Stepwise Stepwise model to study folate and pancreatic model to study folate and pancreatic cancer in the international study settingcancer in the international study setting

- Results from the European Prospective Investigation into Cancer and Nutrition study (EPIC)

Jin Young Park, PhDDietary Exposure Assessment Group, IARC

3rd November, 2011, ICCC4, Republic of Korea

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

Pancreatic cancer: epidemiology

Source: GLOBOCAN 2008, IARC and WHO mortality database (accessed on 20/10/2011)

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

Rationale & objectives

Folate & pancreatic cancer risk in Europe

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)M

eth

od

olo

gic

al

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)

Exp

osu

re

assessm

en

t (i

nclu

din

g

bio

mark

ers

)

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)

Ap

plicati

on

of

ep

idem

iolo

gic

al

stu

die

s

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)M

eth

od

olo

gic

al

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)

Exp

osu

re

assessm

en

t (i

nclu

din

g

bio

mark

ers

)

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)

Ap

plicati

on

of

ep

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gic

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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

Dietary folate intake in 10 countries in EPICResults from the newly updated and standardised folate

database

0

50

100

150

200

250

300

350

400

Me

an in

take

of

fola

te (

µg/

d),

wo

me

n

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Food sources of folate intake (women)Miscellaneous

Soups, bouillons

Sugar and confectionary

Cakes and biscuits

Condiments and sauces

Egg and egg products

Fish and shellfish

Alcoholic beverages

Non alcoholic beverages

Potatoes and other tubers

Meat and meat products

Legumes

Dairy products

Fruits, nuts and seeds

Cereal and cereal products

Vegetables

Park JY et al. 2011

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Salty biscuits, aperitif biscuits, crackers

Flour, flakes, starches, semolina

Dough and pastry (puff, short-crust, pizza)

Pasta, rice, other grains

Breakfast cereals

Bread, crispbread, rusks

Percentage contribution of cereal sources to the intake of folate by country ordered from south to north in women

Park JY et al. 2011

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

351

811

663

0

1,207

229

1,117

596

878

107

328

621

210

361

802

619

435

632

Greece

Spain

Italy

France

Germany

The Netherlands

United Kingdom

Denmark

Sweden

Women

Men

Serum: folate, riboflavin, pyridoxal’ 5-phosphate (PLP), cobalamin, methionine, and homocysteine

Diet (estimated by FFQ): folate, riboflavin, vitB6, and cobalamin

Results

0

50

100

150

200

250

300

350

400

FFQ

-esti

mat

ed d

ieta

ry fo

late

(mcg

/d)

0

2

4

6

8

10

12

14

16

18Se

rum

fola

te (µ

mol

/l)

Serum folate

FFQ-estimated dietary folate

0

50

100

150

200

250

300

350

FFQ-estimated folate (men) FFQ-estimated folate (women)

FFQ

-esti

mat

ed d

ieta

ry fo

late

(mcg

/d)

SouthCentral

SouthNorthCentral

North

South

SouthCentral

Central

NorthNorth

0

2

4

6

8

10

12

14

16

Serum folate (men) Serum folate (women)

Seru

m fo

late

(µm

ol/l

)Se

rum

fola

te (µ

mol

/l)

Correlations between serum and FFQ values

Serum metabolites Folate Riboflavin Vitamin B6 Vitamin B12 Folate Riboflavin Vitamin B6 Vitamin B12

Folate 0.28 0.25

P value <0.0001 <0.0001

Riboflavin 0.23 0.21

P value <0.0001 <0.0001

Vitamin B6 0.19 0.20

P value <0.0001 <0.0001

Vitamin B12 0.12 0.15

P value <0.0001 <0.0001

WomenMen

FFQ values 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

0

2

4

6

8

10

12

14

16

18

0 100 200 300 400 500 600

FFQ-estimated dietary folate intake (mcg/d)

Seru

m fo

late

((µm

ol/l

)

Kruskal-Wallis test P<0.001Kruskal-Wallis test P<0.001

0

2

4

6

8

10

12

14

0 100 200 300 400 500 600

FFQ-estimated dietary folate intake (mcg/d)

Seru

m h

omoc

yste

ine

((µm

ol/l

)

Kruskal-Wallis test P<0.001Kruskal-Wallis test P<0.001

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)M

eth

od

olo

gic

al

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)

Exp

osu

re

assessm

en

t (i

nclu

din

g

bio

mark

ers

)

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)

