IJC

International Journal of Cancer

Variety in vegetable and fruit consumption and the risk of

gastric and esophageal cancer in the European Prospective
Investigation into Cancer and Nutrition
S.M. Jeurnink1,2, F.L. Büchner2,3, H.B. Bueno-de-Mesquita1,2, P.D. Siersema1, H.C. Boshuizen2,4, M.E. Numans5,
C.C. Dahm6,7, K. Overvad7, A. Tjønneland8, N. Roswall8, F. Clavel-Chapelon9,10, M.C. Boutron-Ruault9,10, S. Morois9,10,
R. Kaaks11, B. Teucher11, H. Boeing12, B. Buijsse12, A. Trichopoulou13,14, V. Benetou13, D. Zylis13,14, D. Palli15,
S. Sieri16, P. Vineis17,18, R. Tumino19, S. Panico20, M.C. Ocke
2, P.H.M. Peeters5, G. Skeie21, M. Brustad21, E. Lund21,
E. Sa
nchez-Cantalejo 22,23
, C. Navarro 23,24
, P. Amiano 23,25
, E. Ardanaz23,26, J. Ramo
n Quiro

s27, G. Hallmans28,
28 29
I. Johansson , B. Lindkvist , S. Regne
r , K.T. Khaw , N. Wareham , T.J. Key , N. Slimani32, T. Norat17,
29 30 30 31

A.C. Vergnaud , D. Romaguera and C.A. Gonzalez33

17 17

1
Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands
2
National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
3
Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
4
Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
5
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
6
Department of Cardiology, Aarhus University Hospital, Aalborg, Denmark
7
Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark
8
Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark
9
INSERM, Centre for Research in Epidemiology and Population Health, U1018, Institut Gustave Roussy, Villejuif, France
10
Paris South University, UMRS 1018, Villejuif, France
11
Division of Clinical Epidemiology, Deutsches Krebsforschungszentrum, Heidelberg, Germany
12
German Institute of Human Nutrition, Potsdam-Rehbucke, Germany
13
WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical
School, Athens, Greece
14
Hellenic Health Foundation, Athens, Greece
15
Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute-ISPO, Florence, Italy
16
Nutritional Epidemiology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
17
School of Public Health, Imperial College London, London, United Kingdom
18
HuGeF Foundation, Torino, Italy
19
Cancer Registry and Histopathology Unit, Civile-M.P. Arezzo Hospital, Ragusa, Italy
20
Department of Clinical and Experimental Medicine, Federico II University, Medical School, Naples, Italy
21
Department of Community Medicine, University of Tromsø, Tromsø, Norway
22
Andalusian School of Public Health, Granada, Spain
23
CIBER de Epidemiologia y Salud Publica (CIBERESP), Spain

Epidemiology
Key words: gastric cancer, esophageal cancer, vegetable and fruit, variety, EPIC
Grant sponsors: European Commission: Public Health and Consumer Protection Directorate 1993–2004; Research Directorate-General
2005; Ligue contre le Cancer, Institut Gustave Roussy, Mutuelle G
en
erale de l’Education Nationale, Institut National de la Sant
e et de la
Recherche M
edicale (INSERM) (France); German Cancer Aid, 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,
CIBER en Epidmeiologica y Salud Publica (CIBERESP), ISCIII RETIC (RD06/0020), Spanish Regional Governments of Andalusia, Asturias,
Basque Country, Murcia (No. 6236), Catalan Institute of Oncology (Spain); Cancer Research UK, Medical Research Council, Stroke
Association, British Heart Foundation, Department of Health, Food Standards Agency, the Wellcome Trust (United Kingdom); Greek
Ministry of Health and Social Solidarity, Hellenic Health Foundation and Stavros Niarchos Foundation (Greece); Italian Association for
Research on Cancer, National Research Council (Italy); Dutch Ministry of Health, Welfare and Sports, Dutch Prevention Funds, LK Research
Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Swedish
Cancer Society, Swedish Scientific Council, Regional Government of Skane (Sweden); Nordforsk (Centre of excellence programme Helga)
(Norway)
DOI: 10.1002/ijc.27517
History: Received 4 Sep 2011; Accepted 12 Jan 2012; Online 6 Mar 2012
Correspondence to: H.B. Bueno-de-Mesquita, Centre for Nutrition and Health, National Institute of Public Health and the Environment,
P.O. Box 1, 3720 BA Bilthoven, The Netherlands, Tel.: þ31-30-274-2019, Fax: þ31-30-2744466, E-mail: bas.bueno.de.mesquita@rivm.nl

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 E964 Variety in vegetable and fruit and gastroesophageal cancer risk

24
Department of Epidemiology, Murcia Regional Health Authority, Spain
25
Public Health Division of Gipuzkoa, Instituto Investigacion BioDonostia, Basque Regional Health Department, Spain
26
Navarre Public Health Institute, Pamplona, Spain
27
Public Health and Health Planning Directorate, Asturias, Spain
28
Department of Public Health and Clinical Medicine, Nutritional Research, University of Umeå, Umeå, Sweden
29
Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
30
Medical Research Council Dunn Human Nutrition Unit, Cambridge, United Kingdom
31
Cancer Research UK Epidemiology Unit, University of Oxford, Oxford, United Kingdom
32
International Agency for Research on Cancer (IARC-WHO), Lyon, France
33
Department of Epidemiology, Catalan Institute of Oncology, Barcelona, Spain

