Circulating copper and zinc levels and risk of hepatobiliary cancers in Europeans.
BACKGROUND
Copper and zinc are essential micronutrients and cofactors of many enzymatic reactions that may be involved in liver-cancer development. We aimed to assess pre-diagnostic circulating levels of copper, zinc and their ratio (Cu/Zn) in relation to hepatocellular carcinoma (HCC), intrahepatic bile duct (IHBD) and gall bladder and biliary tract (GBTC) cancers.


METHODS
A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition cohort. Serum zinc and copper levels were measured in baseline blood samples by total reflection X-ray fluorescence in cancer cases (HCC n=106, IHDB n=34, GBTC n=96) and their matched controls (1:1). The Cu/Zn ratio, an indicator of the balance between the micronutrients, was computed. Multivariable adjusted odds ratios and 95% confidence intervals (OR; 95% CI) were used to estimate cancer risk.


RESULTS
For HCC, the highest vs lowest tertile showed a strong inverse association for zinc (OR=0.36; 95% CI: 0.13-0.98, Ptrend=0.0123), but no association for copper (OR=1.06; 95% CI: 0.45-2.46, Ptrend=0.8878) in multivariable models. The calculated Cu/Zn ratio showed a positive association for HCC (OR=4.63; 95% CI: 1.41-15.27, Ptrend=0.0135). For IHBC and GBTC, no significant associations were observed.


CONCLUSIONS
Zinc may have a role in preventing liver-cancer development, but this finding requires further investigation in other settings.
Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), 39372 Lyon Cedex 08, France.
Magdalena
M
Stepien
Department of Physiology and Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
David J
DJ
Hughes
Institut for Experimental Endocrinology, Charité-Universitatsmedizin Berlin, 13353 Berlin, Germany.
Sandra
S
Hybsier
Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens 115 27, Germany.|Hellenic Health Foundation, Athens 115 27, Germany.
Christina
C
Bamia
Diet, Genes and Environment Unit, Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark.
Anne
A
Tjønneland
Department of Public Health, Aarhus University, DK-8000 Aarhus C, Denmark.
Kim
K
Overvad
Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, F-94805 Villejuif, France.|Institut Gustave Roussy F-94805 Villejuif, France.
Aurélie
A
Affret
Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, F-94805 Villejuif, France.|Institut Gustave Roussy F-94805 Villejuif, France.
Mathilde
M
His
Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, F-94805 Villejuif, France.|Institut Gustave Roussy F-94805 Villejuif, France.
Marie-Christine
MC
Boutron-Ruault
Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany.
Verena
V
Katzke
Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany.
Tilman
T
Kühn
Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke, 14558 Nuthetal, Germany.
Krasimira
K
Aleksandrova
Hellenic Health Foundation, Athens 115 27, Germany.|WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology, Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens 115 27, Germany.|Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute-ISPO, 50139 Florence, Italy.
Antonia
A
Trichopoulou
Hellenic Health Foundation, Athens 115 27, Germany.|WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology, Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens 115 27, Germany.
Pagona
P
Lagiou
Hellenic Health Foundation, Athens 115 27, Germany.|WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology, Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens 115 27, Germany.
Phlippos
P
Orfanos
Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute-ISPO, 50139 Florence, Italy.
Domenico
D
Palli
Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Sabina
S
Sieri
Cancer Registry and Histopathology Unit, 'Civic-M.P.Arezzo' Hospital, ASP 97100 Ragusa, Italy.
Rosario
R
Tumino
Unit of Epidemiology, Regional Health Service ASL TO3, Grugliasco, 10095 Turin, Italy.|Unit of Cancer Epidemiology, Department of Medical Sciences, University of Turin, 10126 Turin, Italy.
Fulvio
F
Ricceri
Dipartamento di Medicina Clinicae Chirurgias, Federico II University, 80131 Naples, Italy.
Salvatore
S
Panico
Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands.|Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, W2 1NY London, UK.|Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
H B As
HB
Bueno-de-Mesquita
Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands.|Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, The School of Public Health, Imperial College, W2 1NY London, UK.
Petra H
PH
Peeters
Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, N-9037 Tromsø, Norway.|Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, NO-0304 Oslo, Norway.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 Stockholm, Sweden.|Genetic Epidemiology Group, Folkhälsan Research Center, 00250 Helsinki, Finland.
Elisabete
E
Weiderpass
Department of Functional Biology, Faculty of Medicine, University of Oviedo, CP 33006 Oviedo, Asturias, Spain.
Cristina
C
Lasheras
Unit of Nutrition and Cancer.Cancer Epidemiology Research Programme, Catalan Institute of Oncology (ICO), 08908 Barcelona, Spain.
Catalina
C
Bonet Bonet
Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, 18080 Granada, Spain.|Consortium for Biomedical Research in Epidemiology and Public Health (CIBER- CIBERESP), 28029 Madrid, Spain.
Elena
E
Molina-Portillo
Public Health Direction and Biodonostia Research Institute-Ciberesp Basque Regional Health Department, s/n 20014 San Sebastian, Spain.
Miren
M
Dorronsoro
Consortium for Biomedical Research in Epidemiology and Public Health (CIBER- CIBERESP), 28029 Madrid, Spain.|Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, E-30008 Murcia, Spain.
José María
JM
Huerta
Consortium for Biomedical Research in Epidemiology and Public Health (CIBER- CIBERESP), 28029 Madrid, Spain.|Navarra Public Health Institute, Pamplona, Spain.|Navarra Institute for Health Research (IdiSNA), 31003 Pamplona, Spain.
Aurelio
A
Barricarte
Department of Internal Medicine, Skåne University Hospital, Lund University, SE-205 92 Malmö, Sweden.
Bodil
B
Ohlsson
Department of Gastroenterology and Nutrition, Skåne University Hospital, Lund University, SE-205 92 Malmö, Sweden.
Klas
K
Sjöberg
Department of Public Health and Medicine, Umeå University, SE-901 85 Umeå, Sweden.
Mårten
M
Werner
Department of Public Health and Clinical Medicine and Institute of Odontology Umeå University, SE-901 85 Umeå, Sweden.
Dmitry
D
Shungin
MRC Epidemiology Unit, University of Cambridge, CB2 0QQ Cambridge, UK.
Nick
N
Wareham
Clinical Gerontology, School of Clinical Medicine, University of Cambridge, CB2 0QQ Cambridge, UK.
Kay-Tee
KT
Khaw
Cancer Epidemiology Unit, Nuffield Department of Population Health University of Oxford, OX3 7LF Oxford, UK.
Ruth C
RC
Travis
Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), 39372 Lyon Cedex 08, France.
Heinz
H
Freisling
Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, W2 1NY London, UK.
Amanda J
AJ
Cross
Institut for Experimental Endocrinology, Charité-Universitatsmedizin Berlin, 13353 Berlin, Germany.
Lutz
L
Schomburg
Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), 39372 Lyon Cedex 08, France.
Mazda
M
Jenab
D000368:Aged; D001661:Biliary Tract Neoplasms / Q000453:epidemiology*; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology*; D016022:Case-Control Studies; D003300:Copper / Q000097:blood*; D005060:Europe / Q000453:epidemiology; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000453:epidemiology*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D015032:Zinc / Q000097:blood*
D003300:Copper; D015032:Zinc