The altered serum lipidome and its diagnostic potential for Non-Alcoholic Fatty Liver (NAFL)-associated hepatocellular carcinoma: Diagnosis of NAFLD-HCC utilising serum lipidomics
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- The altered serum lipidome and its diagnostic potential for Non-Alcoholic Fatty Liver (NAFL)-associated hepatocellular carcinoma
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Background: Non-alcoholic fatty liver disease (NAFLD) is affecting more people globally. Indeed, NAFLD is a spectrum of metabolic dysfunctions that can progress to hepatocellular carcinoma (NAFLD-HCC). This development can occur in a non-cirrhotic liver and thus, often lack clinical surveillance. The aim of this study was to develop non-invasive surveillance method for NAFLD-HCC. Methods: Using comprehensive ultra-high-performance liquid chromatography mass-spectrometry, we investigated 1,295 metabolites in serum from 249 patients. Area under the receiver operating characteristic curve was calculated for all detected metabolites and used to establish their diagnostic potential. Logistic regression analysis was used to establish the diagnostic score. Findings: We show that NAFLD-HCC is characterised by a complete rearrangement of the serum lipidome, which distinguishes NAFLD-HCC from non-cancerous individuals and other HCC patients. We used machine learning to build a diagnostic model for NAFLD-HCC. We quantified predictive metabolites and developed the NAFLD-HCC Diagnostic Score (NHDS), presenting superior diagnostic potential compared to alpha-fetoprotein (AFP). Patients’ metabolic landscapes show a progressive depletion in unsaturated fatty acids and acylcarnitines during transformation. Upregulation of fatty acid transporters in NAFLD-HCC tumours contribute to fatty acid depletion in the serum. Interpretation: NAFLD-HCC patients can be efficiently distinguished by serum metabolic alterations from the healthy population and from HCC patients related to other aetiologies (alcohol and viral hepatitis). Our model can be used for non-invasive surveillance of individuals with metabolic syndrome(s), allowing for early detection of NAFLD-HCC. Therefore, serum metabolomics may provide valuable insight to monitor patients at risk, including morbidly obese, diabetics, and NAFLD patients. Funding: The funding sources for this study had no role in study design, data collection, data analyses, interpretation or writing of the report as it is presented herein.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 103661 |
| Tidsskrift | EBioMedicine |
| Vol/bind | 73 |
| ISSN | 2352-3964 |
| DOI | |
| Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
We thank the participating patients and their families as well as clinical staff at all contributing centres. We thank the French Liver Biobanks network – INCa (BB-0033-00085) for the contribution of NAFLD-HCC samples (participating hospitals: Beaujon, Bordeaux, Grenoble, Henri-Mondor, Paris-SUD, and Rennes). We thank the section of Biostatistics at Department of Public Health, University of Copenhagen for statistical advice. The results are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga . We thank all funding sources: The laboratory of JBA is supported by the Novo Nordisk Foundation (14040, 0058419), Danish Cancer Society (R98-A6446, R167-A10784, R278-A16638), and the Danish Medical Research Council (4183-00118A, 1030-00070B). Data used for validation in this study provided by JMB was funded by the Spanish Ministry of Economy and Competitiveness and ’Instituto de Salud Carlos III’ grants (PI18/01075, Miguel Servet Programme CON14/00129 and CPII19/00008) co-financed by ’Fondo Europeo de Desarrollo Regional’ (FEDER); CIBERehd, Spain; IKERBASQUE, Basque foundation for Science, Spain; BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD); Department of Health of the Basque Country (2017111010), Euskadi RIS3 (2019222054, 2020333010); Department of Industry of the Basque Country (Elkartek: KK-2020/00008), AECC Scientific Foundation and European Commission Horizon 2020 program (ESCALON project no.: 825510). Similarly, MAJ was funded by grants from the Fondo Nacional De Ciencia y Tecnología de Chile (FONDECYT #1191145 to M.A.) and the Comisión Nacional de Investigación, Ciencia y Tecnología (CONICYT, AFB170005, CARE Chile UC).
Funding Information:
Conceptualization: ML, JBA. Data curation: ML, ASL, EZ, RJA, EE, MJP, MPS, FKK, MRG, MAJ, SKO, GEV, TD, CPO, BS, RIR, JMB, JBA. Formal Analysis: ML, EA, EZ, CA. Writing ? original draft: ML, JBA. All authors read and approved the manuscript. ML, JBA have verified the underlying data. We thank the participating patients and their families as well as clinical staff at all contributing centres. We thank the French Liver Biobanks network ? INCa (BB-0033-00085) for the contribution of NAFLD-HCC samples (participating hospitals: Beaujon, Bordeaux, Grenoble, Henri-Mondor, Paris-SUD, and Rennes). We thank the section of Biostatistics at Department of Public Health, University of Copenhagen for statistical advice. The results are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. We thank all funding sources: The laboratory of JBA is supported by the Novo Nordisk Foundation (14040, 0058419), Danish Cancer Society (R98-A6446, R167-A10784, R278-A16638), and the Danish Medical Research Council (4183-00118A, 1030-00070B). Data used for validation in this study provided by JMB was funded by the Spanish Ministry of Economy and Competitiveness and ?Instituto de Salud Carlos III? grants (PI18/01075, Miguel Servet Programme CON14/00129 and CPII19/00008) co-financed by ?Fondo Europeo de Desarrollo Regional? (FEDER); CIBERehd, Spain; IKERBASQUE, Basque foundation for Science, Spain; BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD); Department of Health of the Basque Country (2017111010), Euskadi RIS3 (2019222054, 2020333010); Department of Industry of the Basque Country (Elkartek: KK-2020/00008), AECC Scientific Foundation and European Commission Horizon 2020 program (ESCALON project no.: 825510). Similarly, MAJ was funded by grants from the Fondo Nacional De Ciencia y Tecnolog?a de Chile (FONDECYT #1191145 to M.A.) and the Comisi?n Nacional de Investigaci?n, Ciencia y Tecnolog?a (CONICYT, AFB170005, CARE Chile UC). The data used in this study will according to IRBs be made available upon request if the requestor has an approved protocol.
Publisher Copyright:
© 2021 The Author(s)
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