title: Alteration of amino acid and biogenic amine metabolism in hepatobiliary cancers: Findings from a prospective cohort study.
abstract: Perturbations in levels of amino acids (AA) and their derivatives are observed in hepatocellular carcinoma (HCC). Yet, it is unclear whether these alterations precede or are a consequence of the disease, nor whether they pertain to anatomically related cancers of the intrahepatic bile duct (IHBC), and gallbladder and extrahepatic biliary tract (GBTC). Circulating standard AA, biogenic amines and hexoses were measured (Biocrates AbsoluteIDQ-p180Kit) in a case-control study nested within a large prospective cohort (147 HCC, 43 IHBC and 134 GBTC cases). Liver function and hepatitis status biomarkers were determined separately. Multivariable conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (OR; 95%CI) for log-transformed standardised (mean = 0, SD = 1) serum metabolite levels and relevant ratios in relation to HCC, IHBC or GBTC risk. Fourteen metabolites were significantly associated with HCC risk, of which seven metabolites and four ratios were the strongest predictors in continuous models. Leucine, lysine, glutamine and the ratio of branched chain to aromatic AA (Fischer's ratio) were inversely, while phenylalanine, tyrosine and their ratio, glutamate, glutamate/glutamine ratio, kynurenine and its ratio to tryptophan were positively associated with HCC risk. Confounding by hepatitis status and liver enzyme levels was observed. For the other cancers no significant associations were observed. In conclusion, imbalances of specific AA and biogenic amines may be involved in HCC development.
authors.affiliation: Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
authors.forename: Magdalena
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authors.lastname: Stepien
authors.affiliation: Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
authors.forename: Talita
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authors.lastname: Duarte-Salles
authors.affiliation: Department of Epidemiology, Rollins School of Public Health, Winship Cancer Institute, Emory University, Atlanta, GA.
authors.forename: Veronika
authors.initials: V
authors.lastname: Fedirko
authors.affiliation: Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Floegel
authors.affiliation: Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
authors.forename: Dinesh Kumar
authors.initials: DK
authors.lastname: Barupal
authors.affiliation: Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
authors.forename: Sabina
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authors.lastname: Rinaldi
authors.affiliation: Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Achaintre
authors.affiliation: Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
authors.forename: Nada
authors.initials: N
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authors.affiliation: Diet, Genes and Enviroment Unit, Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Tjønneland
authors.affiliation: Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark.
authors.forename: Kim
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authors.affiliation: Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, Villejuif, F-94805, France.|Université Paris Sud, UMRS 1018, Villejuif, F-94805, France.|Institut Gustave Roussy, Villejuif, F-94805, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Bastide
authors.affiliation: Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, Villejuif, F-94805, France.|Université Paris Sud, UMRS 1018, Villejuif, F-94805, France.|Institut Gustave Roussy, Villejuif, F-94805, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Boutron-Ruault
authors.affiliation: Human Genetics Foundation (HuGeF), Torino, Italy.
authors.forename: Gianluca
authors.initials: G
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authors.affiliation: Department of Cancer Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
authors.forename: Tilman
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authors.affiliation: Department of Cancer Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
authors.forename: Rudolf
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authors.affiliation: Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany.
authors.forename: Krasimira
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authors.lastname: Aleksandrova
authors.affiliation: Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany.
authors.forename: Heiner
authors.initials: H
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authors.affiliation: Hellenic Health Foundation, Athens, Greece.|Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece.
authors.forename: Antonia
authors.initials: A
authors.lastname: Trichopoulou
authors.affiliation: Hellenic Health Foundation, Athens, Greece.|Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Bamia
authors.affiliation: Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece.|Department of Epidemiology, Harvard School of Public Health, Boston, MA.
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authors.initials: P
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authors.affiliation: Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute-ISPO, Florence, Italy.
authors.forename: Calogero
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authors.affiliation: Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy.
authors.forename: Claudia
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authors.affiliation: Dipartamento Di Medicina Clinicae Chirurgias, Federico II University, Naples, Italy.
authors.forename: Salvatore
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authors.affiliation: Cancer Registry and Histopathology Unit, "Civic-M.P. Arezzo" Hospital, ASP Ragusa, Italy.
authors.forename: Rosario
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authors.affiliation: Molecular and Genetic Epidemiology Unit, HuGeF, Human Genetics Foundation, Torino, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Naccarati
authors.affiliation: Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.|Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands.|Department of Epidemiology and Biostatistics, the School of Public Health, Imperial College London, London, United Kingdom.|Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: H B As
authors.initials: HB
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authors.affiliation: Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands.
authors.forename: Petra H
authors.initials: PH
authors.lastname: Peeters
authors.affiliation: Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, the Arctic University of Norway, Tromsø, Norway.|Department of Research, Cancer Registry of Norway, Oslo, Norway.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Samfundet Folkhälsan, Helsinki, Finland.
authors.forename: Elisabete
authors.initials: E
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authors.initials: JR
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authors.affiliation: Escuela Andaluza De Salud Pública, Instituto De Investigación Biosanitaria Ibs, GRANADA, Hospitales Universitarios De Granada/Universidad De Granada, Granada, Spain.|Consortium for Biomedical Research in Epidemiology and Public Health (CIBER- CIBERESP), Spain.
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authors.initials: MJ
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authors.affiliation: Consortium for Biomedical Research in Epidemiology and Public Health (CIBER- CIBERESP), Spain.|Department of Epidemiology, Regional Health Council, Murcia, Spain.|IMIB-Arrixaca, Murcia, Spain.
authors.forename: Diana
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authors.affiliation: Consortium for Biomedical Research in Epidemiology and Public Health (CIBER- CIBERESP), Spain.|Navarre Public Health Institute, Pamplona, Spain.
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authors.affiliation: Department of Clinical Sciences, Division of Internal Medicine, Skåne University Hospital Malmö, Sweden.
authors.forename: Bodil
authors.initials: B
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authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.|Department of Gastroenterology and Nutrition, Skåne University Hospital, Malmö, Sweden.
authors.forename: Klas
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authors.affiliation: Department of Public Health and Clinical Medicine, Umeå University, Umea, Sweden.
authors.forename: Mårten
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authors.affiliation: Department of Surgical and Perioperative Sciences, Umeå University, Umea, Sweden.
authors.forename: Malin
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authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
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authors.forename: Kay-Tee
authors.initials: KT
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authors.affiliation: Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
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authors.initials: RC
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authors.affiliation: Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
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authors.initials: JA
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authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College, London, United Kingdom.
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authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College, London, United Kingdom.
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authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College, London, United Kingdom.
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authors.affiliation: Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
authors.forename: Isabelle
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authors.affiliation: Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
authors.forename: Augustin
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mesh_terms: D000368:Aged; D000596:Amino Acids / Q000378:metabolism*; D019540:Area Under Curve; D001650:Bile Duct Neoplasms / Q000378:metabolism*; D017734:Bile Ducts, Extrahepatic / Q000378:metabolism / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism / Q000473:pathology; D001679:Biogenic Amines / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005706:Gallbladder Neoplasms / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011446:Prospective Studies; D012372:ROC Curve
chemical_list: D000596:Amino Acids; D001679:Biogenic Amines
keywords: amino acids; biliary tract cancers; hepatocellular carcinoma; prospective cohort; targeted metabolomics