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Aims The aim of this study was to develop, validate, and illustrate an updated prediction model (SCORE2) to estimate 10-year fatal and non-fatal cardiovascular disease (CVD) risk in individuals without previous CVD or diabetes aged 40-69 years in Europe.Methods and results We derived risk prediction models using individual-participant data from 45 cohorts in 13 countries (677 684 individuals, 30 121 CVD events). We used sex-specific and competing risk-adjusted models, including age, smoking status, systolic blood pressure, and total- and HDL-cholesterol. We defined four risk regions in Europe according to country-specific CVD mortality, recalibrating models to each region using expected incidences and risk factor distributions. Region-specific incidence was estimated using CVD mortality and incidence data on 10 776 466 individuals. For external validation, we analysed data from 25 additional cohorts in 15 European countries (1 133 181 individuals, 43 492 CVD events). After applying the derived risk prediction models to external validation cohorts, C-indices ranged from 0.67 (0.65-0.68) to 0.81 (0.76-0.86). Predicted CVD risk varied several-fold across European regions. For example, the estimated 10-year CVD risk for a 50-year-old smoker, with a systolic blood pressure of 140 mmHg, total cholesterol of 5.5 mmol/L, and HDL-cholesterol of 1.3 mmol/L, ranged from 5.9% for men in low- risk countries to 14.0% for men in very high-risk countries, and from 4.2% for women in low-risk countries to 13.7% for women in very high-risk countries.Conclusion SCORE2-a new algorithm derived, calibrated, and validated to predict 10-year risk of first-onset CVD in European populations-enhances the identification of individuals at higher risk of developing CVD across Europe. Acknowledgements We thank investigators and participants of the several studies that contributed data to the Emerging Risk Factors Collaboration (ERFC). This research has been conducted using the UK Biobank Resource under Application Number 26865. Data from the Clinical Practice Research Datalink (CPRD) were obtained under licence from the UK Medicines and Healthcare products Regulatory Agency (protocol 162RMn2). CPRD uses data provided by patients and collected by the NHS as part of their care and support. We thank all EPIC participants and staff for their contribution to the study, the laboratory teams at the Medical Research Council Epidemiology Unit for sample management and Cambridge Genomic Services for genotyping, Sarah Spackman for data management and the team at the EPIC-CVD Coordinating Centre for study co-ordination and administration. Funding The ERFC co-ordinating centre was underpinned by programme grants from the British Heart Foundation (SP/09/002; RG/13/13/30194; RG/18/13/33946), BHF Centre of Research Excellence (RE/18/1/34212), the UK Medical Research Council (MR/L003120/1), and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC1215-20014), with project-specific support received from the UK NIHR [*], British United Provident Association UK Foundation and an unrestricted educational grant from GlaxoSmithKline. A variety of funding sources have supported recruitment, follow-up, and laboratory measurements in the studies contributing data to the ERFC, which are listed on the ERFC website (www.phpc.cam.ac.uk/ceu/erfc/list-of-studies). *The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome. The MORGAM Project has received funding from EU projects MORGAM (Biomed BMH4-CT98-3183), GenomEUtwin (FP5, QLG2-CT-2002-01254), ENGAGE (FP7, HEALTH-F4-2007-201413),CHANCES (FP7, HEALTH-F3-2010-242244), BiomarCaRE (FP7,HEALTH-F2-2011-278913), euCanSHare (Horizon 2020, No. 825903) and AFFECT-EU (Horizon 2020, No. 847770); and Medical Research Council, London (G0601463, No. 80983: Biomarkers in the MORGAM Populations). This has supported central coordination, workshops and part of the activities of the MORGAM Data Centre, the MORGAM Laboratories and the MORGAM Participating Centres EPIC-CVD was funded by the European Research Council (268834), and the European Commission Framework Programme 7 (HEALTH-F2-2012-279233). This work was supported by the Estonian Research Council grant PUTs (PRG687, PUT1660, PUT1665, PRG184), by European Union through the European Regional Development Fund project no. MOBERA5 (Norface Network project no 462.16.107), by the Green ICT programme under Norway Grants 2014 – 2021 (grant number EU53928), by the European Union through Horizon 2020 grant no. 810645 and through the European Regional Development Fund (Project No. 2014-2020.4.01.16-0125) and by the PRECISE4Q consortium. PRECISE4Q project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Grant agreement 777107. This work was partly funded through the CoMorMent project. CoMorMent has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Grant agreement 847776. The KORA study was initiated and financed by the Helmholtz Zentrum Mu¨nchen—German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. The KORA study was supported by a research grant from the Virtual Institute of Diabetes Research (Helmholtz Zentrum Mu¨nchen), the Clinical Cooperation Group Diabetes between Ludwig-Maximilians-Universita¨t Mu¨nchen and Helmholtz Zentrum Mu¨nchen, and by the German Diabetes Center (DDZ). The HAPIEE project, Institute, was supported by grants from the Wellcome Trust (064947/Z/01/Z; WT081081) and US National Institute on Aging (1R01 and AG23522). The co-ordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Ge´ne´rale de l’Education Nationale, Institut National de la Sante´ et de la Recherche Me´dicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch 2448 SCORE2 working group and ESC Cardiovascular Risk Collaboration 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); Health Research Fund (FIS)—Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucı´a, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology—ICO (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Ska˚ne and Va¨sterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (United Kingdom)

Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score (“teloscore”, which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35–1.76; p = 1.54 × 10 −10 ) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73–0.88; p = 1.87 × 10 −6 , p trend = 3.27 × 10 −7 ). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10 −9 for highest vs. lowest quintile; p = 1.82 × 10 −10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer.

Experimental studies have reported on the anti-inflammatory properties of polyphenols. However, results from epidemiological investigations have been inconsistent and especially studies using biomarkers for assessment of polyphenol intake have been scant. We aimed to characterise the association between plasma concentrations of thirty-five polyphenol compounds and low-grade systemic inflammation state as measured by high-sensitivity C-reactive protein (hsCRP). A cross-sectional data analysis was performed based on 315 participants in the European Prospective Investigation into Cancer and Nutrition cohort with available measurements of plasma polyphenols and hsCRP. In logistic regression analysis, the OR and 95 % CI of elevated serum hsCRP (>3 mg/l) were calculated within quartiles and per standard deviation higher level of plasma polyphenol concentrations. In a multivariable-adjusted model, the sum of plasma concentrations of all polyphenols measured (per standard deviation) was associated with 29 (95 % CI 50, 1) % lower odds of elevated hsCRP. In the class of flavonoids, daidzein was inversely associated with elevated hsCRP (OR 0 center dot 66, 95 % CI 0 center dot 46, 0 center dot 96). Among phenolic acids, statistically significant associations were observed for 3,5-dihydroxyphenylpropionic acid (OR 0 center dot 58, 95 % CI 0 center dot 39, 0 center dot 86), 3,4-dihydroxyphenylpropionic acid (OR 0 center dot 63, 95 % CI 0 center dot 46, 0 center dot 87), ferulic acid (OR 0 center dot 65, 95 % CI 0 center dot 44, 0 center dot 96) and caffeic acid (OR 0 center dot 69, 95 % CI 0 center dot 51, 0 center dot 93). The odds of elevated hsCRP were significantly reduced for hydroxytyrosol (OR 0 center dot 67, 95 % CI 0 center dot 48, 0 center dot 93). The present study showed that polyphenol biomarkers are associated with lower odds of elevated hsCRP. Whether diet rich in bioactive polyphenol compounds could be an effective strategy to prevent or modulate deleterious health effects of inflammation should be addressed by further well-powered longitudinal studies.

Fruit and vegetable (F&V) intake is considered as probably protective against overall cancer risk, but results in previous studies are not consistent for thyroid cancer (TC). The purpose of this study is to examine the association between the consumption of fruits, vegetables, fruit juices and differentiated thyroid cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The EPIC study is a cohort including over half a million participants, recruited between 1991 and 2000. During a mean follow-up of 14 years, 748 incident first primary differentiated TC cases were identified. F&V and fruit juice intakes were assessed through validated country-specific dietary questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models adjusted for potential confounding factors. Comparing the highest versus lowest quartile of intake, differentiated TC risk was not associated with intakes of total F&V (HR: 0.89; 95% CI: 0.68–1.15; p-trend = 0.44), vegetables (HR: 0.89; 95% CI: 0.69–1.14; p-trend = 0.56), or fruit (HR: 1.00; 95% CI: 0.79–1.26; p-trend = 0.64). No significant association was observed with any individual type of vegetable or fruit. However, there was a positive borderline trend with fruit juice intake (HR: 1.23; 95% CI: 0.98–1.53; p-trend = 0.06). This study did not find any significant association between F&V intakes and differentiated TC risk; however a positive trend with fruit juice intake was observed, possibly related to its high sugar content.

