IJC International Journal of Cancer

Dairy products and risk of hepatocellular carcinoma: The European Prospective Investigation into Cancer and Nutrition Talita Duarte-Salles1, Veronika Fedirko2,3, Magdalena Stepien1, Antonia Trichopoulou4,5, Christina Bamia4, Pagona Lagiou4,6,7, Annekatrin Lukanova8,9, Elisabeth Trepo10, Kim Overvad11, Anne Tjïnneland12, Jytte Halkjær12, €hn8, Marie-Christine Boutron-Ruault13,14,15, Antoine Racine13,14,15, Claire Cadeau13,14,15, Tilman Ku 16 5,6,7 4 5,17 Krasimira Aleksandrova , Dimitrios Trichopoulos , Konstantinos Tsiotas , Paolo Boffetta , Domenico Palli18, 19 20 21,22 Valeria Pala , Rosario Tumino , Carlotta Sacerdote , Salvatore Panico23, H. B(as) Bueno-de-Mesquita24,25,26, 25 26,27 Vincent K. Dik , Petra H. Peeters , Elisabete Weiderpass28,29,30,31, Inger Torhild Gram28, Anette Hjarta˚ker32, 33 n Quiro s , Ana Fonseca-Nunes34, Esther Molina-Montes35,36,37, Miren Dorronsoro38, Jose Ramo €rn Lindkvist42, Emily Sonestedt43, Ingegerd Johansson44, Carmen Navarro Sanchez35,39,40, Aurelio Barricarte35,41, Bjo 45 46 47 Maria Wennberg , Kay-Tee Khaw , Nick Wareham , Ruth C. Travis48, Isabelle Romieu1, Elio Riboli26 and Mazda Jenab1 1

International Agency for Research on Cancer (IARC-WHO), Lyon, France Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 3 Winship Cancer Institute, Emory University, Atlanta, GA 4 Department of Hygiene, Epidemiology, and Medical Statistics, WHO Collaborating Center for Food and Nutrition Policies, University of Athens Medical School, Athens, Greece 5 Hellenic Health Foundation, Athens, Greece 6 Department of Epidemiology, Harvard School of Public Health, Boston, MA 7 Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece 8 Division of Cancer Epidemiology, German Cancer Research Centre, Heidelberg, Germany 9 Department of Medical Biosciences, Pathology, Umea˚ University, Umea˚, Sweden 10 Centre de Bioloqie Republique, Lyon, France 11 Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark 12 Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark 13 INSERM, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women’s Health team, F-94805, Villejuif, France 14 Univ Paris Sud, UMRS 1018, F-94805, Villejuif, France 15 IGR, F-94805, Villejuif, France 16 €cke, Nuthetal, Germany Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbru 17 Tisch Cancer Institute and Institute for Translational Epidemiology, Icahn School of Medicine, Mount Sinai, New York, NY

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Key words: hepatocellular carcinoma, dairy products, calcium, prospective cohort Abbreviations: BMI: body mass index; CI: confidence interval; EPIC: European Prospective Investigation into Cancer and Nutrition; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; HR: hazard ratio; IARC: International Agency for Research on Cancer; IGF: insulin-like growth factor Additional Supporting Information may be found in the online version of this article. Grant sponsor: The French National Cancer Institute (L’Institut National du Cancer; Grant number: 2009-139; Grant sponsors: The European Commission (DG-SANCO), The 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), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum (DKFZ), Federal Ministry of Education and Research (Germany), Hellenic Health Foundation (Greece), Italian Association for Research on Cancer (AIRC), National Research Council, Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, AIRE-ONLUS Ragusa, AVIS Ragusa, Sicilian Government (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); Grant sponsor: European Research Council (ERC); Grant number: ERC-2009-AdG 232997; Grant sponsors: Nordforsk, Nordic Center of Excellence Programme on Food, Nutrition and Health (Norway), Health Research Fund (FIS); Grant sponsor: Regional Governments of Andalucıa, Asturias, Basque Country, Murcia; Grant number: 6236; Grant sponsor: Navarra; Grant sponsor: ISCIII RETIC, Spain; Grant number: RD06/0020; Grant sponsor: Swedish Cancer Society; Grant sponsor: Cancer Research, United Kingdom; Grant sponsors: Medical Research Council, Stroke Association, British Heart Foundation; Grant sponsor: Department of Health; Grant sponsor: Wellcome Trust, United Kingdom DOI: 10.1002/ijc.28812 History: Received 25 Nov 2013; Accepted 27 Jan 2014; Online 26 Feb 2014 Correspondence to: Mazda Jenab, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372 Lyon, France, Tel.: 133-4-72-73-80-82, Fax: 133-4-72-73-83-20, E-mail: [email protected]

