Details

Autor(en) / Beteiligte

• Pinyol, Roser
• Torrecilla, Sara
• Wang, Huan
• Montironi, Carla
• Piqué-Gili, Marta
• Torres-Martin, 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, Stephanie
• 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, Josep M.

Titel

Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis

Ist Teil von

• Journal of hepatology, 2021-10, Vol.75 (4), p.865-878

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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. 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. NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature. 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. [Display omitted] •The most frequently mutated genes in NASH-HCC were TERT, CTNNB1, TP53 and ACVR2A.•Mutations in ACVR2A – a potential tumour suppressor gene – were more common in NASH-HCC than in other aetiologies.•A novel mutational signature was significantly associated with NASH-HCC.•The Wnt/TGF-β proliferation subclass was more prevalent in NASH-HCC than in HCCs of other aetiologies.•NASH-HCC showed a significantly higher prevalence of an immunosuppressive pro-carcinogenic cancer field.