Several dietary factors have been studied in relation to prostate cancer; however, most studies have not reported on subtypes of fruit and vegetables or tumor characteristics, and results obtained so far are inconclusive. This study aimed to examine the prospective association of total and subtypes of fruit and vegetable intake with the incidence of prostate cancer overall, by grade and stage of disease, and prostate cancer death. Lifestyle information for 142,239 men participating in the European Prospective Investigation into Cancer and Nutrition from 8 European countries was collected at baseline. Multivariable Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). After an average follow‐up time of 13.9 years, 7,036 prostate cancer cases were identified. Compared with the lowest fifth, those in the highest fifth of total fruit intake had a significantly reduced prostate cancer risk (HR = 0.91; 95% CI = 0.83–0.99; p‐trend = 0.01). No associations between fruit subtypes and prostate cancer risk were observed, except for citrus fruits, where a significant trend was found (HR = 0.94; 95% CI = 0.86–1.02; p‐trend = 0.01). No associations between total and subtypes of vegetables and prostate cancer risk were observed. We found no evidence of heterogeneity in these associations by tumor grade and stage, with the exception of significant heterogeneity by tumor grade (p heterogeneity, What's new? The role of diet in prostate‐cancer etiology is uncertain, and associations may vary by tumor characteristics. In this prospective, longitudinal study, the authors examined the association of total and subtypes of fruit and vegetable intake with the overall incidence of prostate cancer. They then analyzed incidence by grade, stage of disease, and prostate‐cancer death. They found that higher fruit intake was associated with a small reduction in prostate cancer risk, and that this association did not differ by tumor characteristics.

Epidemiological data regarding tea and coffee consumption and risk of esophageal cancer (EC) is still inconclusive. We examined the association of tea and coffee consumption with EC risk among 442,143 men and women without cancer at baseline from 9 countries of the European Prospective Investigation into Cancer and Nutrition. Tea and coffee intakes were recorded using country-specific validated dietary questionnaires. Cox regression models were used to analyze the relationships between tea and coffee intake and EC risk. During a mean follow-up of 11.1 years, 339 participants developed EC, of which 142 were esophageal adenocarcinoma (EAC) and 174 were esophageal squamous cell carcinoma (ESCC). In the multivariable models, no significant associations between tea (mostly black tea), and coffee intake and risk of EC, EAC and ESCC were observed. In stratified analyses, among men coffee consumption was inversely related to ESCC (HR for comparison of extreme tertiles 0.42, 95% CI 0.20-0.88; p-trend=0.022), but not among women. In current smokers, a significant and inverse association was observed between ESCC risk and tea (HR 0.46, 95% CI 0.23-0.93; p-trend=0.053) and coffee consumption (HR 0.37, 95% CI 0.19-0.73; p-trend=0.011). However, no statistically significant findings were observed using the continuous variable (per 100 mL/d). These data did not show a significant association between tea and coffee consumption and EC, EAC and ESCC, although a decreased risk of ESCC among men and current smokers is suggested, but need to be confirmed in further prospective studies including more cases. What's new? Tea and coffee, because of their high polyphenol content, may help reduce the risk of esophageal cancer (EC), but data across multiple studies have been inconsistent. In this cohort study of men and women from nine European countries, no significant association was found between coffee and tea consumption and overall risk of EC and its subtypes. Among current smokers or men, an inverse association with esophageal squamous cell carcinoma was suggested, although further prospective studies are needed to confirm the potential relationship. © 2014 UICC.

