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http://hdl.handle.net/2445/199885
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DC Field | Value | Language |
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dc.contributor.author | Pinyol, Roser | - |
dc.contributor.author | Torrecilla, Sara | - |
dc.contributor.author | Wang, Huan | - |
dc.contributor.author | Montironi, Carla | - |
dc.contributor.author | Piqué Gili, Marta | - |
dc.contributor.author | Torres Martín, Miguel | - |
dc.contributor.author | Wei-Qiang, Leow | - |
dc.contributor.author | Willoughby, Catherine E. | - |
dc.contributor.author | Ramadori, Pierluigi | - |
dc.contributor.author | Andreu Oller, Carmen | - |
dc.contributor.author | Taik, Patricia | - |
dc.contributor.author | Lee, Youngmin A. | - |
dc.contributor.author | Moeini, Agrin | - |
dc.contributor.author | Peix, Judit | - |
dc.contributor.author | Faure-Dupuy, Suzanne | - |
dc.contributor.author | Riedl, Tobias | - |
dc.contributor.author | Schuehle, Svenja | - |
dc.contributor.author | Oliveira, Claudia P. | - |
dc.contributor.author | Alves, Venancio A. | - |
dc.contributor.author | Boffetta, Paolo | - |
dc.contributor.author | Lachenmayer, Anja | - |
dc.contributor.author | Roessler, Sthephanie | - |
dc.contributor.author | Minguez, Beatriz | - |
dc.contributor.author | Schirmacher, Peter | - |
dc.contributor.author | Dufour, Jean-François | - |
dc.contributor.author | Thung, Swan N. | - |
dc.contributor.author | Reeves, Helen L. | - |
dc.contributor.author | Carrilho, Flair J. | - |
dc.contributor.author | Chang, Charissa | - |
dc.contributor.author | Uzilov, Andrew V. | - |
dc.contributor.author | Heikenwälder, Mathias | - |
dc.contributor.author | Sanyal, Arun | - |
dc.contributor.author | Friedman, Scott L. | - |
dc.contributor.author | Sia, Daniela | - |
dc.contributor.author | Llovet i Bayer, Josep Maria | - |
dc.date.accessioned | 2023-06-26T14:48:02Z | - |
dc.date.available | 2023-06-26T14:48:02Z | - |
dc.date.issued | 2021-05-13 | - |
dc.identifier.issn | 0168-8278 | - |
dc.identifier.uri | http://hdl.handle.net/2445/199885 | - |
dc.description.abstract | Background and aims: Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterising NASH-HCC compared to other HCC aetiologies. Methods: We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n = 53 NASH-HCC; n = 74 NASH) and whole exome sequencing (n = 52 NASH-HCC) data were compared to HCCs of other aetiologies (n = 184). Three NASH-HCC mouse models were analysed by RNA-seq/expression-array (n = 20). Activin A receptor type 2A (ACVR2A) was silenced in HCC cells and proliferation assessed by colorimetric and colony formation assays. Results: Mutational profiling of NASH-HCC tumours revealed TERT promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% vs. 3%, p <0.05). In vitro, ACVR2A silencing prompted a significant increase in cell proliferation in HCC cells. We identified a novel mutational signature (MutSig-NASH-HCC) significantly associated with NASH-HCC (16% vs. 2% in viral/alcohol-HCC, p = 0.03). Tumour mutational burden was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 vs. 0.94 mutations/megabase; p <0.0017). Compared to other aetiologies of HCC, NASH-HCCs were enriched in bile and fatty acid signalling, oxidative stress and inflammation, and presented a higher fraction of Wnt/TGF-β proliferation subclass tumours (42% vs. 26%, p = 0.01) and a lower prevalence of the CTNNB1 subclass. Compared to other aetiologies, NASH-HCC showed a significantly higher prevalence of an immunosuppressive cancer field. In 3 murine models of NASH-HCC, key features of human NASH-HCC were preserved. Conclusions: NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature. Lay summary: The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH) is increasing globally, but its molecular traits are not well characterised. In this study, we uncovered higher rates of ACVR2A mutations (10%) - a potential tumour suppressor - and the presence of a novel mutational signature that characterises NASH-related HCC. | - |
dc.format.extent | 34 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Elsevier | - |
dc.relation.isformatof | Versió postprint del document publicat a: https://doi.org/10.1016/j.jhep.2021.04.049 | - |
dc.relation.ispartof | Journal of Hepatology, 2021, vol. 75, num. 4, p. 865-878 | - |
dc.relation.uri | https://doi.org/10.1016/j.jhep.2021.04.049 | - |
dc.rights | cc-by-nc-nd (c) Elsevier, 2021 | - |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | - |
dc.source | Articles publicats en revistes (Medicina) | - |
dc.subject.classification | Models animals en la investigació | - |
dc.subject.classification | Càncer de fetge | - |
dc.subject.classification | Síndrome metabòlica | - |
dc.subject.classification | Models moleculars | - |
dc.subject.classification | Mutació (Biologia) | - |
dc.subject.classification | Obesitat | - |
dc.subject.other | Animal models in research | - |
dc.subject.other | Liver cancer | - |
dc.subject.other | Metabolic syndrome | - |
dc.subject.other | Molecular models | - |
dc.subject.other | Mutation (Biology) | - |
dc.subject.other | Obesity | - |
dc.title | Molecular characterization of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.identifier.idgrec | 718036 | - |
dc.date.updated | 2023-06-26T14:48:02Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.idimarina | 9242365 | - |
dc.identifier.pmid | 33992698 | - |
Appears in Collections: | Articles publicats en revistes (Medicina) Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) |
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