Diets high in vegetables and fruits have been suggested to be inversely associated with risk of gastric cancer. However, the
evidence of the effect of variety of consumption is limited. We therefore investigated whether consumption of a variety of
vegetables and fruit is associated with gastric and esophageal cancer in the European Prospective Investigation into Cancer
and Nutrition study. Data on food consumption and follow-up on cancer incidence were available for 452,269 participants
from 10 European countries. After a mean follow-up of 8.4 years, 475 cases of gastric and esophageal adenocarcinomas (180
noncardia, 185 cardia, gastric esophageal junction and esophagus, 110 not specified) and 98 esophageal squamous cell
carcinomas were observed. Diet Diversity Scores were used to quantify the variety in vegetable and fruit consumption. We
used multivariable Cox proportional hazard models to calculate risk ratios. Independent from quantity of consumption, variety
in the consumption of vegetables and fruit combined and of fruit consumption alone were statistically significantly inversely
associated with the risk of esophageal squamous cell carcinoma (continuous hazard ratio per 2 products increment 0.88; 95%
CI 0.79–0.97 and 0.76; 95% CI 0.62–0.94, respectively) with the latter particularly seen in ever smokers. Variety in vegetable
and/or fruit consumption was not associated with risk of gastric and esophageal adenocarcinomas. Independent from quantity
of consumption, more variety in vegetable and fruit consumption combined and in fruit consumption alone may decrease the
risk of esophageal squamous cell carcinoma. However, residual confounding by lifestyle factors cannot be excluded.

Over the past fifty years, incidence and mortality of gastric
cancer have decreased worldwide, especially in developed
countries, while the incidence of esophageal adenocarcinomas
is rising. Gastric cancer is however still the 3rd and esophageal
cancer the 7th cancer-related cause of death world-wide.1
A positive association with gastric cancer risk has been
observed for consumption of processed meat,2 nitrite,3 low
Epidemiology
tion into Cancer and Nutrition (EPIC) cohort, a suggestion
of an inverse association between vegetables and the intesti-
nal type of gastric cancer and adenocarcinoma of the esopha-
gus has been found, which was based on 330 gastric adeno-
carcinomas and 65 adenocarcinomas of the esophagus.8 A
case–control study nested within EPIC showed an inverse

association between vitamin C levels and gastric cancer

socio-economic status,4 smoking5 and infection with Helico-
bacter Pylori (H. Pylori).4,6 Inverse associations with gastric
cancer risk have been reported for consumption of fruit and
(raw) vegetables,4,7,8 dietary fibres9,10 and physical activity.11
Esophageal adenocarcinoma risk has been positively asso-
ciated with male gender,12 reflux symptoms,12 obesity,12
smoking12 and the consumption of processed meat.2 Inverse
associations were found for the consumption of vegetables
and fruit.8
The risk of esophageal squamous cell carcinoma has been
positively associated with low socio-economic status, smoking
and alcohol consumption,13 whereas an inverse association
has been reported for dietary fibres,9 dietary antioxidants and
the consumption of vegetables and fruit.14
In 2007, the evidence that diets rich in vegetables and
fruits are inversely associated with gastric and esophageal
cancer risk was considered probable by the World Cancer
Research Fund/American Institute for Cancer Research
(WCRF/AICR).15 Within the European Prospective Investiga-
risk.16 Another study from EPIC observed a strong inverse
association between quantity of vegetables and fruits and risk
of upper aerodigestive squamous cell cancers, with about one
quarter arising in the esophagus.17
To our knowledge, no cohort studies have investigated the
relationship between the variety in vegetable and fruit con-
sumption and gastric and esophageal cancer risk. Different
vegetables and fruits contain different bioactive compounds
suggesting that a mix of anti-carcinogenic substances, like
antioxidants, may be responsible for the inverse associations
observed.18 Only two case–control studies evaluated the influ-
ence of variability in the consumption of vegetables and fruit
and both suggested an inverse association with both gastric
and esophageal cancers.19,20
The aim of this prospective study was to evaluate the
association between the variety in vegetable and fruit con-
sumption, independent from quantity of total vegetable and
fruit consumption, and the risk of gastric and esophageal
cancer among participants in the EPIC.