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Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute—ISPO, Florence, Italy Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 20 Cancer Registry and Histopathology Unit, “Civic-M.P.Arezzo” Hospital, ASP Ragusa, Italy 21 Unit of Cancer Epidemiology, AO Citta’ della Salute e della Scienza, University of Turin and Center for Cancer Prevention (CPO), Turin, Italy 22 Human Genetics Foundation (HuGeF), Turin, Italy 23 Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy 24 National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands 25 Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands 26 Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, United Kingdom 27 Julius Center, University Medical Center Utrecht, Utrecht, The Netherlands 28 Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsï, Norway 29 Department of Research, Cancer Registry of Norway, Oslo, Norway 30 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden 31 Samfundet Folkh€alsan, Helsinki, Finland 32 Department of Nutrition, University of Oslo, Oslo, Norway 33 Public Health Directorate, Asturias, Spain 34 Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology, ICO-IDIBELL, L’Hospitalet de Llobregat, Spain 35 blica-CIBERESP), Madrid, Spain Consortium for Biomedical Research in Epidemiology and Public Health (CIBER Epidemiologıa y Salud Pu 36 blica, Granada, Spain Escuela Andaluza de Salud Pu 37 n Biosanitaria de Granada (Granada.bs), Granada, Spain Instituto de Investigacio 38 Public Health Division of Gipuzkoa, Basque Regional Health Department and CIBERESP-BIODONOSTIA, San Sebastian, Spain 39 Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain 40 Department of Health and Social Sciences, Universidad de Murcia, Spain 41 Navarre Public Health Institute, Pamplona, Spain 42 Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 43 €, Lund University, Lund, Sweden Department of Clinical Sciences Malmo 44 Department of Odontology, Umea˚ University, Umea˚, Sweden 45 Department of Public Health and Clinical Medicine, Occupational Medicine, Umea˚ University, Umea˚, Sweden 46 School of Clinical Medicine, Clinical Gerontology Unit, University of Cambridge, Cambridge, United Kingdom 47 MRC Epidemiology Unit, Cambridge, United Kingdom 48 Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom

Intake of dairy products has been associated with risk of some cancers, but findings are often inconsistent and information on hepatocellular carcinoma (HCC) risk is limited, particularly from prospective settings. The aim of our study was to investigate the association between consumption of total and specific dairy products (milk/cheese/yogurt) and their components (calcium/vitamin D/fats/protein), with first incident HCC (Ncases 5 191) in the European Prospective Investigation into Cancer and Nutrition cohort, including a nested case–control subset (Ncases 5 122) with the assessment of hepatitis B virus/hepatitis C virus infections status, liver damage and circulating insulin-like growth factor (IGF)-I levels. For cohort analyses, multivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI). For nested case– control analyses, conditional logistic regression was used to calculate odds ratios and 95% CI. A total of 477,206 participants were followed-up for an average of 11 years (person-years follow-up 5 5,415,385). In the cohort study, a significant positive HCC risk association was observed for total dairy products (highest vs. lowest tertile, HR 5 1.66, 95% CI: 1.13–2.43; ptrend 5 0.012), milk (HR 5 1.51, 95% CI: 1.02–2.24; ptrend 5 0.049), and cheese (HR 5 1.56, 95% CI: 1.02–2.38; ptrend 5 0.101), but not yogurt (HR 5 0.94, 95% CI: 0.65–1.35). Dietary calcium, vitamin D, fat and protein from dairy sources were associated with increased HCC risk, whereas the same nutrients from nondairy sources showed inverse or null associations. In the nested case–control study, similar results were observed among hepatitis-free individuals. Results from this large prospective cohort study suggest that higher consumption of dairy products, particularly milk and cheese, may be associated with increased HCC risk. Validation of these findings in other populations is necessary. Potential biologic mechanisms require further exploration.

What’s new? Currently, the role of dairy product intake in the development of hepatocellular carcinoma (HCC) is unclear. Using detailed data from a large multi-centric prospective cohort, this study investigated the association between consumption of total and specific dairy products with first incident HCC. The study found that higher dairy product consumption, particularly milk and cheese, was associated with increased HCC risk. Dietary calcium, vitamin D, fat and protein did not explain the observed associations. However, higher circulating IGF-I levels may play a role.

