Roser Pinyol1, Sara Torrecilla1, Huan Wang2, Carla Montironi1, Marta Piqué-Gili1, Miguel Torres-Martin3, Leow Wei-Qiang4, Catherine E Willoughby1, Pierluigi Ramadori5, Carmen Andreu-Oller3, Patricia Taik2, Youngmin A Lee6, Agrin Moeini1, Judit Peix1, Suzanne Faure-Dupuy5, Tobias Riedl5, Svenja Schuehle5, Claudia P Oliveira7, Venancio A Alves7, Paolo Boffetta8, Anja Lachenmayer9, Stephanie Roessler10, Beatriz Minguez11, Peter Schirmacher10, Jean-François Dufour9, Swan N Thung12, Helen L Reeves13, Flair J Carrilho7, Charissa Chang12, Andrew V Uzilov14, Mathias Heikenwalder5, Arun Sanyal15, Scott L Friedman12, Daniela Sia12, Josep M Llovet16. 1. Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain. 2. Sema4, Stamford, Connecticut, USA. 3. Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain; Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA. 4. Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore. 5. Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany. 6. Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Department of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA. 7. Departments of Gastroenterology and Pathology, University of São Paulo - School of Medicine, São Paulo, Brazil. 8. Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Department of Medical and Surgical Sciences, University of Bologna, Italy. 9. Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, CH-3010, Bern, Switzerland. 10. Institute of Pathology, University Hospital Heidelberg, Germany. 11. Liver Unit, Vall d´Hebron Hospital Universitari, Liver Diseases Research Group, Vall d´Hebron Institut of Research (VHIR), Vall d´Hebron Hospital Campus. CIBERehd, Universitat Autonoma de Barcelona, Barcelona, Catalonia, Spain. 12. Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA. 13. Newcastle University Translational and Clinical Research Institute and Newcastle University Centre for Cancer, Medical School, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK; Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK. 14. Sema4, Stamford, Connecticut, USA; Department of Genetics and Genomic Sciences and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, USA. 15. Divisions of Gastroenterology and Hepatology, Virginia Commonwealth University, Richmond, VA, USA. 16. Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain; Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain. Electronic address: josep.llovet@mssm.edu.
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.
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.
Authors: Stanley W K Ng; Foad J Rouhani; Simon F Brunner; Natalia Brzozowska; Sarah J Aitken; Ming Yang; Federico Abascal; Luiza Moore; Efterpi Nikitopoulou; Lia Chappell; Daniel Leongamornlert; Aleksandra Ivovic; Philip Robinson; Timothy Butler; Mathijs A Sanders; Nicholas Williams; Tim H H Coorens; Jon Teague; Keiran Raine; Adam P Butler; Yvette Hooks; Beverley Wilson; Natalie Birtchnell; Huw Naylor; Susan E Davies; Michael R Stratton; Iñigo Martincorena; Raheleh Rahbari; Christian Frezza; Matthew Hoare; Peter J Campbell Journal: Nature Date: 2021-10-13 Impact factor: 49.962
Authors: Christopher D Green; Cynthia Weigel; Ryan D R Brown; Pierre Bedossa; Mikhail Dozmorov; Arun J Sanyal; Sarah Spiegel Journal: FASEB J Date: 2022-07 Impact factor: 5.834
Authors: Xiaobo Wang; Sharon Zeldin; Hongxue Shi; Changyu Zhu; Yoshinobu Saito; Kathleen E Corey; Stephanie A Osganian; Helen E Remotti; Elizabeth C Verna; Utpal B Pajvani; Robert F Schwabe; Ira Tabas Journal: J Hepatol Date: 2021-12-11 Impact factor: 30.083
Authors: Josep M Llovet; Roser Pinyol; Robin K Kelley; Anthony El-Khoueiry; Helen L Reeves; Xin Wei Wang; Gregory J Gores; Augusto Villanueva Journal: Nat Cancer Date: 2022-04-28