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Jeurnink et al.
Material and Methods
Study participants
EPIC is an ongoing multicenter cohort study designed to
investigate the relation between diet, lifestyle, metabolic and
environmental factors and the incidence of chronic diseases.
The cohort consists of cohorts of men and women recruited
in 23 centers in 10 European countries: Denmark, France,
Germany, Greece, Italy, The Netherlands, Norway, Spain,
Sweden and the United Kingdom. The populations and
methods have been described in full elsewhere.21 In brief, the
EPIC cohort consists of 521,468 subjects, mostly aged 35–70
years, recruited in the period 1992–2000 mostly from the
general population, with some exceptions in specific geo-
graphical areas, i.e., in France, Norway, Utrecht (The Nether-
lands) and Naples (Italy) only women were recruited. All
participants gave written informed consent. The study was
approved by the local ethics committee in the participating
countries and the Internal Review Board of the International
Agency for Research on Cancer.
Diet and lifestyle questionnaires
At baseline, the usual diet reflecting the situation 12 months
before enrolment was assessed by country-specific validated
questionnaires designed to capture local dietary habits, and
to provide high compliance.22 Although the design of the
questionnaires was based on the same general format, there
were differences between the questionnaires used in several
countries. Extensive quantitative dietary questionnaires were
used in three centers in northern Italy, The Netherlands and
Germany (self-administered), as well as in Greece (inter-
viewer-administered). In France (self-administered), Spain
and Ragusa (Italy) interviewer-administered questionnaires
similar to the dietary questionnaires, but structured by meals,
were used. In order to increase compliance, the centers in
Spain and Ragusa performed a face-to-face interview using a
computerized program. Semi-quantitative food frequency
questionnaires with the same standard portion assigned to all
participants were used in Denmark, Norway, Naples (Italy)
and Umeå (Sweden). In Malm€o (Sweden), a nonquantitative
food frequency questionnaire was combined with a 14-day
record on hot meals. Details of the food items included in
the selected vegetable and fruit subgroups used in the analy-
sis have been reported in full by Agudo et al.23
Lifestyle questionnaires included questions on education,
occupation, medical history, lifetime history of tobacco use
and physical activity.21,24
Diet Diversity Scores for vegetable and fruit consumption
Country-specific dietary questionnaires differed in the num-
ber of vegetables and fruits included. In order to improve
between-country comparability of the scores, we decided to
only select vegetable and fruit items that were included in
four or more country-specific dietary questionnaires. This
included the majority of products.
Int. J. Cancer: 131, E963–E973 (2012) V
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E965
Based on the baseline dietary questionnaires, four different
Diet Diversity Scores (DDS) were calculated, with DDSvegfr
(range 0–40) counting the total number of individual vegeta-
ble and fruit products eaten at least once in two weeks.
DDSvegsub (range 0–8) counted the total number of vegeta-
ble subgroups eaten at least once in two weeks. The eight
subgroups of vegetables used included: leafy vegetables, fruit-
ing vegetables, root vegetables, cabbages, mushrooms, grain
and pod vegetables, onion and garlic and stalk vegetables.25
DDSveg (range 0–26) counted the total number of individual
vegetable products eaten at least once in two weeks. DDSfruit
(range 0–14) counted the total number of individual fruit
products eaten at least once in two weeks. The consumption
of fruit included fresh, dried and canned fruits but excluded
nuts, seeds and olives (Appendix).
Follow-up and endpoints
Follow-up was based on population-based cancer registries in
seven of the participating countries: Denmark, Italy, Nether-
lands, Spain, Sweden, United Kingdom and Norway. In
France, Germany and Greece, a combination of methods was
used, including health insurance records, cancer and pathol-
ogy hospital registries and active follow-up. Mortality data
were also collected from registries at the regional or national
level.21 Cancer of the stomach and esophagus included can-
cers coded to C16 and C15 according to the 10th Revision of
the International Statistical Classification of Diseases, Injuries
and Causes of Death (ICD-10). For the current analysis, par-
ticipants were followed from study entry until a first primary
gastric or esophageal cancer, death, emigration or end of fol-
low-up period.
Gastric and esophageal cancer cases classified as malignant
lymphoma (morphology code 9590) and small cell carcinoma
(morphology code 8041–8045) or coded as ‘‘benign" (5th
digit of the morphology code is zero), ‘‘uncertain whether be-
Epidemiology
nign or malignant" (5th digit of the morphology code is one)
or ‘‘carcinoma in situ’’ (5th digit of the morphology code is
two) were censored at time of diagnosis. Only cancer cases
coded as ‘‘malignant" (5th digit of the morphology code is
three) were included as cases. We classified cases according
to five major histological types, i.e., gastric cardia adenocarci-
noma, noncardia gastric adenocarcinoma, adenocarcinoma of
the gastric esophageal junction (GEJ), adenocarcinoma of the
esophagus (8140) and squamous cell carcinoma of the esoph-
agus (8070). GEJ was defined as the proximal end of the gas-
tric folds (at macroscopy) or by the proximal limit of the
gastric oxyntic mucosa (by histology).26 For the purpose of
this study, tumors crossing the GEJ and those developing just
below it were grouped in a broad group of the ‘‘cardia"
carcinomas.26
Validation and confirmation of the diagnosis, classification
of tumor site and morphology of tumor (according to
ICDO2 Classification and Lauren classification) of the gastric
and esophageal adenocarcinomas was performed by a panel
of pathologists, including a representative from each
 E966