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Liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide.1,2 Hepatocellular carcinoma (HCC), the most common type of liver cancer,3 is highly malignant, usually diagnosed at late stages and often has poor prognosis with limited treatment options. HCC is primarily associated with chronic hepatitis B and C viruses (HBV/HCV) infection.4 Other major risk factors include dietary aflatoxin exposure, obesity, type 2 diabetes, tobacco smoking and heavy alcohol drinking mediated by liver cirrhosis.5–7 Although dietary exposures have been strongly suspected to play a role in the HCC etiology, current evidence is limited, particularly in regions with low HBV/ HCV prevalence and aflatoxin exposure in which HCC incidence rates have increased over the past years, including Western Europe.2 Dairy products are important components of a Westerntype diet, but their association with cancer risk is controversial. For example, an increased intake of dairy products and calcium has been associated with decreased risk of colorectal cancer,8,9 but increased risk of prostate cancer.10 It has been suggested that these associations may be explained by some of the macro- and micronutrient components of dairy products. Although the association between dairy intake and colorectal cancer has been attributed to the high calcium and vitamin D content of this food group,11 the association with prostate cancer has been proposed to be owing to the rich saturated fat and calcium content of dairy products.12,13 Higher dairy products intake may also increase circulating levels of insulin-like growth factor-I (IGF-I).14–18 IGF-I has been shown to promote hepatocarcinogenesis in experimental studies,19–23 and higher levels have been associated with a moderately increased cancer risk at some sites.24–26 To date, the association between intake of dairy products and risk of HCC has not been well explored, and the existing epidemiologic evidence is limited or inconsistent. The association has been investigated in only two prospective9,27 and several case–control studies.28–32 However, few of these were based on European populations29–31 and none explored the role of different subgroups of dairy products, nor micro- or macronutrient components of this food group (i.e., calcium, vitamin D, fats and protein). Therefore, the aim of our study was to investigate the association between intakes of total dairy products, individual dairy products, and micro- and macronutrient components of the food group with the incidence of HCC. The study is based on the European Prospective Investigation into Cancer and Nutrition (EPIC) study and includes a nested case–control subset with the assessment of HBV/HCV infection status, liver damage and circulating IGF-I levels.

Subjects and Methods Study design

EPIC is a large prospective cohort study designed to investigate the association between diet, lifestyle and environmental

Dairy product intake and HCC in EPIC

factors and the incidence of cancers and other chronic diseases. Detailed information on the study design, rationale and methods of the EPIC study, including assessment of diet and lifestyle factors, has been described previously.33,34 Briefly, between 1991 and 2000 more than 520,000 men and women aged 20–85 years were recruited in 23 centers throughout ten European countries (Denmark, France, Germany, Greece, Italy, The Netherlands, Norway, Spain, Sweden and United Kingdom). At recruitment, standardized dietary, lifestyle and socio-demographic questionnaires including information on physical activity, education, smoking and medical history, anthropometric data and blood samples were collected from participants. Blood samples are stored at the International Agency for Research on Cancer (IARC, Lyon, France) in 2196 C liquid nitrogen for all countries except Denmark (nitrogen vapour, 2150 C) and Sweden (freezers, 280 C). Approval for our study was obtained from the IARC ethical review board (Lyon, France) and local participating centers. Dietary assessment

Diet was assessed at baseline by validated country-specific questionnaires designed to ensure high compliance with local dietary habits over the past years.35,36 For dairy products, a Spearman coefficient of 0.68 was previously reported for the correlation between intakes reported in questionnaires and the average of 12 24-hr recalls in a sample of EPIC participants.37 Daily food intakes were calculated in grams per day. Total dietary intakes of calcium (mg/day), vitamin D (mg/ day), fat (g/day), protein (g/day), fiber (g/day) and energy (kcal/day) were estimated using standardized country-specific food composition tables.38 Individual dairy products were categorized as milk, cheese and yogurt. Total milk was assessed as the sum of all types of milk consumed (whole fat, skimmed, semi-skimmed and not specified) and, in Norway, included fermented milk. Cheese included all kinds of fresh, fermented and matured cheese. Yogurt included natural, flavored in all cohorts and additionally sour milk in Sweden and Denmark. Owing to relatively low intakes and incomplete measurements across centers, other individual dairy products including subtypes of milk, ice cream, cream desserts and milk-based puddings, milk beverages, dairy creams and creamers for milk and coffee were not analyzed individually. The sum of all dairy subtypes reported in the dietary questionnaire was used to calculate dietary intake of total dairy products (g/day). Follow-up and cancer case ascertainment

The follow-up was based mostly on population cancer registries (complete up to December 2006), except for France, Germany and Greece, where a combination of methods including health insurance records, cancer and pathology hospital registries and active follow-up was used (complete up to June 2010). C 2014 UICC Int. J. Cancer: 135, 1662–1672 (2014) V

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Table 1. HRs and 95%CI for HCC by intake1 of milk and dairy food in EPIC No. of cases/PYs

Crude2 HR (95% CI)

Multivariable3 HR (95% CI)

Dairy products and risk of hepatocellular carcinoma: the European Prospective Investigation into Cancer and Nutrition.

Intake of dairy products has been associated with risk of some cancers, but findings are often inconsistent and information on hepatocellular carcinom...
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