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

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  • Magdalena Stepien, International Agency for Research on Cancer (IARC-WHO), Lyon, France., France
  • Pekka Keski-Rahkonen, International Agency for Research on Cancer (IARC-WHO), Lyon, France., France
  • Agneta Kiss, International Agency for Research on Cancer (IARC-WHO), Lyon, France., France
  • Nivonirina Robinot, International Agency for Research on Cancer (IARC-WHO), Lyon, France., France
  • Talita Duarte-Salles, International Agency for Research on Cancer (IARC-WHO), Lyon, France., Institut Universitari d'Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Barcelona, Spain., France
  • Neil Murphy, International Agency for Research on Cancer (IARC-WHO), Lyon, France., France
  • Gabriel Perlemuter, Antoine-Béclère Hospital, INSERM UMRS U996 - Intestinal Microbiota, Macrophages and Liver Inflammation, DHU Hepatinov, Clamart, Université Paris-Sud, Paris-Saclay, Clamart, France
  • Vivian Viallon, International Agency for Research on Cancer (IARC-WHO), Lyon, France., France
  • Anne Tjønneland, Danish Cancer Society Research Center, The Danish Cancer Society, Copenhagen, Denmark
  • Agnetha Linn Rostgaard-Hansen, Danish Cancer Society Research Center, The Danish Cancer Society, Copenhagen, Denmark
  • Christina C Dahm
  • Kim Overvad
  • Marie-Christine Boutron-Ruault, CESP, Faculté de Médecine - Univ. Paris-Sud, Faculté de Médecine - UVSQ, INSERM, Université Paris-Saclay, Villejuif, France; Gustave Roussy, Villejuif, France., France
  • Francesca Romana Mancini, CESP, Faculté de Médecine - Univ. Paris-Sud, Faculté de Médecine - UVSQ, INSERM, Université Paris-Saclay, Villejuif, France; Gustave Roussy, Villejuif, France., Institut Gustave Roussy, F-94805, Villejuif, France
  • Yahya Mahamat-Saleh, Institut Gustave Roussy, Paris, France., CESP, Faculté de Médecine - Univ. Paris-Sud, Faculté de Médecine - UVSQ, INSERM, Université Paris-Saclay, Villejuif, France; Gustave Roussy, Villejuif, France., France
  • Krasimira Aleksandrova, German Institute of Human Nutrition, Germany
  • Rudolf Kaaks, German Cancer Research Center (DKFZ), Germany
  • Tilman Kühn, German Cancer Research Center (DKFZ), Germany
  • Antonia Trichopoulou, National and Kapodistrian University of Athens, Hellenic Health Foundation, Athens, Greece., Greece
  • Anna Karakatsani, “ATTIKON” University Hospital, Hellenic Health Foundation, Athens, Greece., Greece
  • Salvatore Panico, Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy., Italy
  • Rosario Tumino, Cancer Registry and Histopathology Department , Provincial Health Authority (ASP), Ragusa, Italy., Italy
  • Domenico Palli, Cancer Research and Prevention Institute – ISPO, Italy
  • Giovanna Tagliabue, Lombardy Cancer Registry Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Italy
  • Alessio Naccarati, Italian Institute for Genomic Medicine (IIGM/HuGeF), Torino, Italy., Italy
  • Roel C H Vermeulen, Univ Utrecht, Utrecht University, Utrecht University Medical Center, UMC Utrecht, Dept Hematol, Netherlands
  • H Bas Bueno-de-Mesquita, National Institute for Public Health and the Environment (RIVM), Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK., Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Pantai Valley, Kuala Lumpur, Malaysia., Netherlands
  • Elisabete Weiderpass, International Agency for Research on Cancer (IARC-WHO), Lyon, France., France
  • Guri Skeie, University of Tromsø, Tromsø, Norway
  • J Ramón Quirós, Public Health Directorate, Asturias, Spain., Spain
  • Eva Ardanaz, Navarra Public Health Institute, IdiSNA, Navarra Institute for Health Research, Pamplona, Spain., CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain
  • Olatz Mokoroa, Biodonostia Health Research Institute, CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain
  • Núria Sala, Medical Oncology, Catalan Institute of Oncology, IDIBELL., Spain
  • Maria-Jose Sánchez, Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs, Granada Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain., CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain
  • José María Huerta, Department of Epidemiology, Murcia Regional Health Authority, Murcia, Spain; Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain., CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain
  • Anna Winkvist, Univ Gothenburg, University of Gothenburg, Gothenburg Global Biodivers Ctr, Umeå University, Department of Public Health and Clinical Medicine, Nutritional Research, Sweden
  • Sophia Harlid, Umeå University, Sweden
  • Bodil Ohlsson, Department of Nephrology in Lund, Clinical Sciences Lund, Skåne University Hospital and Lund University, Lund, Sweden., Sweden
  • Klas Sjöberg, Department of Nephrology in Lund, Clinical Sciences Lund, Skåne University Hospital and Lund University, Lund, Sweden., Sweden
  • Julie A Schmidt, Nuffield Department of Population Health, University of Oxford, Oxford, UK., United Kingdom
  • Nick Wareham, Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom; Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom;, United Kingdom
  • Kay-Tee Khaw, Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom; Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom;, United Kingdom
  • Pietro Ferrari, International Agency for Research on Cancer (IARC-WHO), Lyon, France., France
  • Joseph A Rothwell, International Agency for Research on Cancer (IARC-WHO), Lyon, France., Institut Gustave Roussy, Villejuif, France., France
  • Marc Gunter, International Agency for Research on Cancer (IARC-WHO).
  • ,
  • Elio Riboli, Imperial Coll London, Imperial College London, Imperial Clin Trials Unit
  • ,
  • Augustin Scalbert, International Agency for Research on Cancer (IARC-WHO), Lyon, France., France
  • Mazda Jenab, International Agency for Research on Cancer (IARC-WHO), Lyon, France., France

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 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; 14 of which 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, 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. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalInternational Journal of Cancer
Volume148
Issue3
Pages (from-to)609-625
Number of pages17
ISSN0020-7136
DOIs
Publication statusPublished - Feb 2021

    Research areas

  • hepatocellular carcinoma, prospective observational cohort, untargeted metabolomics

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