IJC International Journal of Cancer

Coffee and tea consumption, genotype-based CYP1A2 and NAT2 activity and colorectal cancer risk—Results from the EPIC cohort study Vincent K. Dik1, H. B(as) Bueno-de-Mesquita1,2,3, Martijn G.H. Van Oijen1, Peter D. Siersema1, Cuno S.P.M. Uiterwaal4, €nzel J.B. Van Duijnhoven2,5, Stephane Cauchi6,7,8, Loic Yengo6,7,8, Philippe Froguel3,6,7,8, Carla H. Van Gils4, Fra 9 Kim Overvad , Bodil H. Bech9, Anne Tjïnneland10, Anja Olsen10, Marie-Christine Boutron-Ruault11,12,13, €hn14, Daniele Campa14, Heiner Boeing15, Antoine Racine11,12,13, Guy Fagherazzi11,12,13, Tilman Ku 15 16 Krasimira Aleksandrova , Antonia Trichopoulou , Eleni Peppa16, Eleni Oikonomou17, Domenico Palli18, Sara Grioni19, Paolo Vineis3,20, Rosaria Tumino21, Salvatore Panico22, Petra H.M. Peeters4, Elisabete Weiderpass23,24,25,26,  Sa nchez27,30,31, Dagrun Engeset23, Tonje Braaten23, Miren Dorronsoro27,28, Marıa-Dolores Chirlaque27,29, Marıa-Jose 27,32 33 34 35 36 €m , Peter Wallstro €m , Lena M. Nilsson37,38, €elles , Karin Jirstro Aurelio Barricarte , Raul Zamora-Ros , Marcial Argu 37,39 40 41 42 43 Ingrid Ljuslinder , Ruth C. Travis , Kay-Tee Khaw , Nick Wareham , Heinz Freisling , Idlir Licaj43, Mazda Jenab43, 3 Marc J. Gunter , Neil Murphy3, Dora Romaguera-Bosch3,44 and Elio Riboli3 1

Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands 3 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom 4 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands 5 Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands 6 CNRS UMR 8199, Pasteur Institute of Lille, Lille, France 7 University de Lille 2, Lille, France 8 European Genomic Institute for Diabetes (EGID), Lille, France 9 Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark 10 Danish Cancer Society Research Center, Copenhagen, Denmark 11 Nutrition, Hormones and Women’s Health team, Inserm Center for Research in Epidemiology and Population Health (CESP), Villejuif, France. 12 Paris South University, Villejuif, France 13 Institut Gustave Roussy, Villejuif, France 14 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany 15 Department of Epidemiology, German Institute of Human Nutrition, Potsdam, Germany 16 Hellenic Health Foundation, Athens, Greece 17 Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Food and Nutrition Policies, University of Athens Medical School, Athens, Greece 18 Molecular and Nutritional Epidemiology Unit, Cancer Research and Pevention Institute—ISPO, Florence, Italy 19 Epidemiology and Prevention Unit, Fondazione IRCCS Istitutio Nazionale dei Tumori, Milan, Italy 20 HuGeF Foundation, Turin, Italy 21 Cancer Registry and Histopathology Unit, “Civile M.P. Arezzo” Hospital, Ragusa, Italy 22 Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy

Key words: Colorectal cancer, coffee, tea, CYP1A2, NAT2 Additional Supporting Information may be found in the online version of this article. Grant sponsors: European Commission: Public Health and Consumer Protection Directorate (1993–2004); Research Directorate-General, 2005; Ligue contre le Cancer, Societe 3M, 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, Federal Ministry of Education and Research (Germany); Danish Cancer Society (Denmark); Health Research Fund (FIS) of the Spanish Ministry of Health, the participating regional governments and institutions (Spain); Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, the Wellcome Trust (United Kingdom); Hellenic Health Foundation (Greece); Italian Association for Research on Cancer, 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 (The Netherlands), Statistics Netherlands; Swedish Cancer Society, Swedish Scientific Council, Regional Government of Skane (Sweden); The Norwegian Research Council and NordForsk (Norway) DOI: 10.1002/ijc.28655 History: Received 6 Nov 2013; Accepted 11 Nov 2013; Online 7 Dec 2013 Correspondence to: Vincent K. Dik, Department of Gastroenterology and Hepatology (F02.618), University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands, Tel.: 131 (0)88 755 0224, E-mail: [email protected]