Ap

plicati

on

of

ep

idem

iolo

gic

al

stu

die

s

• 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

Nutrient PC1 PC2 PC3

Total proteins 0.146 0.471 0.175

Saturated Fatty Acids 0.514 -0.064 -0.012

Monounsaturated Fatty Acids 0.357 0.05 -0.353

Polyunsaturated Fatty Acids 0.079 0.161 -0.649

Cholesterol 0.603 0.345 -0.019

Starch -0.151 -0.324 -0.098

Sugar -0.341 0.091 0.374

Dietary fibre -0.635 0.351 -0.013

Thiamin B1 -0.265 0.389 0.138

Riboflavin B2 0.129 0.546 0.496

Vitamin B6 -0.272 0.591 0.1

Folate B9 -0.452 0.654 0.156

Vitamin B12 – Cobalamin 0.599 0.589 0.226

Vitamin C -0.55 0.548 0.167

Beta-carotene -0.573 0.681 -0.139

Retinol 0.763 0.442 0.101

Vitamin E -0.144 0.387 -0.599

Vitamin D 0.404 0.437 -0.554

Calcium -0.053 0.337 0.483

Phosphorus 0.01 0.504 0.369

Iron -0.177 0.43 0.01

Potassium -0.402 0.61 0.243

Magnesium -0.341 0.402 0.195

Proportion of explained variance (%) 27.3 24.2 9.3

Cumulative explained variance (%) 27.3 51.5 60.7

Preliminary resultsNutrient pattern CasesPerson years

Crude HR HRa HRb

PC1

Quintile 1 156 1,088,793 1 1 1Quintile 2 168 1,082,532 1.12 0.90 - 1.39 1.09 0.88 - 1.36 1.07 0.86 - 1.33Quintile 3 190 1,080,666 1.29 1.04 - 1.60 1.23 0.99 - 1.52 1.18 0.95 - 1.47Quintile 4 202 1,082,788 1.36 1.10 - 1.68 1.26 1.01 - 1.56 1.19 0.96 - 1.48Quintile 5 192 1,081,439 1.31 1.06 - 1.62 1.15 0.92 - 1.43 1.05 0.84 - 1.31

P value for trend

HR continuous 1.15 1.06 - 1.25 1.09 1.00 - 1.19 1.05 0.96 - 1.14

PC2

Quintile 1 187 1,083,154 1 1 1Quintile 2 174 1,078,550 0.92 0.74 - 1.13 0.95 0.77 - 1.17 0.96 0.78 - 1.18Quintile 3 179 1,078,924 0.90 0.74 - 1.11 0.97 0.79 - 1.19 0.98 0.80 - 1.21Quintile 4 170 1,084,816 0.81 0.66 - 1.00 0.90 0.73 - 1.11 0.91 0.73 - 1.13Quintile 5 198 1,090,773 0.91 0.75 - 1.11 1.06 0.86 - 1.30 1.07 0.86 - 1.32

P value for trend

HR continuous 0.94 0.86 - 1.02 1.00 0.91 - 1.09 1.01 0.92 - 1.10

PC3

Quintile 1 192 1,084,242 1 1 1Quintile 2 164 1,086,357 0.82 0.67 - 1.02 0.84 0.68 - 1.03 0.84 0.68 - 1.03Quintile 3 170 1,082,400 0.85 0.69 - 1.05 0.87 0.71 - 1.07 0.87 0.71 - 1.07Quintile 4 196 1,082,327 0.96 0.79 - 1.18 1.00 0.82 - 1.22 1.00 0.82 - 1.22Quintile 5 186 1,080,891 0.93 0.76 - 1.14 0.97 0.79 - 1.19 0.96 0.78 - 1.18

P value for trend

HR continuous 1.01 0.88 - 1.16 1.04 0.90 - 1.19 1.03 0.89 - 1.19a Cox regression model adjusted for center, total energy intake, gender and for each PC scoreb Cox regression model adjusted for center, total energy intake, gender, alcohol, smoking status, height, weight, physical activity level and for each score

95% CIa95% CI 95% CIb

<0.001 0.09 0.42

0.21 0.87 0.81

0.97 0.67 0.74

• 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 SlimaniAurelie MoskalGeneviève Nicolas Pietro Ferrari

Vitamin B and pancreatic cancer working group, EPIC

Simone Eussen Per Ueland Stein Emil VollsetØivind Midttun Carlos González Paul BrennanMattias JohanssonBas Bueno-de-Mesquita Paolo Vineis Shu-Chun Chuang