TY - JOUR
T1 - Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis
AU - Pinyol, Roser
AU - Torrecilla, Sara
AU - Wang, Huan
AU - Montironi, Carla
AU - Piqué-Gili, Marta
AU - Torres-Martin, Miguel
AU - Wei-Qiang, Leow
AU - Willoughby, Catherine E.
AU - Ramadori, Pierluigi
AU - Andreu-Oller, Carmen
AU - Taik, Patricia
AU - Lee, Youngmin A.
AU - Moeini, Agrin
AU - Peix, Judit
AU - Faure-Dupuy, Suzanne
AU - Riedl, Tobias
AU - Schuehle, Svenja
AU - Oliveira, Claudia P.
AU - Alves, Venancio A.
AU - Boffetta, Paolo
AU - Lachenmayer, Anja
AU - Roessler, Stephanie
AU - Minguez, Beatriz
AU - Schirmacher, Peter
AU - Dufour, Jean François
AU - Thung, Swan N.
AU - Reeves, Helen L.
AU - Carrilho, Flair J.
AU - Chang, Charissa
AU - Uzilov, Andrew V.
AU - Heikenwalder, Mathias
AU - Sanyal, Arun
AU - Friedman, Scott L.
AU - Sia, Daniela
AU - Llovet, Josep M.
N1 - Publisher Copyright:
© 2021 European Association for the Study of the Liver
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
KW - animal model
KW - liver cancer
KW - metabolic syndrome
KW - molecular class
KW - mutational signature
KW - obesity
UR - http://www.scopus.com/inward/record.url?scp=85107624977&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2021.04.049
DO - 10.1016/j.jhep.2021.04.049
M3 - Article
C2 - 33992698
AN - SCOPUS:85107624977
SN - 0168-8278
VL - 75
SP - 865
EP - 878
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 4
ER -