Background Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown. Methods and Findings The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m2), (2) metabolically healthy/overweight (BMI ≥ 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI ≥ 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [≥80 cm for women and ≥94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of, Gunter and colleagues analyse a large European dataset to determine how body size and metabolic profile associates with the risk of developing colorectal cancer., Editors' Summary Background Colorectal cancer is the third most common cancer worldwide and is a leading cause of cancer-related death, killing around 700,000 people every year. It develops when cells in the colon (the final part of the digestive system, which is also known as the large intestine or large bowel) or the rectum (the lower end of the colon) acquire genetic changes that allow them to divide uncontrollably to form a tumor and to move around the body (metastasize). Symptoms of colorectal cancer include blood in the stool, a change in bowel habits, and unexplained weight loss. Treatments for colorectal cancer include surgery, chemotherapy, and radiation. As with other types of cancer, these treatments are more likely to be successful if started when the tumor is very small. Consequently, many countries run screening programs that use colonoscopy, the fecal occult blood test, and other tests to detect the earliest signs of colorectal cancer in apparently healthy people. Why Was This Study Done? Being obese—having too much body fat—is associated with an increased colorectal cancer risk (other risk factors include age, having a family history of colorectal cancer, and eating a high-fat, low-fiber diet). Obesity is also associated with several other chronic diseases, and recent evidence suggests that some obese individuals have a higher risk of developing these diseases than others. For example, overweight/obese individuals who have hyperinsulinemia (abnormally high blood levels of insulin; “metabolically unhealthy”) seem to have a higher risk of cardiovascular disease than their non-hyperinsulinemic (“metabolically healthy”) overweight counterparts. If certain combinations of metabolic health status and body size (“metabolically defined body size phenotypes”) are also associated with colorectal cancer, measurement of insulin levels in conjunction with body fat (adiposity) measurements such as body mass index (BMI; an indicator of body fat calculated by dividing a person’s weight in kilograms by their height in meters squared) might improve colorectal cancer risk assessment. In this nested case–control study, the researchers assess the associations between metabolically defined body size phenotypes and colorectal cancer risk. A nested case–control study identifies everyone in a group (here, participants in the European Prospective Investigation into Cancer and Nutrition [EPIC] study) who has a specific condition, identifies matched individuals in the same group without the condition, and asks whether these controls and the cases differ in terms of a specific characteristic or outcome. What Did the Researchers Do and Find? The researchers matched 737 participants in the EPIC study who developed colorectal cancer after study enrollment with 737 controls and used serum concentrations of C-peptide, a marker of insulin secretion, and BMI measurements to classify each individual as metabolically healthy/normal weight, metabolically healthy/overweight, metabolically unhealthy/normal weight, or metabolically unhealthy/overweight. Specifically, the researchers categorized people as metabolically unhealthy if they had a C-peptide level above an arbitrarily chosen cut-off value based on the distribution of C-peptide levels in the control participants and as overweight if they had a BMI of ≥25 kg/m2 (the standard definition of overweight). Compared to metabolically healthy normal weight individuals, metabolically unhealthy normal weight and overweight individuals had an increased colorectal cancer risk; metabolically healthy overweight individuals had a similar colorectal cancer risk to metabolically healthy normal weight individuals. Among overweight individuals, metabolically healthy individuals had a lower colorectal cancer risk than metabolically unhealthy individuals. Finally, similar associations were seen when the researchers used waist circumference instead of BMI as the measure of adiposity. What Do These Findings Mean? These findings suggest that normal weight individuals with hyperinsulinemia (the metabolically unhealthy normal weight phenotype) have a higher risk of colorectal cancer than normal weight individuals without hyperinsulinemia. They also suggest that metabolically unhealthy overweight individuals have a higher risk of colorectal cancer than metabolically healthy overweight individuals. The accuracy of these findings may be limited by the method the researchers used to classify individuals as hyperinsulinemic—there is no universally accepted clinical definition for using C-peptide level to diagnose hyperinsulinemia. Nevertheless, these findings suggest that the assessment of insulin levels in conjunction with adiposity measures might be a better way to assess an individual’s colorectal cancer risk than simply measuring adiposity, and might help to identify those individuals at high risk of colorectal cancer who are most likely to benefit from targeted interventions designed to prevent the onset of clinical disease. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001988. The US National Cancer Institute provides information for patients about all aspects of colorectal cancer; it also provides more detailed information colorectal cancer for health professionals and information on cancer risk and obesity The UK National Health Service Choices website has information and personal stories about colorectal cancer and information on obesity The not-for-profit organization Cancer Research UK provides information about colorectal cancer and about the association between cancer and obesity MedlinePlus provides links to further resources about colorectal cancer and about obesity Wikipedia has a page on hyperinsulinemia (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages) More information about the EPIC study is available

Previously, a lower risk of colorectal cancer was observed with fruit and vegetable consumption in the European Prospective Investigation into Cancer and Nutrition within a follow-up period of 9 years which was not fully supported by a recent meta-analysis. Therefore, we were interested in the relation with extended follow-up, also focusing on single subtypes and a variety of intake of fruit and vegetables. Fruit and vegetable consumption was assessed at baseline. After an average of 13 years of follow-up, 3,370 participants were diagnosed with colon or rectal cancer. Diet diversity scores were constructed to quantify variety in fruit and vegetable consumption. A lower risk of colon cancer was observed with higher self-reported consumption of fruit and vegetable combined (HR Q4 vs. Q1 0.87, 95% CI 0.75-1.01, p for trend 0.02), but no consistent association was observed for separate consumption of fruits and vegetables. No associations with risk of rectal cancer were observed. The few observed associations for some fruit and vegetable subtypes with colon cancer risk may have been due to chance. Variety in consumption of fruits and vegetables was not associated with a lower risk of colon or rectal cancer. Although a lower risk of colon cancer is suggested with high consumption of fruit and vegetables, this study does not support a clear inverse association between fruit and vegetable consumption and colon or rectal cancer beyond a follow-up of more than 10 years. Attenuation of the risk estimates from dietary changes over time cannot be excluded, but appears unlikely. What's new? Eating a healthy diet loaded with fruits and vegetables will help you stave off cancer - that's the conventional wisdom. But the relationship between diet and cancer is complex. This study probed the effects of fruits and vegetables on colorectal cancer risk. The authors combed through data from the European Prospective Investigation into Cancer and Nutrition (EPIC) and analyzed total fruit and vegetable consumption as well as individual subtypes. Contrary to earlier results, they found no correlation between fruit and vegetable intake and colorectal cancer risk over a period of more than ten years.

