1. Stepwise model to study folate and pancreatic cancer in the international study setting - Results from the European Prospective Investigation into Cancer and Nutrition study (EPIC) Jin Young Park, PhD Dietary Exposure Assessment Group, IARC 3 rd November, 2011, ICCC4, Republic of Korea

2. Folate A water-soluble B vitamin Rich in green leafy vegetables, dried peas, beans and lentils, fruits, nuts and seeds as well as in offal such as beef and chicken liver Critical nutrient for one-carbon transfer reactions which include the synthesis of nucleotides that are needed for DNA synthesis and repair, as well as methylation of DNA and other molecules Inadequate folate intake has been linked to the risk of: –Anaemia –Neuropsychiatric disorders –Neural tube defects (NTDs) –Cardiovascular disease through elevated plasma homocysteine concentrations –Some cancers, especially colorectal cancer

3. Pancreatic cancer: epidemiology Source: GLOBOCAN 2008, IARC and WHO mortality database (accessed on 20/10/2011)

4. Folate and pancreatic cancer risk – unresolved question Folates and associated compounds (total folate) Folates from supplements only Folates, dietary only Source: WCRF/AICR Expert Report, 2007

5. Rationale & objectives Folate & pancreatic cancer risk in Europe

6. Stepwise approach to investigate folate in relation to cancer risk in international study settings Inventory of folate databases in 18 countries Harmonisation and compilation of the nutrient databases Inventory of validation studies on dietary folate intake against biomarkers Dietary intake and biological measurement of folate: A review of validation studies. JY Park et al. (In preparation) Methodological work Critical evaluation of folate data in European and international databases. K Bouckaert et al. Mol Nutr Food Res 2011;55: 66-180 Standardization of folate database for international nutritional research: report of the experience from the EPIC study. G Nicolas et al. (in preparation) First comparison of standardised dietary folate intake in Europe Relationships between dietary and corresponding serum B vitamins involved in one-carbon metabolism in the EPIC study Serum vitamin B profiles and their association with food intakes: results from a cross-sectional study within the EPIC. (JY Park et al. Approved project in EPIC. In preparation) Comparison of standardised dietary folate intake across 10 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). JY Park et al. Br J Nutr 2011 (in press) Exposure assessment (including biomarkers) Nutrients patterns and pancreatic cancer risk in EPIC Patterns of dietary & serum one- carbon metabolism-related nutrients and pancreatic cancer risk in EPIC To be integrated in a broader ongoing EPIC project entitled “Dietary patterns in EPIC and their application in studies on disease risk: concepts and work plans” (Nutritional Working Group, N Slimani et al.) Five sets of already established nested case-control data within EPIC (N=9,574) Granted access to the expanded pancreatic cancer dataset in EPIC WCRF granted project (PI: Prof Vineis) (JY Park et al. Approved project in EPIC. In preparation) Application of epidemiological studies

7. Stepwise approach to investigate folate in relation to cancer risk in international study settings Inventory of folate databases in 18 countries Harmonisation and compilation of the nutrient databases Inventory of validation studies on dietary folate intake against biomarkers Dietary intake and biological measurement of folate: A review of validation studies. JY Park et al. (In preparation) Methodological work Critical evaluation of folate data in European and international databases. K Bouckaert et al. Mol Nutr Food Res 2011;55: 66-180 Standardization of folate database for international nutritional research: report of the experience from the EPIC study. G Nicolas et al. (in preparation) First comparison of standardised dietary folate intake in Europe Relationships between dietary and corresponding serum B vitamins involved in one-carbon metabolism in the EPIC study Serum vitamin B profiles and their association with food intakes: results from a cross-sectional study within the EPIC. (JY Park et al. Approved project in EPIC. In preparation) Comparison of standardised dietary folate intake across 10 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). JY Park et al. Br J Nutr 2011 (in press) Exposure assessment (including biomarkers) Nutrients patterns and pancreatic cancer risk in EPIC Patterns of dietary & serum one- carbon metabolism-related nutrients and pancreatic cancer risk in EPIC To be integrated in a broader ongoing EPIC project entitled “Dietary patterns in EPIC and their application in studies on disease risk: concepts and work plans” (Nutritional Working Group, N Slimani et al.) Five sets of already established nested case-control data within EPIC (N=9,574) Granted access to the expanded pancreatic cancer dataset in EPIC WCRF granted project (PI: Prof Vineis) (JY Park et al. Approved project in EPIC. In preparation) Application of epidemiological studies

8. Materials and methods The European Prospective Investigation into Cancer and Nutrition (EPIC) –Investigation of the relationships between diet, nutritional status, lifestyle, environmental factors and the incidence of cancer and other chronic diseases among ~520,000 participants in 10 European countries (baseline: 1993- 1999) –~26,000 incident cancer cases and ~16,000 deaths recorded in 2004 Detailed information on diet & lifestyle –Lifestyle questionnaires –Blood samples Fasting (45.5%) or non-fasting (54.5%) blood samples of at least 30mL were drawn Standardised protocol for collection, storage, and laboratory analyses Main dietary methods –Country-specific dietary questionnaire (DQ) from whole cohort, N= ~520,000 –Standardised 24-h dietary recall (24HDR) using EPIC-Soft® programme from calibration subsample, N= 36,994