participating country and a coordinator. The panel reviewed
material provided by the centers (original histological slides
and/or slides obtained from paraffin blocks, as well as origi-
nal histopathological reports).26 Validation and confirmation
of the esophageal squamous cell carcinomas was not
performed.
Statistical methods
Cox proportional hazard regression was used to analyze the
association between the DDSs and gastric and esophageal
cancer. Entry time was defined as age at recruitment and fol-
low-up time as age of diagnosis (cases) or age at censoring
(at-risk subjects). All analyses were stratified by age at base-
line to control for length of follow-up, and by gender, and
center to control for country effects such as follow-up proce-
dures and questionnaire design. Cases diagnosed after censor-
ing date were considered as noncases. Individuals with miss-
ing information on (non)dietary habits were excluded from
the analysis (n ¼ 814). Also individuals in the upper and
lower 1% percentiles of ‘‘energy consumption/required
energy" of the total EPIC cohort were excluded (n ¼ 459),
because of the likelihood of unrealistic reporting of consump-
tion of food-products.
Due to possible differences in etiology, separate analyses
were performed for 3 groups of cancers (i) noncardia adeno-
carcinomas of the stomach, (ii) adenocarcinomas of the esoph-
agus, the GEJ and the gastric cardia and (iii) esophageal squa-
mous cell carcinomas. In addition, gastric adenocarcinomas
were subdivided in diffuse and intestinal adenocarcinomas.
The DDS were divided into tertiles (T1–3), according to
the distribution observed in the full cohort, with the lowest
tertile as reference category. Additionally, we analyzed the
effect of DDS continuously per 2 products increment for
DDSvegfr, DDSveg, DDSfruit and with increments of 1 sub-
group for DDSvegsub.
Epidemiology
Individuals with a more varied consumption of vegetables
and fruits are more likely to eat more vegetables and fruits,
therefore we controlled for the quantity of consumption of
vegetables and/or fruit (g/day). Also smoking status (current,
former and never), smoking duration (years), lifetime smok-
ing dose (number of cigarettes/day), BMI (kg/m2), alcohol
consumption (g/day) and combined red and processed meat
consumption (g/day) were taken into account as confounders.
In order to improve error correction, estimated energy intake
was divided into energy from fat and from other macronu-
trients, because it is mostly the nonfat components of the
diet that contribute to fruit and vegetable intake. All models
included energy intake from fat and nonfat sources (kcal/
day).27 Indicator values were used for missing values.
We derived probability values for a linear trend from
regression models using a continuous variable with values
equal to the tertile medians, to take the unequal distances of
the tertiles into account.
The potential modifying effect of H. Pylori infection was
analyzed in a subset of 1,260 participants, including 88 with
Variety in vegetable and fruit and gastroesophageal cancer risk
noncardia adenocarcinoma, for whom H. Pylori status was
known. This subgroup was reported in a previous EPIC
study.28 We also tested the highest educational level as proxy
for social economic status and physical activity but these var-
iables had no influence on the models.
Analyses were performed on the full cohort, but also with-
out the first two years of follow-up, including 89 cases of gas-
tric and esophageal adenocarcinomas and 25 esophageal squa-
mous cell carcinomas, to exclude potential pre-diagnostic
changes in diet in patients with pre-clinical gastric cancer. The
cohort was also split in a northern (Germany, The Nether-
lands, Sweden, Denmark, United Kingdom and Norway) and
a southern (France, Italy, Spain and Greece) cohort, because
of the differences in food patterns and incidence of H. Pylori
infection. For the subgroup of gastric adenocarcinomas, we
performed separate analyses for intestinal and diffuse gastric
adenocarcinomas, because of differences in etiology. For all
subgroups, we performed separate analyses for ever (former
and current combined) and never smokers. Interactions (on
the multiplicative scale) were tested using the interaction term
of vegetable and fruit variety (in tertiles) with smoking (ever
vs. never) and cohort (north vs. south). Finally, analyses were
performed separately for males and females.
All analyses were performed using SAS version 9.1 (SAS
Institute Inc., Cary, NC). A p < 0.05 was considered to be
significant.
Results
After a mean follow-up of 8.4 years, 475 gastric and esopha-
geal adenocarcinomas and 98 esophageal squamous cell carci-
nomas were diagnosed. Of the patients with an adenocarci-
noma, 180 were classified as noncardia adenocarcinomas and
185 as adenocarcinomas of the esophagus, GEJ or gastric car-
dia. In 110 patients, the location of the adenocarcinoma was
unknown. Table 1 shows the frequency of adenocarcinomas
and squamous cell carcinomas by country.
Selected characteristics across tertiles of variety in vegeta-
ble and fruit consumption (DDSvegfr) are shown in Table 2.
In general, differences were most apparent for participants in
the highest third of DDSvegfr, which were more often
women, more often never smokers, more often H. Pylori neg-
ative and reported higher education. Additionally, they con-
sumed more vegetables and fruit, less red and processed
meat and were more often alcohol consumers.
Table 3 shows the adjusted hazard ratios (HRs) and 95%
confidence intervals (95% CI) separately for (i) noncardia
adenocarcinomas, (ii) adenocarcinomas of the esophagus,
GEJ and gastric cardia, and (iii) esophageal squamous cell
carcinomas. None of the analyses showed a difference
between males and females (data not shown).
Results on noncardia adenocarcinoma risk suggested a
positive association comparing the highest tertile of variety of
consumption of vegetable and fruit products (DDSvegfr) with
the lowest tertile (HR 1.82; 95% CI 1.02–3.25, p-trend ¼
0.04). However, the continuous variable did not show a
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Jeurnink et al. E967