C 2013 UICC Int. J. Cancer: 135, 401–412 (2014) V




Coffee and tea consumption and colorectal cancer risk


Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsï, Norway Department of Research, Cancer Registry of Norway, Oslo, Norway 25 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden 26 Samfundet Folkh€alsan, Helsinki, Finland 27 blica-CIBERESP), Madrid, Spain Consortium for Biomedical Research in Epidemiology and Public Health (CIBER Epidemiologıa y Salud Pu 28 Public Health Direction, Basque Regional Health Department and Biodonostia Research Institute, Sebastian, Spain 29 Department of Epidemiology, Regional Health Council, Murcia, Spain 30 blica, Granada, Spain Escuela Andaluza de Salud Pu 31 n Biosanitaria de Granada (Granda.bs), Granada, Spain Instituto de Investigacio 32 Navarre Public Health Institute, Pamplona, Spain 33 Unit of Nutrition, Environment and Cancer Catalan Institute of Oncology, Barcelona, Spain 34 Public Health Directorate, Asturias, Spain 35 Department of Clinical Sciences, Division of Pathology, Lund University, Ska˚ne University Hospital, Lund, Sweden 36 €, Sweden Department of Clinical Sciences, Nutrition Epidemiology Research Group, Lund University, Malmo 37 Arctic Research Centre, Umea˚ University, Umea˚, Sweden 38 Department of Public Health and Clinical Medicine, Umea˚ University, Umea˚, Sweden 39 Department of Radiation Sciences, Oncology, Umea˚ University, Umea˚, Sweden 40 Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom 41 University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge, United Kingdom 42 Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom 43 International Agency for Research on Cancer (IARC-WHO), Lyon, France 44 n (CIBER-OB), Madrid, Spain CIBER Fisiopatologıa de la Obesidad y Nutricio



Coffee and tea contain numerous antimutagenic and antioxidant components and high levels of caffeine that may protect against colorectal cancer (CRC). We investigated the association between coffee and tea consumption and CRC risk and studied potential effect modification by CYP1A2 and NAT2 genotypes, enzymes involved in the metabolization of caffeine. Data from 477,071 participants (70.2% female) of the European Investigation into Cancer and Nutrition (EPIC) cohort study were analyzed. At baseline (1992–2000) habitual (total, caffeinated and decaffeinated) coffee and tea consumption was assessed with dietary questionnaires. Cox proportional hazards models were used to estimate adjusted hazard ratio’s (HR) and 95% confidence intervals (95% CI). Potential effect modification by genotype-based CYP1A2 and NAT2 activity was studied in a nested case–control set of 1,252 cases and 2,175 controls. After a median follow-up of 11.6 years, 4,234 participants developed CRC (mean age 64.7 6 8.3 years). Total coffee consumption (high vs. non/low) was not associated with CRC risk (HR 1.06, 95% CI 0.95–1.18) or subsite cancers, and no significant associations were found for caffeinated (HR 1.10, 95% CI 0.97–1.26) and decaffeinated coffee (HR 0.96, 95% CI 0.84–1.11) and tea (HR 0.97, 95% CI 0.86–1.09). High coffee and tea consuming subjects with slow CYP1A2 or NAT2 activity had a similar CRC risk compared to non/low coffee and tea consuming subjects with a fast CYP1A2 or NAT2 activity, which suggests that caffeine metabolism does not affect the link between coffee and tea consumption and CRC risk. This study shows that coffee and tea consumption is not likely to be associated with overall CRC.

What’s new? Coffee and tea contain numerous compounds that may protect against colorectal cancer (CRC). In this study of more than 475,000 participants over more than a decade, the authors investigated whether coffee or tea consumption is associated with an altered risk of developing CRC. They also asked whether genetic variations in two enzymes involved in caffeine metabolism (CYP1A2 and NAT2) might affect this risk. They conclude that neither consumption patterns, nor genetic differences in caffeine metabolism, appear to have a significant impact on CRC risk.

Coffee and tea are among the most widespread and most consumed beverages in the world. Both beverages contain a mixture of components. Some of these have shown potential anticarcinogenic effects in animal models and human cell cultures and may play a protective role against colorectal cancer (CRC).1–4 These components include phenolic com-

pounds, chlorogenic acid and diterpenes (cafestol and kahweol) in coffee and catechins and polyphenols in tea.5,6 In addition, cafestol and kahweol may lower CRC risk by reducing bile acid synthesis and secretion, while caffeine inhibits colon cancer cell growth and may lower carcinogen exposure of colonic epithelial cells by increasing colonic motility.6–9 C 2013 UICC Int. J. Cancer: 135, 401–412 (2014) V


Dik et al.

Methods Study population

The European Investigation into Cancer and Nutrition (EPIC) study is an ongoing multicenter population-based cohort study to investigate the relation between diet, nutritional and metabolic characteristics, lifestyle factors and subsequent cancer incidence and cause specific mortality. The cohort consists of 521,448 participants (70% women and C 2013 UICC Int. J. Cancer: 135, 401–412 (2014) V

mostly aged between 25 and 70 years), enrolled between 1992 and 2000, and followed within 23 centers in 10 different countries, i.e. Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden and United Kingdom. Detailed information about the selection of the studypopulation, data collection and follow-up procedures were reported previously.19,20 All participants of the EPIC cohort gave written informed consent. The study was approved by the International Agency for Research on Cancer ethical review committee and by the local committees at the participating centers.

