Original ResearchFull Report: Basic and Translational—LiverAn Immune Gene Expression Signature Associated With Development of Human Hepatocellular Carcinoma Identifies Mice That Respond to Chemopreventive Agents
Section snippets
Human Cohort
Gene expression data from a cohort of 167 surgically resected fresh-frozen samples (Heptromic data set, GSE63898) with matched tumor and adjacent nontumor tissue were analyzed. Samples were previously collected (1998–2008) in the setting of the HCC Genomic Consortium after institutional review board approval. Full descriptions of the cohort and RNA profiling data are available in previous publications.15, 16 Supplementary Table 1 provides a summary of the clinicopathologic variables of the
Identification of a Novel Immune-Mediated Cancer Field Effect in Nontumor Liver Tissue of Patients With Early Hepatocellular Carcinoma
To characterize the immune features governing the unresolved cancer field in which new cancers arise, transcriptome-based analysis of a compendium of approximately 5000 annotated immunology-specific gene sets18 was performed in the nontumor liver tissue of patients with early-stage HCC. This analysis showed the presence of an ICF in approximately 60% (98/167) of samples (Figure 1A and Supplementary Figure 1). Specifically, these samples were characterized by enrichment of several gene sets
Discussion
This study represents an in-depth analysis of the inflammatory milieu associated with the field cancerization in the chronically injured liver and investigates its clinical implications for the prediction and prevention of HCC occurrence in patients with cirrhosis.
The role of the cancer field effect in promoting neoplastic transformation has gained much interest in recent years, and currently an altered microenvironment is considered a promoter of cancer.8, 10 Although under physiologic
Acknowledgements
The authors thank Juan José Lozano for technical assistance in the normalization of the transcriptomic array of the animal model. This study was developed at the building of Centre Esther Koplowitz from IDIBAPS/CERCA Programme/Generalitat de Catalunya. The authors also acknowledge Angelo Sangiovanni and Massimo Colombo for providing the seminal cohort of patients with cirrhotic in our previous studies.12, 14
Author contributions: Study concept and design: Agrin Moeini, Victoria Tovar, Daniela
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Conflicts of interest These authors disclose the following: Part of the study was supported with an investigator-initiated research grant by Boehringer Ingelheim. Josep M. Llovet has been a consultant and advisory board member and has received research funding from Boehringer Ingelheim and is receiving research support from Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb, and Ipsen and consulting fees from Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Eisai Inc, Celsion Corporation, Eli Lilly, Exelixis, Merck, Ipsen, Glycotest, Navigant, Leerink Swann LLC, Midatech Ltd, Fortress Biotech, Sprink Pharmaceuticals, and Nucleix. Scott L. Friedman has been a consultant for Abide Therapeutics, Allergan Pharmaceuticals, Angion Biomedica, Blade Therapeutics, Can-Fite Biopharma, Enanta Pharmaceuticals, Escient Therapeutics, Forbion, Galmed, Genfit, Glycotest, Glympse Bio, Metacrine Inc, Mistral Biosciences, Morphic Rock Therapeutics, North Sea Therapeutics, Novartis, Novo Nordisk, Pfizer Pharmaceuticals, Salix Pharmaceuticals, Scholar Rock, Seal Rock Therapeutics, Second Genome, Surrozen, Symic Bio, Viking Therapeutics, and Kintai; has received research funding from Blade Therapeutics, Can-Fite Biopharma, Ferring Research Institute, Galmed; and has stock options from Intercept, Exalenz, Madrigal, Akarna Therapeutics, BirdRock Bio, Blade Therapeutics, Conatus, DeuteRx, Exalenz, Galectin, Galmed, Genfit, Glympse. The remaining authors disclose no conflicts.
Funding Josep M. Llovet is supported by the European Commission (EC)/Horizon 2020 Program (HEPCAR, reference no. 667273-2); US Department of Defense (CA150272P3); an Accelerator Award (CRUCK, AECC, AIRC) (HUNTER, reference no. C9380/A26813), NCI Cancer Center Support Grant, National Cancer Institute; Tisch Cancer Institute (P30-CA196521); Samuel Waxman Cancer Research Foundation; Spanish National Health Institute (SAF2016-76390); and the Generalitat de Catalunya/AGAUR (SGR-1358). Agrin Moeini is supported by Spanish National Health Institute. Sara Torrecilla and Judit Peix are funded by Centro de Investigación Biomedica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd-ISCIII). Carla Montironi is a recipient of Josep Font grant. Carmen Andreu-Oller is supported by “la Caixa” INPhINIT Fellowship Grant (LCF/BQ/IN17/11620024). Roser Pinyol is supported by HEPCAR and AECC. Daniela Sia is supported by the Gilead Sciences Research Scholar Program in Liver Disease. Scott L. Friedman is supported by the National Institutes of Health Research project grant (R01,DK5662) and US Department of Defense (CA150272P3). Mathias Heikenwälder was supported by an ERC Consolidator grant (HepatoMetaboPath), the SFBTR 209, 1335 and SFBTR179. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 667273 and the Helmholtz future topic (Zukunftsthema) Immunology and Inflammation.
Author names in bold designate shared co-first authorship.