Table 1. Number of gastric and esophageal cancer cases per country. The EPIC Cohort Study
Gastric and esophageal adenocarcinomas1
Esophageal, Esophageal
Person Noncardia GEJ & cardia squamous cell
Country years Total adenocarcinomas adenocarcinomas Unknown carcinomas
Total Cohort 3,913,294 475 180 185 110 98
Northern Cohort 2,223,832 318 97 157 64 77
Germany 401,486 61 30 18 13 12
The Netherlands 310,057 34 12 14 8 6
Sweden 257,309 32 12 13 7 5
Denmark 412,367 88 22 50 16 33
United Kingdom 632,362 90 16 60 14 20
Norway2 210,251 11 5 2 4 1
Southern Cohort 1,689,462 159 83 28 48 21
France2 737,416 15 7 4 4 0
Italy 376,123 65 34 13 18 7
Spain 395,033 54 32 8 14 13
Greece 180,890 25 10 3 12 1
1
The group gastric and esophageal adenocarcinomas includes adenocarcinomas of the gastric cardia, gastric noncardia, gastroesophageal junction
and esophagus. 2The Norwegian and French cohorts consist of women only.

significant association with risk (HR per 2 products incre-
ment 1.06; 95% CI 0.98–1.14). Excluding the first two years
of follow-up attenuated somewhat the categorical association
(T3 vs. T1 HR 1.71; 95% CI 0.89–3.28, p-trend ¼ 0.11). Ana-
lyzing by H. Pylori status in a subset of 1,260 participants
with known H. Pylori status, further weakened the results in
the H. Pylori positive subgroup (DDSvegfr T1 vs. T3 HR
1.67; 95% CI 0.33–8.44, p-trend ¼ 0.61). The H. Pylori nega-
tive subgroup did not contain a sufficient number of cases to
perform accurate analysis. Stratified analysis by smoking sta-
tus showed a positive association in ever smokers for the va-
(Table 3). In the analysis stratified by smoking status, no
associations between the DDS scores and risk were seen in
ever and never smokers (data not shown).
Results on esophageal squamous cell carcinoma showed
that each increase in consumption of two different products
of vegetables and fruits combined statistically significantly
decreased the risk of esophageal squamous cell carcinoma by
12% (continuous HR 0.88; 95% CI 0.79–0.97) (Table 3).
Excluding the first two years hardly affected the results (con-
tinuous HR 0.89; 95% CI 0.79–1.00). In addition, increasing
diversity in fruit consumption was statistically significantly

riety of consumption of vegetable and fruit products com-
bined (DDSvegfr T1 vs. T3 HR 2.72; 95% CI 1.31–5.68). In
addition, we found a positive association in never smokers
for fruit consumption alone (DDSfruit T1 vs. T2 HR 2.08;
95% CI 1.06–4.07). However, the continuous variable did not
show a significant association (HR per 2 products increment
1.11; 95% CI 1.00–1.23 and HR 1.07; 95% CI 0.87–1.33
respectively) (data not shown).
There was an apparent difference between diffuse and in-
testinal gastric adenocarcinomas with a nonsignificant inverse
association between variety in vegetable and fruit consump-
tion (DDSvegfr) and risk of intestinal gastric adenocarcino-
mas (T2 vs. T1 HR 0.56; 95% CI 0.36–0.87; T3 vs. T1 HR
0.72; 95% CI 0.39–1.35; p-trend ¼ 0.26; data not shown) and
a nonsignificant positive association of variety in vegetable
and fruit consumption and risk of diffuse gastric adenocarci-
nomas (T2 vs. T1 HR 1.63; 95% CI 1.01–2.63; T3 vs. T1 HR
1.64; 95% CI 0.81–3.30; p-trend ¼ 0.17; data not shown).
None of the DDSs were associated with risk of adenocar-
cinomas of the esophagus, GEJ and gastric cardia combined
Epidemiology
and inversely associated with risk of esophageal squamous
cell carcinoma both in the categorical (p-trend ¼ 0.04) as in
the continuous analysis with a 24% risk reduction for each
increase in consumption of two different fruit products (con-
tinuous HR 0.76; 95%CI 0.62–0.94). Excluding the first two
years hardly affected the strength of this association (continu-
ous HR 0.79; 95% CI 0.62–1.02). When analyzing ever smok-
ers separately for esophageal squamous cell carcinomas, we
found a significant inverse association for a varied fruit con-
sumption (continuous HR per 2 products increment 0.74;
95% CI 0.57–0.96, Table 4). In the subgroup of never smok-
ers we did not find a significant association for a varied fruit
consumption and esophageal squamous cell carcinoma risk
(continuous HR per 2 products increment 1.03; 95% CI
0.67–1.61). However, this subgroup did not contain a suffi-
cient number of cases (n ¼ 21) to perform an accurate
analysis.
We found no difference in associations between vegetable
and fruit consumption and risks of gastric cancer between
the northern and southern countries. In addition, the

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 E968 Variety in vegetable and fruit and gastroesophageal cancer risk

Table 2. Baseline characteristics by tertiles of the Diet Diversity Score for intake of vegetables and fruits (for quantitative variables mean
(SD) or median (range) and for qualitative variables (percentages). The EPIC Cohort Study
DDS vegetable & fruit products (DDSvegfr)
Full Cohort 1 2 3
Cutoff values tertiles 0–11 12–19 20–40
General characteristics
Mean age at recruitment (years) 51 (9.9) 50 (8.7) 52 (9.8) 50 (10.9)
Gender (% men) 29 33 37 18
BMI (kg/m2) 25.4 (4.3) 25.5 (4.3) 26.2 (4.3) 24.6 (4.2)
Helicobacter Pylori infection (%)1 69 70 69 66
Smoking status (%)
Never 50 45 46 58
Former 27 26 28 25
Current 22 27 25 15
Unknown 1 2 1 1
Education level (%)
None 4 4 7 2
Primary school completed 23 28 27 13
Technical/professional school 23 26 26 16
Secondary School 24 22 20 31
University degree 24 20 19 33
Not specified 2 0 2 5
Diet (median, range)
Observed overall intake vegetables (g/day) 177.6 (0–2,979) 108.2 (0–1,525) 166.6 (0–1,848) 267.9 (3.6–2,979)
Observed overall intake fruit (g/day) 195.0 (0–4,647) 117.2 (0–2,576) 199.7 (0–4,174) 268.3 (0–4,647)
Overall energy intake (kcal) 1987.9 (589–6,088) 1819.1 (589–6,088) 2019.2 (659–5,830) 2103.2 (700–5,947)
Alcohol nonconsumers (%) 5 9 5 2
Overall alcohol consumption (g/day)2 6.2 (>0–344) 4.8 (>0–32) 7.3 (>0–286) 6.6 (>0–344)
Overall red and processed meat intake (g/day) 66.6 (0–907) 62.6 (0–815) 74.8 (0–814) 61.8 (0–907)
1 2
Based on 1,260 participants. Median consumption of alcohol excluding nonconsumers.
Epidemiology

