Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer

Authors

  • Krasimira Aleksandrova,

    Corresponding author
    1. Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
    • Address reprint requests to: Krasimira Aleksandrova, Ph.D., M.P.H., Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert Allee 114-116, 14558 Nuthetal, Germany. E-mail: krasimira.aleksandrova@dife.de; fax: +49 33200 88 2 721.

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  • Heiner Boeing,

    1. Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
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  • Ute Nöthlings,

    1. Institute of Epidemiology, Christian-Albrechts University of Kiel, Kiel, Germany
    2. Nutritional Epidemiology Unit, Department of Nutritional and Food Science, Institut für Ernährungs- und Lebensmittelwissenschaften, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
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  • Mazda Jenab,

    1. International Agency for Research on Cancer (IARC/World Health Organization [WHO]), Lyon, France
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  • Veronika Fedirko,

    1. International Agency for Research on Cancer (IARC/World Health Organization [WHO]), Lyon, France
    2. Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA
    3. Winship Cancer Institute, Emory University, Atlanta, GA
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  • Rudolf Kaaks,

    1. Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
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  • Annekatrin Lukanova,

    1. Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
    2. Department of Medical Biosciences/Pathology, University of Umeå, Umeå, Sweden
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  • Antonia Trichopoulou,

    1. WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece
    2. Hellenic Health Foundation, Athens, Greece
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  • Dimitrios Trichopoulos,

    1. Hellenic Health Foundation, Athens, Greece
    2. Department of Epidemiology, Harvard School of Public Health, Boston, MA
    3. Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece
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  • Paolo Boffetta,

    1. Institute for Translational Epidemiology, Mount Sinai School of Medicine, New York, NY
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  • Elisabeth Trepo,

    1. Centre de Bioloqie Republique, Lyon, France
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  • Sabine Westhpal,

    1. Institute of Clinical Chemistry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
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  • Talita Duarte-Salles,

    1. International Agency for Research on Cancer (IARC/World Health Organization [WHO]), Lyon, France
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  • Magdalena Stepien,

    1. International Agency for Research on Cancer (IARC/World Health Organization [WHO]), Lyon, France
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  • Kim Overvad,

    1. Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark
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  • Anne Tjønneland,

    1. Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark
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  • Jytte Halkjær,

    1. Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark
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  • Marie-Christine Boutron-Ruault,

    1. Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, Villejuif, France
    2. Université Paris Sud, Villejuif, France
    3. Institut Gustave Roussy, Villejuif, France
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  • Laure Dossus,

    1. Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, Villejuif, France
    2. Université Paris Sud, Villejuif, France
    3. Institut Gustave Roussy, Villejuif, France
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  • Antoine Racine,

    1. Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, Villejuif, France
    2. Université Paris Sud, Villejuif, France
    3. Institut Gustave Roussy, Villejuif, France
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  • Pagona Lagiou,

    1. WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece
    2. Department of Epidemiology, Harvard School of Public Health, Boston, MA
    3. Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece
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  • Christina Bamia,

    1. WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece
    2. Hellenic Health Foundation, Athens, Greece
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  • Vassiliki Benetou,

    1. WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece
    2. Hellenic Health Foundation, Athens, Greece
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  • Claudia Agnoli,

    1. Nutritional Epidemiology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
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  • Domenico Palli,

    1. Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy
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  • Salvatore Panico,

    1. Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy
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  • Rosario Tumino,

    1. Cancer Registry and Histopathology Unit, “M.P. Arezzo” Hospital, Ragusa, Italy
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  • Paolo Vineis,

    1. HuGeF Foundation, Turin, Italy
    2. Division of Epidemiology, Public Health and Primary Care, Imperial College, London, UK
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  • Bas Bueno-de-Mesquita,

    1. National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands
    2. Department of Gastroenterology and Hepatology, University Medical Center, Utrecht, the Netherlands
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  • Petra H. Peeters,

    1. Division of Epidemiology, Public Health and Primary Care, Imperial College, London, UK
    2. Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, the Netherlands
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  • Inger Torhild Gram,

    1. Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway
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  • Eiliv Lund,

    1. Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway
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  • Elisabete Weiderpass,

    1. Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway
    2. Department of Research, Cancer Registry of Norway, Oslo, Norway
    3. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
    4. Samfundet Folkhälsan, Helsinki, Finland
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  • J. Ramón Quirós,

    1. Public Health Directorate, Asturias, Spain
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  • Antonio Agudo,

    1. Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, Barcelona, Spain
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  • María-José Sánchez,

    1. Andalusian School of Public Health, Granada, Spain
    2. Consortium for Biomedical Research in Epidemiology and Public Health (CIBER Epidemiología y Salud Pública-CIBERESP), Madrid, Spain
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  • Diana Gavrila,