9. Dietary folate intake in 10 countries in EPIC Results from the newly updated and standardised folate database Park JY et al. 2011 Percentage contribution of cereal sources to the intake of folate by country ordered from south to north in women Park JY et al. 2011

10. Serum vitamin B profiles and their association with food intakes: results from a cross-sectional study within EPIC Relationships between dietary and corresponding serum B vitamins involved in one-carbon metabolism in the EPIC study (Park et al, in preparation) –Five sets of already established nested case-control data within EPIC (N=9,574) with information on both serum and dietary B vitamins Colorectal cancer nested case-control study (1,460 cases & 2,632 controls); Gastric cancer (325 cases & 796 controls); Lung cancer (887 cases & 1,806 controls); Prostate cancer (525 cases & 644 controls); and Pancreatic cancer (456 cases and 454 controls) Head & Neck cancer dataset to be included To be the single largest study to date that provides comprehensive information on dietary intake of B vitamins obtained from highly standardised nutrient databases as well as their corresponding nutrient ascertained by biochemical indices Serum: folate, riboflavin, pyridoxal’ 5- phosphate (PLP), cobalamin, methionine, and homocysteine Diet (estimated by FFQ): folate, riboflavin, vitB6, and cobalamin

11. Results Serum folate FFQ-estimated dietary folate

12. Correlations between serum and FFQ values r=-0.08, P<0.01 r=-0.09, P<0.01 r=0.28, P<0.001 r=0.25, P<0.001 Kruskal-Wallis test P<0.001

13. Stepwise approach to investigate folate in relation to cancer risk in international study settings Inventory of folate databases in 18 countries Harmonisation and compilation of the nutrient databases Inventory of validation studies on dietary folate intake against biomarkers Dietary intake and biological measurement of folate: A review of validation studies. JY Park et al. (In preparation) Methodological work Critical evaluation of folate data in European and international databases. K Bouckaert et al. Mol Nutr Food Res 2011;55: 66-180 Standardization of folate database for international nutritional research: report of the experience from the EPIC study. G Nicolas et al. (in preparation) First comparison of standardised dietary folate intake in Europe Relationships between dietary and corresponding serum B vitamins involved in one-carbon metabolism in the EPIC study Serum vitamin B profiles and their association with food intakes: results from a cross-sectional study within the EPIC. (JY Park et al. Approved project in EPIC. In preparation) Comparison of standardised dietary folate intake across 10 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). JY Park et al. Br J Nutr 2011 (in press) Exposure assessment (including biomarkers) Nutrients patterns and pancreatic cancer risk in EPIC Patterns of dietary & serum one- carbon metabolism-related nutrients and pancreatic cancer risk in EPIC To be integrated in a broader ongoing EPIC project entitled “Dietary patterns in EPIC and their application in studies on disease risk: concepts and work plans” (Nutritional Working Group, N Slimani et al.) Five sets of already established nested case-control data within EPIC (N=9,574) Granted access to the expanded pancreatic cancer dataset in EPIC WCRF granted project (PI: Prof Vineis) (JY Park et al. Approved project in EPIC. In preparation) Application of epidemiological studies

14. Prospective association between patterns of 26 standardised nutrients obtained from calibrated FFQ data and pancreatic cancer risk in EPIC (Park et al. in preparation) –To identify and describe the different nutrient patterns from the calibrated FFQ data in the whole EPIC cohort (N=~520,000) using a principal component analysis and to investigate the association between the identified nutrient patterns and pancreatic cancer risk –FFQ derived 23 nutrient variables including: –Macronutrients (e.g. protein, fat, alcohol and sugar) –Micronutrients (e.g. beta-carotene, calcium, iron, magnesium, phosphorus, potassium, retinol, thiamin, folate, riboflavin, vitB6, vitB12 (cobalamin), vitC, vitD, and vitE) –A total of 908 pancreatic cancer incident cases with an average follow-up period of 11 years in 477,312 participants are currently included in the analysis –Cox proportional hazard regression models used –Analysis to be updated (only preliminary results shown here) –More pancreatic cancer cases to be added by the end of this year –Sensitivity analysis, stratified analysis are planned Nutrient dietary patterns and pancreatic cancer risk in the EPIC cohort study

15. Preliminary results

16. The work reported/ proposed here has been undertaken during the tenure of a Postdoctoral Fellowship from the International Agency for Research on Cancer, partially supported by the European Commission FP7 Marie Curie Actions – People – Co-funding of regional, national and international programmes Acknowledgements Section of Nutrition and Metabolism, IARC Nadia Slimani Aurelie Moskal Geneviève Nicolas Pietro Ferrari Vitamin B and pancreatic cancer working group, EPIC Simone Eussen Per Ueland Stein Emil Vollset Øivind Midttun Carlos González Paul Brennan Mattias Johansson Bas Bueno-de-Mesquita Paolo Vineis Shu-Chun Chuang