interaction was not statistically significant for noncardia ade-
nocarcinoma risk (p ¼ 0.75) and risk of adenocarcinoma of
the esophagus, GEJ and gastric cardia (p ¼ 0.92). For esoph-
ageal squamous cell carcinoma a somewhat stronger and stat-
istically significant inverse association was only seen in the
northern countries (Northern cohorts continuous HR 0.87;
95% CI 0.78–0.97 vs. Southern cohorts continuous HR 0.96;
95% CI 0.73–1.25). However, subgroups were small especially
in southern countries. In addition, the test for interaction
was not statistically significant (p ¼ 0.88).
Discussion
Overall, we found that, independent from quantity of con-
sumption of total vegetable and fruit, more variety in vegeta-
ble and fruit consumption and fruit consumption alone were
associated with a decreased risk of esophageal squamous cell
carcinoma. This association was particularly seen among ever
smokers. Variety in vegetable and/or fruit consumption was
not associated with risk of gastric and esophageal adenocarci-
nomas. However, our results did show a nonsignificant
inverse association between variety in vegetable and fruit
consumption and risk of intestinal gastric adenocarcinomas.
In a previous EPIC analysis based on 330 gastric adeno-
carcinomas and 65 adenocarcinomas of the esophagus,8 no
association was found between total vegetable or fruit con-
sumption and gastric adenocarcinomas risk (vegetable HR
0.91; 95% CI 0.65–1.28 and fruit HR 1.04; 95%CI 0.91–1.20
per 100 g). However, a statistically nonsignificant inverse
association between vegetable consumption and esophageal
adenocarcinoma risk was observed (HR 0.72; 95% CI 0.32–
1.64 per 100 g). Our current results using a larger number of
cases suggest that there is however no association between
the variety in vegetable and/or fruit consumption and gastric
and esophageal adenocarcinoma risks.
DDS have previously been used to describe the variety
within diets or food groups in relation to mortality and gas-
tric and esophageal cancer risk. Jansen et al. (2004)29 looked
specifically into diversity of vegetable and fruit consumption

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Jeurnink et al. E969

Table 3. Adjusted1 hazard ratios and 95% confidence intervals (95% CIs) for gastric and esophageal cancer of the four different Diet
Diversity Scores (DDS) for the full cohort. The EPIC cohort study
Noncardia Esophageal, GEJ and Esophageal squamous
adenocarcinoma cardia adenocarcinomas cell carcinomas
N of Adjusted hazard Adjusted hazard Adjusted hazard
Range participants N ratio (95% CI) N ratio (95% CI) N ratio (95% CI)
DDS vegetables & fruits (DDSvegfr)2,3
T1 0–11 141,491 63 1 69 1 39 1
T2 12–19 158,162 79 1.17 (0.78–1.76) 79 0.76 (0.52–1.12) 45 0.79 (0.47–1.33)
T3 20–40 152,616 38 1.82 (1.02–3.25) 37 0.76 (0.43–1.33) 14 0.42 (0.17–1.04)
p-trend 0.04 0.33 0.07
Continuous per 2 products increment 1.06 (0.98–1.14) 0.97 (0.91–1.04) 0.88 (0.79–0.97)
DDS vegetable subgroups (DDSvegsub)3
T1 0–5 172,759 91 1 61 1 37 1
T2 6–7 172,080 61 0.80 (0.55–1.17) 68 1.01 (0.66–1.53) 38 0.94 (0.55–1.60)
T3 8 107,430 28 1.10 (0.62–1.94) 56 1.17 (0.70–2.94) 23 0.59 (0.29–1.22)
p-trend 0.61 0.62 0.26
Continuous per 1 product increment 1.02 (0.90–1.15) 1.00 (0.88–1.12) 0.92 (0.78–1.09)
DDS vegetables (DDSveg)3
T1 0–7 137,567 67 1 58 1 34 1
T2 8–13 169,349 82 0.93 (0.64–1.36) 87 1.04 (0.70–1.55) 43 0.82 (0.49–1.39)
T3 14–26 145,353 31 1.09 (0.61–1.94) 40 0.81 (0.46–1.43) 21 0.72 (0.32–1.62)
p-trend 0.86 0.46 0.41
Continuous per 2 products increment 1.07 (0.97–1.19) 0.94 (0.85–1.03) 0.89 (0.77–1.03)
DDS fruits (DDSfruit)2
T1 0–3 150,466 68 1 77 1 53 1
T2 4–7 165,479 72 1.10 (0.75–1.62) 83 0.98 (0.69–1.39) 34 0.59 (0.36–0.97)
T3 8–14 136,324 40 1.33 (0.76–2.33) 25 0.83 (0.46–1.49) 11 0.48 (0.21–1.11)
p-trend 0.32 0.58 0.04
Continuous per 2 products increment 1.08 (0.94–1.25) 1.01 (0.88–1.17) 0.76 (0.62–0.94)
1
Cox regression model stratified by age at recruitment, gender and centre and adjusted for smoking status, duration of smoking, lifetime number of