    1. Servicio de Epidemiología, Department of Epidemiology, Consejería de Sanidad y Politica Social, Murcia, Spain
    2. Navarre Public Health Institute, Pamplona, Spain
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  • Aurelio Barricarte,

    1. Consortium for Biomedical Research in Epidemiology and Public Health (CIBER Epidemiología y Salud Pública-CIBERESP), Madrid, Spain
    2. Navarre Public Health Institute, Pamplona, Spain
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  • Miren Dorronsoro,

    1. Public Health Direction, Basque Regional Health Department and BioDonostia Research Institute-CIBERESP, San Sebastian, Spain
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  • Bodil Ohlsson,

    1. Department of Clinical Sciences, Division of Internal Medicine, Skåne University Hospital, Lund University, Malmö, Sweden
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  • Björn Lindkvist,

    1. Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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  • Anders Johansson,

    1. Department of Odontology/Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
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  • Malin Sund,

    1. Department of Surgical and Perioperative Sciences, Surgery and Public Health, Nutrition Research, Umea University, Umea, Sweden
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  • Kay-Tee Khaw,

    1. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
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  • Nicholas Wareham,

    1. MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK
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  • Ruth C. Travis,

    1. Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
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  • Elio Riboli,

    1. Division of Epidemiology, Public Health and Primary Care, Imperial College, London, UK
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  • Tobias Pischon

    1. Molecular Epidemiology Group, Max Delbrück Center for Molecular Medicine Berlin-Buch, Berlin-Buch, Germany
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  • Potential conflict of interest: Nothing to report.

  • This work was supported by the Federal Ministry of Education and Research, the German Research Foundation, a grant from the German Research Foundation (PI 419/3-1; Germany), and the French National Cancer Institute (L'Institut National du Cancer; INCA; grant no.: 2009-139). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by the Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM; France), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, the Hellenic Health Foundation, the Stavros Niarchos Foundation and the Hellenic Ministry of Health and Social Solidarity (Greece), the Italian Association for Research on Cancer (AIRC), the National Research Council, AIRE-ONLUS Ragusa, AVIS Ragusa, Sicilian Government (Italy), the Dutch Ministry of Public Health, Welfare and Sports (VWS), the Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), the World Cancer Research Fund (WCRF), Statistics Netherlands (the Netherlands), the European Research Council (ERC; grant no.: ERC-2009-AdG 232997), Nordforsk, the Nordic Center of Excellence Programme on Food, Nutrition and Health (Norway), the Health Research Fund (FIS), Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RETIC (RD06/0020; Spain), the Swedish Cancer Society, the Swedish Scientific Council, the Regional Government of Skåne and Västerbotten (Sweden), Cancer Research UK, the Medical Research Council, the Stroke Association, the British Heart Foundation, the Department of Health, the Food Standards Agency, and Wellcome Trust (UK).

  • See Editorial on Page 779

Abstract

Obesity and associated metabolic disorders have been implicated in liver carcinogenesis; however, there are little data on the role of obesity-related biomarkers on liver cancer risk. We studied prospectively the association of inflammatory and metabolic biomarkers with risks of hepatocellular carcinoma (HCC), intrahepatic bile duct (IBD), and gallbladder and biliary tract cancers outside of the liver (GBTC) in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Over an average of 7.7 years, 296 participants developed HCC (n = 125), GBTC (n = 137), or IBD (n = 34). Using risk-set sampling, controls were selected in a 2:1 ratio and matched for recruitment center, age, sex, fasting status, and time of blood collection. Baseline serum concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), C-peptide, total high-molecular-weight (HMW) adiponectin, leptin, fetuin-a, and glutamatdehydrogenase (GLDH) were measured, and incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. After adjustment for lifestyle factors, diabetes, hepatitis infection, and adiposity measures, higher concentrations of CRP, IL-6, C-peptide, and non-HMW adiponectin were associated with higher risk of HCC (IRR per doubling of concentrations = 1.22; 95% CI = 1.02-1.46; P = 0.03; 1.90; 95% CI = 1.30-2.77; P = 0.001; 2.25; 95% CI = 1.43-3.54; P = 0.0005; and 2.09; 95% CI = 1.19-3.67; P = 0.01, respectively). CRP was associated also with risk of GBTC (IRR = 1.22; 95% CI = 1.05-1.42; P = 0.01). GLDH was associated with risks of HCC (IRR = 1.62; 95% CI = 1.25-2.11; P = 0.0003) and IBD (IRR = 10.5; 95% CI = 2.20-50.90; P = 0.003). The continuous net reclassification index was 0.63 for CRP, IL-6, C-peptide, and non-HMW adiponectin and 0.46 for GLDH, indicating good predictive ability of these biomarkers. Conclusion: Elevated levels of biomarkers of inflammation and hyperinsulinemia are associated with a higher risk of HCC, independent of obesity and established liver cancer risk factors. (Hepatology 2014;60:858–871)

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