Dietary flavanols and flavonols, flavonoid subclasses, have been recently associated with a lower risk of type 2 diabetes (T2D) in Europe. Even within the same subclass, flavonoids may differ considerably in bioavailability and bioactivity. We aimed to examine the association between individual flavanol and flavonol intakes and risk of developing T2D across European countries. The European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study was conducted in 8 European countries across 26 study centers with 340,234 participants contributing 3.99 million person-years of follow-up, among whom 12,403 incident T2D cases were ascertained and a center-stratified subcohort of 16,154 individuals was defined. We estimated flavonoid intake at baseline from validated dietary questionnaires using a database developed from Phenol-Explorer and USDA databases. We used country-specific Prentice-weighted Cox regression models and random-effects meta-analysis methods to estimate HRs. Among the flavanol subclass, we observed significant inverse trends between intakes of all individual flavan-3-ol monomers and risk of T2D in multivariable models (all P-trend < 0.05). We also observed significant trends for the intakes of proanthocyanidin dimers (HR for the highest vs. the lowest quintile. 0.81; 95% Cl: 0.71, 0.92; P-trend = 0.003) and trimers (HR: 0.91; 95% Cl: 0.80, 1.04; P-trend = 0.07) but not for proanthocyanidins with a greater polymerization degree. Among the flavonol subclass, myricetin (HR: 0.77; 95% Cl: 0.64, 0.93; P-trend = 0.001) was associated with a lower incidence of T2D. This large and heterogeneous European study showed inverse associations between all individual flavan-3-ol monomers, proanthocyanidins with a low polymerization degree, and the flavonol myricetin and incident T2D. These results suggest that individual flavonoids have different roles in the etiology of T2D.

Limited epidemiological evidence suggests a protective role for plant foods rich in flavonoids and antioxidants in hepatocellular cancer (HCC) etiology. Our aim was to prospectively investigate the association between dietary intake of flavonoids, lignans and nonenzymatic antioxidant capacity (NEAC) and HCC risk. Data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort including 477,206 subjects (29.8% male) recruited from ten Western European countries, was analyzed. Flavonoid, lignan and NEAC intakes were calculated using a compilation of existing food composition databases linked to dietary information from validated dietary questionnaires. Dietary NEAC was based on ferric reducing antioxidant capacity (FRAP) and total radical-trapping antioxidant parameter (TRAP). Hepatitis B/C status was measured in a nested case-control subset. During a mean follow-up of 11-years, 191 incident HCC cases (66.5% men) were identified. Using Cox regression, multivariable adjusted models showed a borderline nonsignificant association of HCC with total flavonoid intake (highest versus lowest tertile, HR=0.65, 95% CI: 0.40-1.04; p=0.065), but not with lignans. Among flavonoid subclasses, flavanols were inversely associated with HCC risk (HR=0.62, 95% CI: 0.39-0.99; p=0.06). Dietary NEAC was inversely associated with HCC (FRAP: HR 0.50, 95% CI: 0.31-0.81; p=0.001; TRAP: HR 0.49, 95% CI: 0.31-0.79; p=0.002), but statistical significance was lost after exclusion of the first 2 years of follow-up. This study suggests that higher intake of dietary flavanols and antioxidants may be associated with a reduced HCC risk. What's new? Coffee, tea, fruits and vegetables, and certain other foods may protect against hepatocellular carcinoma (HCC), thanks to their antioxidant ingredients. This study lends fresh support to that idea, revealing specifically that dietary flavanols, which possess antioxidant activity, could play a favourable role in HCC prevention. Dietary antioxidant capacity from coffee intake in particular was found to be inversely associated with HCC risk, though statistical significance was lost after exclusion of the first two years of follow-up. Assessment of the bioavailability of flavonoids and other antioxidants is needed to confirm links between antioxidant intake and HCC risk. Department, Catalan Institute of Oncology, IDIBELL, Hospital Duran i Reynals, Gran Via 199-203, E-08908 L'Hospitalet de Llobregat, Barcelona, Spain. © 2013 UICC.

