Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification.

Autor:	Montironi C; Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.; Pathology Department & Molecular Biology CORE, Hospital Clinic de Barcelona, Barcelona, Spain., Castet F; Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain., Haber PK; Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Pinyol R; Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain., Torres-Martin M; Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain., Torrens L; Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain., Mesropian A; Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain., Wang H; Sema4, Stamford, Connecticut, USA., Puigvehi M; Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Hepatology Section, Gastroenterology Department, Consorci Parc de Salut Mar, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain., Maeda M; Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Leow WQ; Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Department of Anatomical Pathology, Singapore General Hospital, Singapore., Harrod E; Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Royal Surrey County Hospital, Guildford, UK.; University of Surrey, Guildford, UK., Taik P; Sema4, Stamford, Connecticut, USA., Chinburen J; Hepato-Pancreatico-Biliary Surgery Department, National Cancer Center, Ulaanbaatar, Mongolia., Taivanbaatar E; Hepato-Pancreatico-Biliary Surgery Department, National Cancer Center, Ulaanbaatar, Mongolia., Chinbold E; Hepato-Pancreatico-Biliary Surgery Department, National Cancer Center, Ulaanbaatar, Mongolia., Solé Arqués M; Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain., Donovan M; Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Thung S; Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Neely J; Bristol-Myers Squibb, Princeton, New Jersey, USA., Mazzaferro V; Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, Milan, Italy., Anderson J; Bristol-Myers Squibb, Princeton, New Jersey, USA., Roayaie S; Department of Surgery, White Plains Hospital Center, White Plains, New York, USA., Schwartz M; Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Villanueva A; Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Friedman SL; Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Uzilov A; 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, New York, USA., Sia D; Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA josep.llovet@mountsinai.org daniela.sia@mssm.edu., Llovet JM; Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain josep.llovet@mountsinai.org daniela.sia@mssm.edu.; Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Institució Catalana De Recerca i Estudis Avançats, Barcelona, Catalonia, Spain.
Jazyk:	angličtina
Zdroj:	Gut [Gut] 2023 Jan; Vol. 72 (1), pp. 129-140. Date of Electronic Publication: 2022 Feb 23.
DOI:	10.1136/gutjnl-2021-325918
Abstrakt:	Objective: We previously reported a characterisation of the hepatocellular carcinoma (HCC) immune contexture and described an immune-specific class. We now aim to further delineate the immunogenomic classification of HCC to incorporate features that explain responses/resistance to immunotherapy. Design: We performed RNA and whole-exome sequencing, T-cell receptor (TCR)-sequencing, multiplex immunofluorescence and immunohistochemistry in a novel cohort of 240 HCC patients and validated our results in other cohorts comprising 660 patients. Results: Our integrative analysis led to define: (1) the inflamed class of HCC (37%), which includes the previously reported immune subclass (22%) and a new immune-like subclass (15%) with high interferon signalling, cytolytic activity, expression of immune-effector cytokines and a more diverse T-cell repertoire. A 20-gene signature was able to capture ~90% of these tumours and is associated with response to immunotherapy. Proteins identified in liquid biopsies recapitulated the inflamed class with an area under the ROC curve (AUC) of 0.91; (2) The intermediate class, enriched in TP53 mutations (49% vs 29%, p=0.035), and chromosomal losses involving immune-related genes and; (3) the excluded class, enriched in CTNNB1 mutations (93% vs 27%, p<0.001) and PTK2 overexpression due to gene amplification and promoter hypomethylation. CTNNB1 mutations outside the excluded class led to weak activation of the Wnt-βcatenin pathway or occurred in HCCs dominated by high interferon signalling and type I antigen presenting genes. Conclusion: We have characterised the immunogenomic contexture of HCC and defined inflamed and non-inflamed tumours. Two distinct CTNNB1 patterns associated with a differential role in immune evasion are described. These features may help predict immune response in HCC. Competing Interests: Competing interests: JA and JN are staff scientists from Bristol-Myers Squibb. JML is receiving research support from Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb, Boehringer-Ingelheim and Ipsen, and consulting fees from Eli Lilly, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Eisai Inc, Celsion Corporation, Exelixis, Merck, Ipsen, Genentech, Roche, Glycotest, Nucleix, Sirtex, Mina Alpha Ltd and AstraZeneca. The remaining coauthors have nothing to disclose related to this manuscript. (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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