and MLL4 for tumors and FN1 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 TERT alteration may dysregulate the affected gene function, thereby contributing to hepatocarcinogenesis.</description><subject>Breakpoints</subject><subject>Chromosomes</subject><subject>Enrichment</subject><subject>Genes</subject><subject>Genomes</subject><subject>Hepatitis B</subject><subject>Hepatocellular carcinoma</subject><subject>Infections</subject><subject>Integration</subject><subject>Liver cancer</subject><subject>Mutation</subject><subject>RNA-directed DNA polymerase</subject><subject>Senescence</subject><subject>Telomerase</subject><subject>Telomerase reverse transcriptase</subject><subject>Tumors</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkc1u1DAUha2qqH901wewxKYLAje2E9sbpHYoTKUKEApsLU9y03qU2FPboeIR-tZkOhUqrO7fp6NzdQg5K-Ed5xreu_WYGCu5hKreI0elYKwAqOX-i_6QHKe0BmCcVfqAHHLBQIPUR-Txo0vZ-TbTbzZnjD7R0NPl5U967TPeRptd8NT6jjZX3xt6MczM0y7RFeYHRE-dp800hvhEfQm-2E2NS2nC7XVWduhzog8u39ElbmwOLQ7DNNhIFza2zofRviavejskPH2uJ-THp6tmsSxuvn6-XlzcFC1XOhdt3SPjQpRarqSuwSLUquuk0FzWElBjpTW3UPIOheyEkqCUXSGvre55z_gJ-bDT3UyrEbt2dhbtYDbRjTb-NsE68-_FuztzG34ZxWrFKjULnD8LxHA_YcpmdGn7j_UYpmRYJZQoBQiY0Tf_oeswRT-_t6W0KAFkNVNvd1QbQ0oR-79mSjDbjM3LjPkfRpeZ5w</recordid><startdate>20210701</startdate><enddate>20210701</enddate><creator>Jang, Jeong-Won</creator><creator>Kim, Hye-Seon</creator><creator>Kim, Jin-Seoub</creator><creator>Lee, Soon-Kyu</creator><creator>Han, Ji-Won</creator><creator>Sung, Pil-Soo</creator><creator>Bae, Si-Hyun</creator><creator>Choi, Jong-Young</creator><creator>Yoon, Seung-Kew</creator><creator>Han, Dong-Jin</creator><creator>Kim, Tae-Min</creator><creator>Roberts, Lewis R.</creator><general>MDPI AG</general><general>MDPI</general><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-1456-1450</orcidid><orcidid>https://orcid.org/0000-0002-4476-4868</orcidid><orcidid>https://orcid.org/0000-0003-3255-8474</orcidid><orcidid>https://orcid.org/0000-0001-7885-8574</orcidid><orcidid>https://orcid.org/0000-0002-5780-9607</orcidid><orcidid>https://orcid.org/0000-0003-1865-8225</orcidid></search><sort><creationdate>20210701</creationdate><title>Distinct Patterns of HBV Integration and TERT Alterations between in Tumor and Non-Tumor Tissue in Patients with Hepatocellular Carcinoma</title><author>Jang, Jeong-Won ; 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This study investigated the patterns of HBV integration and correlated them with TERT (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, TERT promoter was identified as the most frequent site (38.5% (10/26)) of HBV integration. TERT 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 TERT and MLL4 for tumors and FN1 for non-tumors. 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| subjects | Breakpoints Chromosomes Enrichment Genes Genomes Hepatitis B Hepatocellular carcinoma Infections Integration Liver cancer Mutation RNA-directed DNA polymerase Senescence Telomerase Telomerase reverse transcriptase Tumors |
| title | Distinct Patterns of HBV Integration and TERT Alterations between in Tumor and Non-Tumor Tissue in Patients with Hepatocellular Carcinoma |
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