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 - Funding Information:
J.M.L. is supported by grants from the European Commission (EC) Horizon 2020 Program (HEP-CAR, proposal number 667273-2), the US Department of Defense (CA150272P3), the National Cancer Institute (P30 CA196521), the NIH (RO1DK56621 and RO1DK128289 to SLF), the Samuel Waxman Cancer Research Foundation, the Spanish National Health Institute (MICINN, SAF-2016-76390 and PID2019-105378RB-I00), through a partnership between Cancer Research UK, Fondazione AIRC and Fundación Científica de la Asociación Española Contra el Cáncer (HUNTER, Ref. C9380/A26813), and by the Generalitat de Catalunya (AGAUR, SGR-1358). S.T. was awarded with a grant from the Spanish National Health Institute (Ref. EEBB-I-17-12316) and with the EASL Andrew K. Burroughs Fellowship. C.M. and C.E.W. are respectively supported by a Rio Hortega fellowship (CM19/00039) and a Sara Borrell fellowship (CD19/00109) from the ISCIII and the European Social Fund. M.P.G. was supported by a MICINN fellowship (PRE2020-094716). C.A.O. was supported by a Fulbright Fellowship and a “laCaixa” INPhINIT Fellowship (LCF/BQ/IN17/11620024). M.H. is supported by the SFB 179 and an ERCCoG (HeparoMetaboPath). A.L. is supported by the Swiss Transplant Cohort Study. H.L.R. is supported by a Cancer Research UK (CR UK) centre grant C9380/A18084; programme grant C18342/A23390 and Accelerator award C9380/A26813. P.S. and SR were supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project-ID 314905040 – SFB/TRR 209 Liver Cancer (B01 to S.R. and Z01, INF to P.S.), the European Union's Horizon 2020 research and innovation programme (grant no. 667273, HEP-CAR), and the Eurostars (grant E! 113707, LiverQR) which was funded by the Bundesministerium für Bildung und Forschung (BMBF). S.R. was supported by the German Cancer Aid (grant no. 70113922). D.S. is supported by the PhD Scientist Innovative Research Award. B. M. received grant support from Instituto de Salud Carlos III (PI18/00961).
Funding Information:
J.M.L. is supported by grants from the European Commission (EC) Horizon 2020 Program ( HEP-CAR , proposal number 667273-2), the US Department of Defense ( CA150272P3 ), the National Cancer Institute ( P30 CA196521 ), the NIH ( RO1DK56621 and RO1DK128289 to SLF), the Samuel Waxman Cancer Research Foundation , the Spanish National Health Institute ( MICINN , SAF-2016-76390 and PID2019-105378RB-I00 ), through a partnership between Cancer Research UK , Fondazione AIRC and Fundación Científica de la Asociación Española Contra el Cáncer (HUNTER, Ref. C9380/A26813 ), and by the Generalitat de Catalunya (AGAUR, SGR-1358 ). S.T. was awarded with a grant from the Spanish National Health Institute (Ref. EEBB-I-17-12316 ) and with the EASL Andrew K. Burroughs Fellowship . C.M. and C.E.W. are respectively supported by a Rio Hortega fellowship ( CM19/00039 ) and a Sara Borrell fellowship ( CD19/00109 ) from the ISCIII and the European Social Fund . M.P.G. was supported by a MICINN fellowship ( PRE2020-094716 ). C.A.O. was supported by a Fulbright Fellowship and a “laCaixa” INPhINIT Fellowship ( LCF/BQ/IN17/11620024 ). M.H. is supported by the SFB 179 and an ERCCoG (HeparoMetaboPath). A.L. is supported by the Swiss Transplant Cohort Study . H.L.R. is supported by a Cancer Research UK (CR UK) centre grant C9380/A18084 ; programme grant C18342/A23390 and Accelerator award C9380/A26813 . P.S. and SR were supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project-ID 314905040 – SFB/TRR 209 Liver Cancer ( B01 to S.R. and Z01 , INF to P.S.), the European Union’s Horizon 2020 research and innovation programme (grant no. 667273 , HEP-CAR), and the Eurostars (grant E! 113707 , LiverQR) which was funded by the Bundesministerium für Bildung und Forschung (BMBF). S.R. was supported by the German Cancer Aid (grant no. 70113922 ). D.S. is supported by the PhD Scientist Innovative Research Award. B. M. received grant support from Instituto de Salud Carlos III ( PI18/00961 ).
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 -