Epidemiology
cigarettes, energy intake from fat and nonfat sources, red and processed meat, BMI and alcohol. 2Cox regression model additionally adjusted for
fruit consumption. 3Cox regression model additionally adjusted for vegetable consumption.

in relation to cancer risk and found decreased overall cancer
risks among the individuals with a higher variety in vegetable
consumption. However, an inverse relation between total
cancer risk and variety in fruit consumption was only seen
after exclusion of the first two years of follow-up.29 One
case–control study on gastric cancer19 and one case–control
study on esophageal squamous cell carcinoma20 found
inverse associations for both cancers for a more varied diet,
especially a more varied consumption of vegetables and fruit.
Nevertheless, the authors not adjust specifically for the total
number of fruit and vegetable servings consumed.
Our results suggest a positive association between variety
in vegetable and fruit consumption and risk of gastric non-
cardia adenocarcinomas, especially in never smokers. This
association weakened after excluding the first 2 years of fol-
low-up and in participants positive for H. Pylori which may
be explained by chance, especially because the continuous
analysis does not support the positive association. For the
subanalysis on H. Pylori the sample size did not contain a
sufficient number of noncardia cancer cases negative for H.
Pylori infection and therefore does not allow definitive con-
clusions to be made. In addition, H. Pylori infection did not
modify the association between the quantity of vegetable and
fruit consumption and risk of gastric and esophageal adeno-
carcinomas in previous studies.8 Large cohort studies with
long-term follow-up are needed to definitely conclude
whether H. Pylori infection affects the association between
variety in vegetable and fruit consumption and risk of gastric
noncardia adenocarcinomas. In addition, our results for never
smokers were underpowered and might be due to chance
and due to relatively small subgroups.
The statistically nonsignificant inverse association between
variety of vegetable and fruit consumption and risk of intesti-
nal gastric adenocarcinomas may be in line with the previous

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 E970 Variety in vegetable and fruit and gastroesophageal cancer risk

Table 4. Adjusted1 hazard ratios and 95% confidence intervals (95% CIs) for esophageal squamous cell cancer of the four different Diet
Diversity Scores (DDS) in ever and never smokers. The EPIC cohort study
Ever smokers Never smokers
Esophageal Adjusted Esophageal Adjusted
N of squamous cell hazard squamous cell hazard ratio
Range participants carcinomas N ratio (95% CI) carcinomas N (95% CI)
DDS vegetables & fruits (DDSvegfr)2,3
T1 0–11 141,491 38 1 1 1
T2 12–19 158,162 32 0.77 (0.43–1.37) 13 3.45 (0.43–27.7)
T3 20–40 152,616 7 0.67 (0.23–1.96) 7 0.95 (0.09–9.94)
Continuous per 2 products increment 0.90 (0.79–.03) 0.93 (0.76–1.14)
3
DDS vegetable subgroups (DDSvegsub)
T1 0–5 172,759 32 1 5 1
T2 6–7 172,080 33 1.22 (0.68–2.19) 5 0.24 (0.06–0.95)
T3 8 107,430 12 0.64 (0.27–1.52) 11 0.37 (0.09–1.59)
Continuous per 2 products increment 0.94 (0.64–.36) 0.76 (0.34–1.69)
DDS vegetables (DDSveg)3
T1 0–7 137,567 32 1 2 1
T2 8–13 169,349 35 0.85 (0.48–1.50) 8 0.96 (0.19–4.79)
T3 14–26 145,353 10 0.73 (0.28–1.95) 11 1.08 (0.17–6.93)
Continuous per 2 products increment 0.94 (0.79–1.12) 0.86 (0.66–1.13)
2
DDS fruits (DDSfruit)
T1 0– 150,466 47 1 6 1
T2 4–7 165,479 26 0.67 (0.38–1.18) 8 0.71 (0.21–2.35)
T3 8–14 136,324 4 0.34 (0.10–1.13) 7 0.81 (0.19–3.47)
Continuous per 2 products increment 0.74 (0.57–0.96) 1.03 (0.67–1.61)
1
Cox regression model stratified by age at recruitment, gender and centre and adjusted for smoking status, duration of smoking, lifetime number of
cigarettes, energy intake from fat and nonfat sources, red and processed meat, BMI and alcohol. 2Cox regression model additionally adjusted for
fruit consumption. 3Cox regression model additionally adjusted for vegetable consumption.

result found in the EPIC cohort (intestinal type n ¼ 116, dif- in part attributed to the effect of fruit alone. A recent EPIC
fuse type n ¼ 120) on quantity of vegetable and fruit intake
Epidemiology