OBJECTIVE: To study the association between dietary flavonoid and lignan intakes, and the risk of development of type 2 diabetes among European populations. RESEARCH DESIGN AND METHODS: The European Prospective Investigation into Cancer and Nutrition-InterAct case-cohort study included 12,403 incident type 2 diabetes cases and a stratified subcohort of 16,154 participants from among 340,234 participants with 3.99 million person-years of follow-up in eight European countries. At baseline, country-specific validated dietary questionnaires were used. A flavonoid and lignan food composition database was developed from the Phenol-Explorer, the U.K. Food Standards Agency, and the U.S. Department of Agriculture databases. Hazard ratios (HRs) from country-specific Prentice-weighted Cox regression models were pooled using random-effects meta-analysis. RESULTS: In multivariable models, a trend for an inverse association between total flavonoid intake and type 2 diabetes was observed (HR for the highest vs. the lowest quintile, 0.90 [95% CI 0.77-1.04]; P value trend = 0.040), but not with lignans (HR 0.88 [95% CI 0.72-1.07]; P value trend = 0.119). Among flavonoid subclasses, flavonols (HR 0.81 [95% CI 0.69-0.95]; P value trend = 0.020) and flavanols (HR 0.82 [95% CI 0.68-0.99]; P value trend = 0.012), including flavan-3-ol monomers (HR 0.73 [95% CI 0.57-0.93]; P value trend = 0.029), were associated with a significantly reduced hazard of diabetes. CONCLUSIONS: Prospective findings in this large European cohort demonstrate inverse associations between flavonoids, particularly flavanols and flavonols, and incident type 2 diabetes. This suggests a potential protective role of eating a diet rich in flavonoids, a dietary pattern based on plant-based foods, in the prevention of type 2 diabetes.

Background: Renal cell carcinoma (RCC) accounts for more than 80% of kidney cancers in adults, and obesity is a known risk factor. Regular consumption of sweetened beverages has been linked to obesity and several chronic diseases, including some types of cancer. It is uncertain whether soft drink and juice consumption is associated with risk of RCC. We investigated the associations of soft drink and juice consumption with RCC incidence and mortality in the European Prospective Investigation into Cancer and Nutrition (EPIC). Methods: A total of 389,220 EPIC participants with median age of 52 years at recruitment (1991–2000) were included. Cox regression yielded adjusted HRs and 95% confidence intervals (CI) for RCC incidence and mortality in relation to intakes of juices and total, sugar-sweetened, and artificially sweetened soft drinks. Results: A total of 888 incident RCCs and 356 RCC deaths were identified. In models including adjustment for body mass index and energy intake, there was no higher risk of incident RCC associated with consumption of juices (HR per 100 g/day increment = 1.03; 95% CI, 0.97–1.09), total soft drinks (HR = 1.01; 95% CI, 0.98–1.05), sugar-sweetened soft drinks (HR = 0.99; 95% CI, 0.94–1.05), or artificially sweetened soft drinks (HR = 1.02; 95% CI, 0.96–1.08). In these fully adjusted models, none of the beverages was associated with RCC mortality (HR, 95% CI per 100 g/day increment 1.06, 0.97–1.16; 1.03, 0.98–1.09; 0.97, 0.89–1.07; and 1.06, 0.99–1.14, respectively). Conclusions: Consumption of juices or soft drinks was not associated with RCC incidence or mortality after adjusting for obesity. Impact: Soft drink and juice intakes are unlikely to play an independent role in RCC development or mortality.