Data collection Exposure assessment. Usual dietary intake was assessed

with country-specific validated dietary questionnaires.21 Coffee and tea consumption in milliliters (ml) per day was calculated for each center separately and was based on the recorded number of cups per day/week/month; the exact questions varied slightly by center and questionnaire. Complete information on both caffeinated and decaffeinated coffee consumption was only available for centers from France, Germany, Italy (Florence, Varese and Turin only), the Netherlands and the United Kingdom. Information on tea consumption was not available in Norway and to low in Greece (median 0.46 ml/day). Nondietary data on demographic characteristics, lifestyle habits, risk factors and presence of chronic diseases were collected through questionnaires at study enrolment. Anthropometric measurements were taken at recruitment by trained health professionals in most centers, except for part of the Oxford cohort, the Norwegian cohort and approximately two-thirds of the French cohort, among whom weight and height were self-reported. The outcomes of interests were first incidence of primary (adeno)carcinoma located in the colorectum. In most of the participating countries, identification of CRC cases is based on the regional cancer registries as well as through self-reporting in the postal follow-up questionnaires (Denmark, Italy, the Netherlands, Norway, Spain, Sweden and the United Kingdom). In addition, information on vital status and movement of participants is obtained through linkage with the municipal administration registries. In France, Germany and Greece participants are actively followed-up to obtain information on cancer cases and vital status. The second edition of the International Classification of Diseases-Oncology (ICD-O) was used to code CRC localization.22 Right/proximal colon tumors included caecum, appendix, ascending colon, hepatic flexure, transverse colon and splenic flexure (C18.0–18.5). Left/distal colon tumors included the descending (C18.6) and sigmoid colon (C18.7). Overlapping (C18.8) and unspecified lesions (C18.9) of the colon were grouped among all colon cancers (C18.0–C18.9). Colorectal cancer ascertainment.


Epidemiological studies are inconsistent regarding coffee and tea consumption and CRC risk. A recent meta-analysis reported a reduced colon cancer risk for high versus non/low coffee consumers (OR 0.79, 95% CI 0.67–0.95) in case–control studies but not in cohort studies (OR 0.93, 95% CI 0.86–1.01) or for rectal cancer.10 However, studies were heterogeneous in design and population. Findings of a recent cohort study, only showed a protective effect of coffee against proximal colon cancer.11 Similarly, in a pooled analysis of cohort studies, high tea consumption was found to be slightly positively associated with colon cancer risk,12 while others have reported inverse or no associations.11,13 These inconclusive findings from epidemiological studies could partly be explained by issues of study design, the number of CRC cases, differences in type of coffee (caffeinated/decaffeinated coffee and brewing methods) and tea (green and black) and residual confounding. If caffeine, as one of the major coffee and tea components, lowers CRC risk, then the association between coffee and tea consumption and CRC risk might be modified by the metabolization rate of caffeine. However, no epidemiological studies have investigated this hypothesis as far as we know. Of the major coffee and tea components thought to impact CRC risk, caffeine is the only one that is almost completely hydroxylated in the liver by the cytochrome P450 isoform CYP1A2 and acetylated by N-acetyltransferase (NAT) 2.14,15 CYP1A2 and NAT2 activity varies widely between subjects and depends on genetic background (single nucleotide polymorphisms; SNPs) and environmental factors such as diet and certain medication.16,17 Due to a limited number of CRC cases in most previous studies, separate analyses for proximal colon, distal colon and rectal cancer are scarce. Since considerable differences may exist for subsite colorectal cancers with regard to particular risk factors and sex,18 subsite analyses on the association between coffee and tea consumption and CRC risk are warranted. Furthermore, the CYP1A2 and NAT2 depended metabolization of caffeine—present in both coffee and tea— with its possible link to CRC risk, makes it of high interest to study genetic heterogeneity in CYP1A2 and NAT2. In the present large size prospective cohort study we aim to clarify the overall effect of coffee, caffeinated coffee, decaffeinated coffee and tea consumption on the risk of developing CRC and subsite cancers. We further study whether CYP1A2 and NAT2 activity modify the association between (caffeinated) coffee and tea consumption and CRC risk within a nested case–control dataset.


