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http://hdl.handle.net/2445/199885
Title: | Molecular characterization of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis |
Author: | Pinyol, Roser Torrecilla, Sara Wang, Huan Montironi, Carla Piqué Gili, Marta Torres Martín, Miguel Wei-Qiang, Leow Willoughby, Catherine E. Ramadori, Pierluigi Andreu Oller, Carmen Taik, Patricia Lee, Youngmin A. Moeini, Agrin Peix, Judit Faure-Dupuy, Suzanne Riedl, Tobias Schuehle, Svenja Oliveira, Claudia P. Alves, Venancio A. Boffetta, Paolo Lachenmayer, Anja Roessler, Sthephanie Minguez, Beatriz Schirmacher, Peter Dufour, Jean François Thung, Swan N. Reeves, Helen L. Carrilho, Flair J. Chang, Charissa Uzilov, Andrew V. Heikenwalder, Mathias Sanyal, Arun Friedman, Scott L. Sia, Daniela Llovet i Bayer, Josep Maria |
Keywords: | Models animals en la investigació Càncer de fetge Síndrome metabòlica Models moleculars Mutació (Biologia) Obesitat Animal models in research Liver cancer Metabolic syndrome Molecular models Mutation (Biology) Obesity |
Issue Date: | 13-May-2021 |
Publisher: | Elsevier |
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. |
Note: | Versió postprint del document publicat a: https://doi.org/10.1016/j.jhep.2021.04.049 |
It is part of: | Journal of Hepatology, 2021, vol. 75, num. 4, p. 865-878 |
URI: | http://hdl.handle.net/2445/199885 |
Related resource: | https://doi.org/10.1016/j.jhep.2021.04.049 |
ISSN: | 0168-8278 |
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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