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Metabolic perturbations prior to hepatocellular carcinoma diagnosis: Findings from a prospective observational cohort study

Stepien M 1 , Keski-Rahkonen P 1 , Kiss A 1 , Robinot N 1 , Duarte-Salles T 1 , Murphy N 1 Show all authors , Perlemuter G 2 , Viallon V 1 , Tjønneland A 3 , Rostgaard-Hansen AL 3 , Dahm CC 4 , Overvad K 4 , Boutron-Ruault MC 5 , Mancini FR 5 , Mahamat-Saleh Y 5 , Aleksandrova K 6 , Kaaks R 7 , Kühn T 7 , Trichopoulou A 8 , Karakatsani A 8 , Panico S 9 , Tumino R 10 , Palli D 11 , Tagliabue G 12 , Naccarati A 13 , Vermeulen RCH 14 , Bueno-de-Mesquita HB 15 , Weiderpass E 1 , Skeie G 16 , Ramón Quirós J 17 , Ardanaz E 18 , Mokoroa O 19 , Sala N 20 , Sánchez MJ 19 , Huerta JM 19 , Winkvist A 21 , Harlid S 22 , Ohlsson B 23 , Sjöberg K 24 , Schmidt JA 25 , Wareham N 26 , Khaw KT 27 , Ferrari P 1 , Rothwell JA 1 , Gunter M 1 , Riboli E 28 , Scalbert A 1 , Jenab M 1

Affiliations 

  • 1 Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
  • 2 INSERM UMRS U996 - Intestinal Microbiota, Macrophages and Liver Inflammation, Clamart, France
  • 3 Diet, Genes and Environment Unit, Danish Cancer Society Research Center, Copenhagen, Denmark
  • 4 Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark
  • 5 CESP, Faculté de médecine-Université Paris-Sud, Faculté de médecine-UVSQ, INSERM, Université Paris-Saclay, Villejuif, France
  • 6 Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Germany
  • 7 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 8 Hellenic Health Foundation, Athens, Greece
  • 9 Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy
  • 10 Cancer Registry and Histopathology Department, Provincial Health Authority (ASP) Ragusa, Ragusa, Italy
  • 11 Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy
  • 12 Lombardy Cancer Registry Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
  • 13 Molecular and Genetic Epidemiology Unit, Italian Institute for Genomic Medicine (IIGM) Torino, Torino, Italy
  • 14 Institute of Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
  • 15 Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
  • 16 Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway
  • 17 Public Health Directorate, Asturias, Spain
  • 18 Navarra Public Health Institute, Pamplona, Spain
  • 19 CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain
  • 20 Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program and Translational Research Laboratory, Catalan Institute of Oncology (IDIBELL), Barcelona, Spain
  • 21 The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
  • 22 Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
  • 23 Skåne University Hospital, Department of Internal Medicine, Lund University, Malmö, Sweden
  • 24 Skåne University Hospital, Department of Gastroenterology and Nutrition, Lund University, Malmö, Sweden
  • 25 Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
  • 26 MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
  • 27 University of Cambridge, School of Clinical Medicine, Clinical Gerontology Unit, Addenbrooke's Hospital, Cambridge, UK
  • 28 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
Int J Cancer, 2021 Feb 01;148(3):609-625.
PMID: 32734650 DOI: 10.1002/ijc.33236

Abstract

Hepatocellular carcinoma (HCC) development entails changes in liver metabolism. Current knowledge on metabolic perturbations in HCC is derived mostly from case-control designs, with sparse information from prospective cohorts. Our objective was to apply comprehensive metabolite profiling to detect metabolites whose serum concentrations are associated with HCC development, using biological samples from within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (>520 000 participants), where we identified 129 HCC cases matched 1:1 to controls. We conducted high-resolution untargeted liquid chromatography-mass spectrometry-based metabolomics on serum samples collected at recruitment prior to cancer diagnosis. Multivariable conditional logistic regression was applied controlling for dietary habits, alcohol consumption, smoking, body size, hepatitis infection and liver dysfunction. Corrections for multiple comparisons were applied. Of 9206 molecular features detected, 220 discriminated HCC cases from controls. Detailed feature annotation revealed 92 metabolites associated with HCC risk, of which 14 were unambiguously identified using pure reference standards. Positive HCC-risk associations were observed for N1-acetylspermidine, isatin, p-hydroxyphenyllactic acid, tyrosine, sphingosine, l,l-cyclo(leucylprolyl), glycochenodeoxycholic acid, glycocholic acid and 7-methylguanine. Inverse risk associations were observed for retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, γ-carboxyethyl hydroxychroman and creatine. Discernible differences for these metabolites were observed between cases and controls up to 10 years prior to diagnosis. Our observations highlight the diversity of metabolic perturbations involved in HCC development and replicate previous observations (metabolism of bile acids, amino acids and phospholipids) made in Asian and Scandinavian populations. These findings emphasize the role of metabolic pathways associated with steroid metabolism and immunity and specific dietary and environmental exposures in HCC development.

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