study on lung cancer also found an inverse association

and risk of intestinal gastric adenocarcinomas (HR 0.66; 95%
CI 0.35–1.22 per 100 g increase).8 In addition, our results are
comparable to a case–control study by Lunet et al.30 Never-
theless, evidence from cohort studies is lacking and the meta-
bolic pathway and features of this histological type are still
unknown. It has been suggested that the intestinal type has a
predominately environmental etiology, resulting in the possi-
bility of a more prominent role of vegetable and fruit con-
sumption in this group, whereas the diffuse type is thought
to be more genetically determined. H. Pylori infection, how-
ever, seems to have similar effects on the risk of both intesti-
nal and diffuse gastric cancer risk.30
Our observation that more variety in vegetable and/or
fruit consumption may decrease the risk of esophageal squa-
mous cell carcinomas may well be in line with the strong
inverse association observed in EPIC between quantity of
vegetables and fruits and risk of upper aerodigestive cancers
of which about one quarter were located in the esophagus.17
However, the effect of vegetable and fruit combined may be
between variety in vegetable and fruit consumption and risk
of squamous cell carcinomas of the lung.31 Compared to
adenocarcinomas, squamous cell carcinomas appear to be
more affected by smoking. The association between vegetable
and fruit consumption and risk of squamous cell carcinoma
may therefore differ between ever and never smokers,
because antioxidants in vegetables and fruit may protect
against the damage caused by free radicals in cigarette smoke.
On the other hand, oxidative stress due to smoking may
reach such high levels that antioxidants are not sufficiently
capable to protect against oxidative stress.32 In our study, we
found a significant inverse association for a varied fruit con-
sumption and esophageal squamous cell carcinoma risk in
ever smokers (continuous HR per 2 products increment 0.74;
95% CI 0.57–0.96). In the subgroup of never smokers, we did
not find a significant association for a varied fruit consump-
tion and esophageal squamous cell carcinoma risk (continu-
ous HR per 2 products increment 1.03; 95% CI 0.67–1.61).
However, the subgroup of never smokers did not contain

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Jeurnink et al. E971

sufficient cancer cases to yield stable risk estimates. Yet abso-
lute risks for never smokers (T1 0.01%, T2 0.001%, T3
0.01%) seem to be lower compared to ever smokers (T1
0.06%, T2 0.03%, T3 0.01%). It should be noted however that
the association in ever smokers may also be caused by resid-
ual confounding. Therefore, our suggested evidence of an
inverse association between variety in vegetables and/or fruits
and the risk of squamous cell cancers of the esophagus in
particular in ever smokers does require further research.
Analyses stratified by geographic region showed only minor
differences in risk estimates between the northern and the
southern cohorts with a suggestion of an inverse association
with risk of esophageal squamous cell carcinomas only in the
northern cohorts. This difference remained even when separate
tertiles were used for northern and southern countries (data
not shown). Such findings may well be explained by chance
since southern cohorts were having substantially fewer cases.
The main limitation of our study is the small size of the
subgroups of cancer types with concomitant loss of power to
detect the usually weak diet–cancer associations. The positive
association in the categorical analyses between a more varied
vegetable and fruit consumption and risk of noncardia
adenocarcinomas may be the result of the multiple tests that
we performed. Another limitation is that dietary question-
naires may not be adequate enough to validly rank partici-
pants according to variety in vegetable and fruit intake. A
recent EPIC study concluded that high blood levels of vita-
min C and carotenoids were inversely associated with gastric
cancer risk, whereas dietary intakes of vitamin C,16 b-caro-
tene and vitamin E33 were not related to risk, suggesting that
blood levels of vitamins and antioxidants may lead to more
accurate results than questionnaires.34 In addition, blood lev-
els of vitamins measure the actual amount of vitamins
absorbed, as absorption may be influenced by other factors,
like H. pylori infection.
EPIC is the largest prospective investigation on diet, life-
style and cancer so far involving 10 European countries.21
Because there is a wide range in dietary and lifestyle habits
within EPIC, the study is well suited to examine diet diversity
and gastric cancer risk. As the dietary questionnaires used in
this project slightly differed between the different EPIC cen-
ters, we calculated the DDSs based on fruit and vegetable
products included in four or more dietary questionnaires.
This makes the DDSs better comparable between countries.
The more vegetable and fruit products are included in a
questionnaire the more likely individuals may report eating
them. And thus, we may have over- or under-estimated the
variety in consumption in the few centers that used question-
naires with longer lists of products; however, this concerns a
minority of products only. Conversely, we may have underes-
timated diversity in centers with only few items included in
dietary questionnaires such as Norway. Finally, we were able
to adjust for quantity of consumption of vegetables and
fruits. It should be kept in mind that the individuals with a
more varied consumption of vegetable and fruit are, in gen-
eral, the individuals consuming more vegetables and fruit
and these individuals probably share also other lifestyle fac-
tors that may be linked to the cancers of interest in this
study and, consequently, our findings may be explained by
residual confounding.
In conclusion, irrespective of the quantity of total vegeta-
ble and fruit consumption, more variety in vegetable and
fruit consumption and in fruit consumption alone is inversely
associated with the risk of esophageal squamous cell carci-
noma; the inverse association for fruits was particularly seen
among ever smokers. Variety in vegetables and/or fruits was
not associated with risk of gastric and esophageal adenocarci-
noma. In participants consuming a diverse diet in vegetables
and fruits, a reduced risk of intestinal adenocarcinomas was
observed but this association was not statistically significant.

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Appendix

Table A1. Food items included in the Diet Diversity Scores

DDSvegsub DDSvegpr DDSfr

Leafy vegetables Endive Apple
Green salad Pear
(iceberg) Lettuce Apricot/peach/nectarine
Spinach Banana
Swiss chard Strawberry
Fruiting Vegetables Artichoke Grape
Avocado Cherry
(green/French) Beans Orange
Tomato Mandarin
Courgette Grapefruit
Cucumber Prune
Egg plant Fig
Sweet pepper Melon
Gherkin Watermelon
Root vegetables Beet root Kiwi
Carrot Pineapple
Celeriac
Cabbages Broccoli
Brussels sprout
Cabbage not specified
Red cabbage
White cabbage
Cauliflower
Mushrooms Mushrooms
Grain and Pod vegetables Corn
Pea

Epidemiology
Broad bean
Onion, Garlic Onion
Garlic
Stalk Vegetables, Sprouts Asparagus
Celery
Fennel
Leek

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