Molecular characterization of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis.

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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 characterizing NASH-HCC compared to other HCC aetiologies.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 with RNAseq/expression-array (n=20). Activin A Receptor Type 2 A (ACVR2A) was silenced in HCC cells and proliferation assessed by colorimetric and colony formation assays.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% versus 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 (TMB) was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 versus 0.94 mutations/Mb; 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% versus 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 three murine models of NASH-HCC, key features of human NASH-HCC were preserved.NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature.Hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH) is increasing globally, but its molecular traits are not well characterized. Our molecular characterization has uncovered higher rates of ACVR2A mutations (10%) -a potential tumour suppressor- and the presence of a novel mutational signature (MutSig-NASH-HCC), as well as a more prominent role of a Wnt/TGF-β proliferation subclass in tumours (42%) and immunosuppressive traits in the adjacent non-tumoral tissue.

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Authors: Roser Pinyol, Sara Torrecilla, Huan Wang, Carla Montironi, Marta Piqué-Gili, Miguel Torres-Martin, Leow Wei-Qiang, Catherine E Willoughby, Pierluigi Ramadori, Carmen Andreu-Oller, Patricia Taik, Youngmin A Lee, Agrin Moeini, Judit Peix, Suzanne Faure-Dupuy, Tobias Riedl, Svenja Schuehle, Claudia P Oliveira, Venancio A Alves, Paolo Boffetta, Anja Lachenmayer, Stephanie Roessler, Beatriz Minguez, Peter Schirmacher, Jean-François Dufour, Swan N Thung, Helen L Reeves, Flair J Carrilho, Charissa Chang, Andrew V Uzilov, Mathias Heikenwalder, Arun Sanyal, Scott L Friedman, Daniela Sia, Josep M Llovet