http://www.diva-portal.org This is the published version of a paper published in International Journal of Cancer. Citation for the original published paper (version of record): Murphy, N., Achaintre, D., Zamora-Ros, R., Jenab, M., Boutron-Ruault, M-C. et al. (2018) A prospective evaluation of plasma polyphenol levels and colon cancer risk International Journal of Cancer, 143(7): 1620-1631 https://doi.org/10.1002/ijc.31563 Access to the published version may require subscription. N.B. When citing this work, cite the original published paper. Permanent link to this version: http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-151155 IJC International Journal of Cancer A prospective evaluation of plasma polyphenol levels and colon cancer risk Neil Murphy 1, David Achaintre1, Raul Zamora-Ros 2, Mazda Jenab1, Marie-Christine Boutron-Ruault3, Franck Carbonnel3,4, Isabelle Savoye3,5, Rudolf Kaaks6, Tilman Kuhn€ 6, Heiner Boeing7, Krasimira Aleksandrova8, Anne Tjønneland9, Cecilie Kyrø 9, Kim Overvad10, J. Ramon Quiros 11, Maria-Jose Sanchez 12,13, Jone M. Altzibar13,14, Jose Marıa Huerta13,15, Aurelio Barricarte13,16,17, Kay-Tee Khaw18, Kathryn E. Bradbury 19, Aurora Perez-Cornago 19, Antonia Trichopoulou20, Anna Karakatsani20,21, Eleni Peppa20, Domenico Palli 22, Sara Grioni23, Rosario Tumino24, Carlotta Sacerdote 25, Salvatore Panico26, H. B(as) Bueno-de-Mesquita27,28,29,30, Petra H. Peeters31,32, Martin Rutega˚rd33, Ingegerd Johansson34, Heinz Freisling1, Hwayoung Noh1, Amanda J. Cross29, Paolo Vineis32, Kostas Tsilidis29,35, Marc J. Gunter1 and Augustin Scalbert1 1 Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France 2 Unit of Nutrition and Cancer, Cancer Epidemiology Research Programme, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain 3 CESP, INSERM U1018, Univ. Paris-Sud, UVSQ, Universite Paris-Saclay, Villejuif Cedex, France 4 Universite Paris Sud and Gastroenterology Unit, Hopitaux^ Universitaires Paris Sud, CHU de Bic^etre, AP-HP, Le Kremlin Bic^etre, France 5 Gustave Roussy, Espace Maurice Tubiana, Villejuif Cedex, France 6 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany 7 Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrucke,€ Germany 8 Department of Epidemiology, Nutrition, Immunity and Metabolism Start-up Lab, Potsdam-Rehbrucke,€ Germany 9 Danish Cancer Society Research Center, Copenhagen, Denmark 10 Cancer Epidemiology Department of Public Health, Aarhus University, Aarhus, Denmark 11 Public Health Directorate, Asturias, Spain 12 Escuela Andaluza de Salud Publica. Instituto de Investigacion Biosanitaria ibs.GRANADA. Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain 13 CIBER de Epidemiologıa y Salud Publica (CIBERESP), Madrid, Spain 14 Osakidetza/Basque Health Service, Breast Cancer Screening Program, Bilbao, Spain 15 Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain Key words: colon cancer, polyphenols, biomarkers, EPIC, nested case–control study Additional Supporting Information may be found in the online version of this article. Disclosure of Potential Conflicts of Interest: The authors declare no potential conflicts of interest. For information on how to submit an application for gaining access to EPIC data and/or biospecimens, please follow the instructions at http://epic.iarc.fr/access/index.php This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Grant sponsors: European Commission (DG-SANCO), International Agency for Research on Cancer, Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l’Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, Federal Ministry of Education and Research (Germany), Hellenic Health Foundation (Greece), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), ERC-2009-AdG 232997 and Nord- forsk, Nordic Centre of Excellence programme on Food, Nutrition and Health; Grant sponsor: Health Research Fund (FIS); Grant numbers: PI13/00061, PI13/01162; Grant sponsor: Regional Governments of Andalucıa, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC; Grant number: RD06/0020; Grant sponsors: Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and V€asterbotten; Grant sponsor: Cancer Research UK; Grant numbers: 14136, C570/A16491, C8221/A19170; Grant sponsor: Medical Research Council; Grant numbers: 1000143, MR/M012190/1; Grant sponsor: Institute of Health Carlos III and the European Social Fund (ESF); Grant number: CP15/00100 DOI: 10.1002/ijc.31563 History: Received 7 Dec 2017; Accepted 26 Mar 2018; Online 26 Apr 2018 Correspondence to: Neil Murphy, PhD, International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon, Cedex 08, France, E-mail: [email protected] and Augustin Scalbert, PhD, International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon, Cedex 08, France, E-mail: [email protected] Int. J. Cancer: 143, 1620–1631 (2018) VC 2018 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC Murphy et al. 1621 16 Navarra Public Health Institute, Pamplona, Spain 17 Navarra Institute for Health Research (IdiSNA), Pamplona, Spain 18 Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom 19 Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom 20 Hellenic Health Foundation, Athens, Greece 21 Pulmonary Medicine Department, School of Medicine, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, Haidari, Greece 22 Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute—ISPO, Florence, Italy 23 Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 24 Cancer Registry and Histopathology Department, Civic - M.P. Arezzo” Hospital, ASP Ragusa, Ragusa, Italy 25 Unit of Cancer Epidemiology, , Citta della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Turin, Italy 26 Dipartimento di Medicina Clinica e Sperimentale, Federico II University, Naples, Italy 27 Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), PO Box 1, Bilthoven, BA 3720, The Netherlands 28 Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands 29 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom 30 Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia 31 Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands 32 MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom 33 Department of Surgical and Perioperative Sciences, Umea˚ University, Umea˚, Sweden 34 Department of Odontology, Umea˚ University, Umea˚, Sweden 35 Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, Ioannina, Greece Polyphenols have been shown to exert biological activity in experimental models of colon cancer; however, human data link- Cancer Epidemiology ing specific polyphenols to colon cancer is limited. We assessed the relationship between pre-diagnostic plasma polyphenols and colon cancer risk in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition study. Using high pressure liquid chromatography coupled to tandem mass spectrometry, we measured concentrations of 35 polyphenols in plasma from 809 incident colon cancer cases and 809 matched controls. We used multivariable adjusted con- ditional logistic regression models that included established colon cancer risk factors. The false discovery rate (qvalues) was computed to control for multiple comparisons. All statistical tests were two-sided. After false discovery rate correction and in continuous log2-transformed multivariable models, equol (odds ratio [OR] per log2-value, 0.86, 95% confidence interval [95% CI] 5 0.79–0.93; qvalue 5 0.01) and homovanillic acid (OR per log2-value, 1.46, 95% CI 5 1.16–1.84; qvalue 5 0.02) were associ- ated with colon cancer risk. Comparing extreme fifths, equol concentrations were inversely associated with colon cancer risk (OR 5 0.61, 95% CI 5 0.41–0.91, ptrend 5 0.003), while homovanillic acid concentrations were positively associated with colon cancer development (OR 5 1.72, 95% CI 5 1.17–2.53, ptrend < 0.0001). No heterogeneity for these associations was observed by sex and across