We thank the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands, for their contribution to, and ongoing support of, the EPIC Study. We thank Aude De Bruycker for her graphical support., (1) Background: Methyl-group donors (MGDs), including folate, choline, betaine, and methionine, may influence breast cancer (BC) risk through their role in one-carbon metabolism; (2) Methods: We studied the relationship between dietary intakes of MGDs and BC risk, adopting data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort; (3) Results: 318,686 pre- and postmenopausal women were followed between enrolment in 1992–2000 and December 2013–December 2015. Dietary MGD intakes were estimated at baseline through foodfrequency questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary intake of MGDs, measured both as a calculated score based on their sum and individually, and BC risk. Subgroup analyses were performed by hormone receptor status, menopausal status, and level of alcohol intake. During a mean follow-up time of 14.1 years, 13,320 women with malignant BC were identified. No associations were found between dietary intakes of the MGD score or individual MGDs and BC risk. However, a potential U-shaped relationship was observed between dietary folate intake and overall BC risk, suggesting an inverse association for intakes up to 350 µg/day compared to a reference intake of 205 µg/day. No statistically significant differences in the associations were observed by hormone receptor status, menopausal status, or level of alcohol intake; (4) Conclusions: There was no strong evidence for an association between MGDs involved in one-carbon metabolism and BC risk. However, a potential U-shaped trend was suggested for dietary folate intake and BC risk. Further research is needed to clarify this association., Research Foundation Flanders (FWO, 189019N), Research Foundation Flanders (FWO, V427019N), International Agency for Research on Cancer (IARC), Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, NIHR Imperial Biomedical Research Center (BRC), Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and 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), Health Research Fund (FIS)—Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology—ICO (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford), (United Kingdom)

There are both limited and conflicting data on the role of dietary fat and specific fatty acids in the development of pancreatic cancer. In this study, we investigated the association between plasma phospholipid fatty acids and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The fatty acid composition was measured by gas chromatography in plasma samples collected at recruitment from 375 incident pancreatic cancer cases and 375 matched controls. Associations of specific fatty acids with pancreatic cancer risk were evaluated using multivariable conditional logistic regression models with adjustment for established pancreatic cancer risk factors. Statistically significant inverse associations were found between pancreatic cancer incidence and levels of heptadecanoic acid (ORT3-T1 [odds ratio for highest versus lowest tertile] =0.63; 95%CI[confidence interval]=0.41-0.98; Ptrend =0.036), n-3 polyunsaturated α-linolenic acid (ORT3-T1 =0.60; 95%CI=0.39-0.92; Ptrend =0.02) and docosapentaenoic acid (ORT3-T1 =0.52; 95%CI=0.32-0.85; Ptrend =0.008). Industrial trans-fatty acids were positively associated with pancreatic cancer risk among men (ORT3-T1 =3.00; 95%CI=1.13-7.99; Ptrend =0.029), while conjugated linoleic acids were inversely related to pancreatic cancer among women only (ORT3-T1 =0.37; 95%CI=0.17-0.81; Ptrend =0.008). Among current smokers, the long-chain n-6/n-3 polyunsaturated fatty acids ratio was positively associated with pancreatic cancer risk (ORT3-T1 =3.40; 95%CI=1.39-8.34; Ptrend =0.007). Results were robust to a range of sensitivity analyses. Our findings suggest that higher circulating levels of saturated fatty acids with an odd number of carbon atoms and n-3 polyunsaturated fatty acids may be related to lower risk of pancreatic cancer. The influence of some fatty acids on the development of pancreatic cancer may be sex-specific and modulated by smoking. This article is protected by copyright. All rights reserved.

ObjectiveTo characterize meal patterns across ten European countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) calibration study.DesignCross-sectional study utilizing dietary data collected through a standardized 24 h diet recall during 1995–2000. Eleven predefined intake occasions across a 24 h period were assessed during the interview. In the present descriptive report, meal patterns were analysed in terms of daily number of intake occasions, the proportion reporting each intake occasion and the energy contributions from each intake occasion.SettingTwenty-seven centres across ten European countries.SubjectsWomen (64 %) and men (36 %) aged 35–74 years (n 36 020).ResultsPronounced differences in meal patterns emerged both across centres within the same country and across different countries, with a trend for fewer intake occasions per day in Mediterranean countries compared with central and northern Europe. Differences were also found for daily energy intake provided by lunch, with 38–43 % for women and 41–45 % for men within Mediterranean countries compared with 16–27 % for women and 20–26 % for men in central and northern European countries. Likewise, a south–north gradient was found for daily energy intake from snacks, with 13–20 % (women) and 10–17 % (men) in Mediterranean countries compared with 24–34 % (women) and 23–35 % (men) in central/northern Europe.ConclusionsWe found distinct differences in meal patterns with marked diversity for intake frequency and lunch and snack consumption between Mediterranean and central/northern European countries. Monitoring of meal patterns across various cultures and populations could provide critical context to the research efforts to characterize relationships between dietary intake and health.

