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Pre-diagnostic copper and zinc biomarkers and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort

Stepien M 1 , Jenab M 1 , Freisling H 1 , Becker NP 1 , Czuban M 1 , Tjønneland A 2 Show all authors , Olsen A 2 , Overvad K 3 , Boutron-Ruault MC 4 , Mancini FR 4 , Savoye I 4 , Katzke V 5 , Kühn T 5 , Boeing H 6 , Iqbal K 6 , Trichopoulou A 7 , Bamia C 7 , Orfanos P 7 , Palli D 8 , Sieri S 9 , Tumino R 10 , Naccarati A 11 , Panico S 12 , Bueno-de-Mesquita HBA 13 , Peeters PH 14 , Weiderpass E 15 , Merino S 16 , Jakszyn P 17 , Sanchez MJ 18 , Dorronsoro M 19 , Huerta JM 19 , Barricarte A 19 , Boden S 20 , van Guelpen B 20 , Wareham N 21 , Khaw KT 22 , Bradbury KE 23 , Cross AJ 24 , Schomburg L 1 , Hughes DJ 25

Affiliations 

  • 1 Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), 39372 Lyon Cedex 08, France, 1Institute for Experimental Endocrinology, Charité - Universitatsmedizin Berlin, 13353 Berlin, Germany
  • 2 Diet, Genes and Environment Unit, Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark
  • 3 Department of Public Health, Aarhus University, DK-8000 Aarhus C, Denmark
  • 4 Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, F-94805 Villejuif, France
  • 5 Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany
  • 6 Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke, 14558 Nuthetal, Germany
  • 7 Hellenic Health Foundation, 115 27 Athens, Greece
  • 8 Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute - ISPO, 50139 Florence, Italy
  • 9 Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
  • 10 Cancer Registry and Histopathology Unit, 'Civic - M.P.Arezzo' Hospital, ASP 97100 Ragusa, Italy
  • 11 Molecular and Genetic Epidemiology Unit, Human Genetics Foundation (HuGeF), 10095 Turin, Italy
  • 12 Dipartamento di Medicina Clinicae Chirurgias, Federico II University, 80131 Naples, Italy
  • 13 Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands
  • 14 Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands
  • 15 Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, N-9037 Tromsø, Norway
  • 16 Public Health Directorate, CP 33006 Oviedo, Asturias, Spain
  • 17 Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology, 08908 Barcelona, Spain
  • 18 Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs.GRANADA. Hospitales Universitarios de Granada/Universidad de Granada, 18080 Granada, Spain
  • 19 CIBER de Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
  • 20 Department of Radiation Sciences, Oncology, Umeå University, SE-901 85 Umeå, Sweden
  • 21 MRC Epidemiology Unit, University of Cambridge, CB2 0QQ Cambridge, UK
  • 22 Clinical Gerontology, School of Clinical Medicine, University of Cambridge, CB2 0QQ Cambridge, UK
  • 23 Cancer Epidemiology Unit, Nuffield Department of Population Health University of Oxford, OX3 7LF Oxford, UK
  • 24 Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, W2 1NY London, UK
  • 25 Department of Physiology & Centre for Systems Medicine, Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland
Carcinogenesis, 2017 Jul 01;38(7):699-707.
PMID: 28575311 DOI: 10.1093/carcin/bgx051

Abstract

Adequate intake of copper and zinc, two essential micronutrients, are important for antioxidant functions. Their imbalance may have implications for development of diseases like colorectal cancer (CRC), where oxidative stress is thought to be etiologically involved. As evidence from prospective epidemiologic studies is lacking, we conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to investigate the association between circulating levels of copper and zinc, and their calculated ratio, with risk of CRC development. Copper and zinc levels were measured by reflection X-ray fluorescence spectrometer in 966 cases and 966 matched controls. Multivariable adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression and are presented for the fifth versus first quintile. Higher circulating concentration of copper was associated with a raised CRC risk (OR = 1.50; 95% CI: 1.06, 2.13; P-trend = 0.02) whereas an inverse association with cancer risk was observed for higher zinc levels (OR = 0.65; 95% CI: 0.43, 0.97; P-trend = 0.07). Consequently, the ratio of copper/zinc was positively associated with CRC (OR = 1.70; 95% CI: 1.20, 2.40; P-trend = 0.0005). In subgroup analyses by follow-up time, the associations remained statistically significant only in those diagnosed within 2 years of blood collection. In conclusion, these data suggest that copper or copper levels in relation to zinc (copper to zinc ratio) become imbalanced in the process of CRC development. Mechanistic studies into the underlying mechanisms of regulation and action are required to further examine a possible role for higher copper and copper/zinc ratio levels in CRC development and progression.

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