HBV DNA Integration into Telomerase or MLL4 Genes and TERT Promoter Point Mutation as Three Independent Signatures in Subgrouping HBV-related HCC with distinct features
Introduction: A set of genetic mutations to classify hepatocellular carcinoma (HCC) useful to clinical studies is an unmet need. Hepatitis B virus-related HCC (HBV-HCC) harbors a unique genetic mutation, namely the HBV integration, among other somatic endogenous gene mutations. We explored a combina...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Karger Publishers
2023-04-01
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| Series: | Liver Cancer |
| Online Access: | https://www.karger.com/Article/FullText/530699 |
| _version_ | 1797828640116834304 |
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| author | Chiao-Ling Li Chia-Lang Hsu You-Yu Lin Ming-Chih Ho Chi-Ling Chen Tung-Ching Ho Yung-Feng Lin Shih-Feng Tsai Sheng-Tai Tzeng Chin-Fang Huang Ya-Chun Wang Shiou-Hwei Yeh Pei-Jer Chen |
| author_facet | Chiao-Ling Li Chia-Lang Hsu You-Yu Lin Ming-Chih Ho Chi-Ling Chen Tung-Ching Ho Yung-Feng Lin Shih-Feng Tsai Sheng-Tai Tzeng Chin-Fang Huang Ya-Chun Wang Shiou-Hwei Yeh Pei-Jer Chen |
| author_sort | Chiao-Ling Li |
| collection | DOAJ |
| description | Introduction: A set of genetic mutations to classify hepatocellular carcinoma (HCC) useful to clinical studies is an unmet need. Hepatitis B virus-related HCC (HBV-HCC) harbors a unique genetic mutation, namely the HBV integration, among other somatic endogenous gene mutations. We explored a combination of HBV DNA integrations and common somatic mutations to classify HBV-HCC by using a capture-sequencing platform. Methods: A total of 153 HBV-HCCs after surgical resection were subjected to capture-sequencing to identify HBV integrations and three common somatic mutations in genomes. Three mutually exclusive mutations, HBV DNA integration into the TERT promoter, HBV DNA integration into MLL4, or TERT promoter point mutation, were identified in HBV-HCC. Results: They were used to classify HBV-HCCs into four groups: G1 with HBV-TERT integration (25.5%); G2 with HBV-MLL4 integration (10.5%); G3 with TERT promoter mutation (30.1%); and G4 without these three mutations (34.0%). Clinically, G3 has the highest male-to-female ratio, cirrhosis rate and associated with higher early recurrence and mortality after resection, but G4 has the best outcome. Transcriptomic analysis revealed a grouping different from the published ones, and G2 with an active immune profile related to immune checkpoint inhibitor response. Analysis of integrated HBV DNA provided clues for HBV genotype and variants in carcinogenesis of different HCC subgroup. This new classification was also validated in another independent cohort. Discussion/Conclusion: A simple and robust genetic classification was developed to aid in understanding HBV-HCC and in harmonizing clinical studies. |
| first_indexed | 2024-04-09T13:07:35Z |
| format | Article |
| id | doaj.art-031608ce259b4f12ae2bc4141f930896 |
| institution | Directory Open Access Journal |
| issn | 2235-1795 1664-5553 |
| language | English |
| last_indexed | 2024-04-09T13:07:35Z |
| publishDate | 2023-04-01 |
| publisher | Karger Publishers |
| record_format | Article |
| series | Liver Cancer |
| spelling | doaj.art-031608ce259b4f12ae2bc4141f9308962023-05-12T12:24:18ZengKarger PublishersLiver Cancer2235-17951664-55532023-04-0110.1159/000530699530699HBV DNA Integration into Telomerase or MLL4 Genes and TERT Promoter Point Mutation as Three Independent Signatures in Subgrouping HBV-related HCC with distinct featuresChiao-Ling LiChia-Lang Hsuhttps://orcid.org/0000-0002-7447-8045You-Yu LinMing-Chih Hohttps://orcid.org/0000-0003-3660-1062Chi-Ling ChenTung-Ching HoYung-Feng LinShih-Feng TsaiSheng-Tai TzengChin-Fang HuangYa-Chun WangShiou-Hwei YehPei-Jer ChenIntroduction: A set of genetic mutations to classify hepatocellular carcinoma (HCC) useful to clinical studies is an unmet need. Hepatitis B virus-related HCC (HBV-HCC) harbors a unique genetic mutation, namely the HBV integration, among other somatic endogenous gene mutations. We explored a combination of HBV DNA integrations and common somatic mutations to classify HBV-HCC by using a capture-sequencing platform. Methods: A total of 153 HBV-HCCs after surgical resection were subjected to capture-sequencing to identify HBV integrations and three common somatic mutations in genomes. Three mutually exclusive mutations, HBV DNA integration into the TERT promoter, HBV DNA integration into MLL4, or TERT promoter point mutation, were identified in HBV-HCC. Results: They were used to classify HBV-HCCs into four groups: G1 with HBV-TERT integration (25.5%); G2 with HBV-MLL4 integration (10.5%); G3 with TERT promoter mutation (30.1%); and G4 without these three mutations (34.0%). Clinically, G3 has the highest male-to-female ratio, cirrhosis rate and associated with higher early recurrence and mortality after resection, but G4 has the best outcome. Transcriptomic analysis revealed a grouping different from the published ones, and G2 with an active immune profile related to immune checkpoint inhibitor response. Analysis of integrated HBV DNA provided clues for HBV genotype and variants in carcinogenesis of different HCC subgroup. This new classification was also validated in another independent cohort. Discussion/Conclusion: A simple and robust genetic classification was developed to aid in understanding HBV-HCC and in harmonizing clinical studies.https://www.karger.com/Article/FullText/530699 |
| spellingShingle | Chiao-Ling Li Chia-Lang Hsu You-Yu Lin Ming-Chih Ho Chi-Ling Chen Tung-Ching Ho Yung-Feng Lin Shih-Feng Tsai Sheng-Tai Tzeng Chin-Fang Huang Ya-Chun Wang Shiou-Hwei Yeh Pei-Jer Chen HBV DNA Integration into Telomerase or MLL4 Genes and TERT Promoter Point Mutation as Three Independent Signatures in Subgrouping HBV-related HCC with distinct features Liver Cancer |
| title | HBV DNA Integration into Telomerase or MLL4 Genes and TERT Promoter Point Mutation as Three Independent Signatures in Subgrouping HBV-related HCC with distinct features |
| title_full | HBV DNA Integration into Telomerase or MLL4 Genes and TERT Promoter Point Mutation as Three Independent Signatures in Subgrouping HBV-related HCC with distinct features |
| title_fullStr | HBV DNA Integration into Telomerase or MLL4 Genes and TERT Promoter Point Mutation as Three Independent Signatures in Subgrouping HBV-related HCC with distinct features |
| title_full_unstemmed | HBV DNA Integration into Telomerase or MLL4 Genes and TERT Promoter Point Mutation as Three Independent Signatures in Subgrouping HBV-related HCC with distinct features |
| title_short | HBV DNA Integration into Telomerase or MLL4 Genes and TERT Promoter Point Mutation as Three Independent Signatures in Subgrouping HBV-related HCC with distinct features |
| title_sort | hbv dna integration into telomerase or mll4 genes and tert promoter point mutation as three independent signatures in subgrouping hbv related hcc with distinct features |
| url | https://www.karger.com/Article/FullText/530699 |
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