Background:Vegetable and/or fruit intakes in association with hepatocellular carcinoma (HCC) risk have been investigated in case-control studies conducted in specific European countries and cohort studies conducted in Asia, with inconclusive results. No multi-centre European cohort has investigated the indicated associations.Methods:In 486 799 men/women from the European Prospective Investigation into Cancer and nutrition, we identified 201 HCC cases after 11 years median follow-up. We calculated adjusted hazard ratios (HRs) for HCC incidence for sex-specific quintiles and per 100 g d(-1) increments of vegetable/fruit intakes.Results:Higher vegetable intake was associated with a statistically significant, monotonic reduction of HCC risk: HR (100 g d(-1) increment): 0.83; 95% CI: 0.71-0.98. This association was consistent in sensitivity analyses with no apparent heterogeneity across strata of HCC risk factors. Fruit intake was not associated with HCC incidence: HR (100 g d(-1) increment): 1.01; 95% CI: 0.92-1.11.Conclusions:Vegetable, but not fruit, intake is associated with lower HCC risk with no evidence for heterogeneity of this association in strata of important HCC risk factors. Mechanistic studies should clarify pathways underlying this association. Given that HCC prognosis is poor and that vegetables are practically universally accessible, our results may be important, especially for those at high risk for the disease.British Journal of Cancer advance online publication, 5 March 2015; doi:10.1038/bjc.2014.654 www.bjcancer.com.

There is limited evidence on the association between dietary folate intake and the risk of breast cancer (BC) by hormone receptor expression in the tumors. We investigated the relationship between dietary folate and BC risk using data from the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 367993 women age 35 to 70 years were recruited in 10 European countries. During a median follow-up of 11.5 years, 11575 women with BC were identified. Dietary folate intake was estimated from country-specific dietary questionnaires. Cox proportional hazards regression models were used to quantify the association between dietary variables and BC risk. BC tumors were classified by receptor status. Subgroup analyses were performed by menopausal status and alcohol intake. Intake of other B vitamins was considered. All statistical tests were two-sided. A borderline inverse association was observed between dietary folate and BC risk (hazard ratio comparing top vs bottom quintile [HRQ5-Q1] = 0.92, 95% CI = 0.83 to 1.01, P (trend) = .037). In premenopausal women, we observed a statistically significant trend towards lower risk in estrogen receptor-negative BC (HRQ5-Q1 = 0.66, 95% CI = 0.45 to 0.96, P (trend) = .042) and progesterone receptor-negative BC (HRQ5-Q1 = 0.70, 95% CI = 0.51 to 0.97, P (trend) = .021). No associations were found in postmenopausal women. A 14% reduction in BC risk was observed when comparing the highest with the lowest dietary folate tertiles in women having a high (> 12 alcoholic drinks/week) alcohol intake (HRT3-T1 = 0.86, 95% CI = 0.75 to 0.98, P (interaction) = .035). Higher dietary folate intake may be associated with a lower risk of sex hormone receptor-negative BC in premenopausal women.

Background Few epidemiological studies have examined the association between dietary trans fatty acids and weight gain, and the evidence remains inconsistent. The main objective of the study was to investigate the prospective association between biomarker of industrial trans fatty acids and change in weight within the large study European Prospective Investigation into Cancer and Nutrition ( EPIC) cohort. Methods Baseline plasma fatty acid concentrations were determined in a representative EPIC sample from the 23 participating EPIC centers. A total of 1,945 individuals were followed for a median of 4.9 years to monitor weight change. The association between elaidic acid level and percent change of weight was investigated using a multinomial logistic regression model, adjusted by length of follow- up, age, energy, alcohol, smoking status, physical activity, and region. Results In women, doubling elaidic acid was associated with a decreased risk of weight loss ( odds ratio ( OR) = 0.69, 95% confidence interval ( CI) = 0.55- 0.88, p = 0.002) and a trend was observed with an increased risk of weight gain during the 5- year follow- up ( OR = 1.23, 95% CI = 0.97- 1.56, p = 0.082) ( p- trend, The EPIC-PANACEA ((European Prospective Investigation into Cancer-Physical Activity, Nutrition, Alcohol, Cessation of Smoking, Eating out of home And obesity) project received funding from the Public Health Programme of the European Union (2005328). EPIC was financially supported by the 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 Institute Carlos III (RTICC Rd06/0020/0091 and Rd12/0036/0018) from 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, Associazione Italiana per la Ricerca sul Cancro-AIRC (Italy); Dutch Ministry of Public Health, Welfare and Sports, Dutch Ministry of Health, Dutch Prevention Funds, LK Research Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF) (The Netherlands); Swedish Cancer Society, Swedish Scientific Council, Regional Government of Skane (Sweden); Norwegian Cancer Society (Norway). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.