Cancer of the rectum included tumors occurring at the rectosigmoid junction (C19) and rectum (C20). Nested case–control study. A subset of CRC cases were

randomly selected from CRC cases diagnosed before 2005 in all EPIC centers except for Denmark and were matched with controls (1:2) by sex, age at blood collection (66–24 months), study center and menopausal status (premenopausal, postmenopausal, perimenopausal, unknown). Controls were selected from all cohort members alive and free of cancer (except nonmelanoma skin cancer) at the time of diagnosis of the matching cases. After excluding subjects with low DNA concentration or low quality of DNA extracted from the buffy coat samples (n 5 484) and removing incomplete case sets (n 5 243), a total of 1,252 CRC cases (829 colon, 423 rectum) and 2,175 matched controls remained for final analyses. The distribution of cases (colon/rectum) per country was: France 27/7, Germany 129/88, Greece 24/22, Italy 166/60, the Netherlands 119/61, Norway 15/4, Spain 99/54, Sweden 72/45, United Kingdom 178/82. There were no samples available from Denmark. Collection and storage of blood samples. In each of the

participating centers, blood samples of at least 30 ml were obtained and stored at 5 C to 10 C, protected from light and transported to local laboratories for processing and stored as previously described.19,20 The blood samples were stored as plasma, serum, buffy coat and erythrocytes in 0.5 ml straws under liquid nitrogen at 2196 C (except for Sweden where samples were stored in 280 C freezers).


Genotyping and classification of CYP1A2 and NAT2 activity.

DNA was extracted from buffy coat samples with the Autopure LS (Qiagen). SNPs were genotyped using the Illumina Metabochip in the CNRS UMR8199 laboratory as previously described.23 Genotyped SNPs included CYP1A2–164A>C (rs762551) and for NAT2 191G>A (rs1801279), 590G>A (rs1799930), 857G>A (rs1799931) and 481C>T (rs1799929). Within controls, the SNP distributions did not deviate from Hardy-Weinberg equilibrium. Subjects carrying a CYP1A2 C/C or A/C genotype were characterized as slow metabolizers, while subjects with an A/A genotype were characterized as fast metabolizers.16 NAT2 haplotype pairs were predicted using Plink software (v1.07),24,25 and were used to classify subjects by most probable acetylation status.26 A slow NAT2 acetylation status was defined as the presence of two slow NAT2 alleles, which are characterized by the presence of one or more of the SNPs 191G>A, 590G>A, 857G>A or 341T>C. For this study 481C>T was used as a proxy for 341T>C (R2 5 0.89). Subjects carrying one or two fast (wild type) alleles were classified as fast acetylators. Data analyses Whole cohort analyses. Analyses of this study were con-

ducted in 477,071 participants (70.2% female) of whom 4,234

Coffee and tea consumption and colorectal cancer risk

developed first primary colorectal (adeno)carcinoma. Before analyses we excluded participants with any type of prevalent cancer at enrolment and/or incomplete follow-up (n 5 28,150), incomplete (non-)dietary data (n 5 6,253), with the highest and lowest 1% of the distribution for the ratio between energy intake to estimated energy requirement (n 5 9,601), carcinoma in situ (n 5 133), unknown histology of the tumor (n 5 105), unknown first incidence tumor (n 5 14) or a colorectal tumor originating from other organs (n 5 3). Follow-up time in person years was calculated from study enrolment until censoring at the date of first diagnosis of any type of cancer, death, loss to follow-up or the date at which follow-up ended, whatever came first. End of follow-up was defined as the last date at which follow-up data were judged to be complete or the last date of contact in the centers that used active follow-up. Cohort-wide quintiles (coffee, caffeinated coffee and tea) or tertiles (decaffeinated coffee) for levels of consumption were computed after excluding nonconsumers. Multivariable Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HR) and corresponding 95% confidence intervals (95% CI) for different levels of consumption, in which non- and low-consumers were combined. Linear trends over different categories were computed using median consumption levels within the categories in all subjects. Additional Cox proportional hazard regression models were used with coffee and tea intake as a continuous variable to compute HR per 100 ml/day increase of consumption. All models were stratified by age (1-year intervals), sex and center to adjust for differences in follow-up procedures and questionnaire design between the participating centers. Age at enrolment and age at end of follow-up were used as the underlying time variables. All models were adjusted for body mass index (BMI; continuous), self-reported diabetes (DM; yes, no), menopausal status (premenopausal, perimenopausal, postmenopausal), hormone replacement therapy (HRT; yes, no), physical activity according to the Cambridge Physical Activity Index (CPAI; inactive, moderately inactive, moderately active, active), educational level as a proxy of socioeconomic status (none, primary school, technical/professional school, secondary school, university), smoking status/duration/intensity (never, former: quitted 10 years, former: quitted

Coffee and tea consumption, genotype-based CYP1A2 and NAT2 activity and colorectal cancer risk-results from the EPIC cohort study.

Coffee and tea contain numerous antimutagenic and antioxidant components and high levels of caffeine that may protect against colorectal cancer (CRC)...
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