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Nutrition and Cancer
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Association Between the Mediterranean Diet and
Cancer Risk: A Review of Observational Studies
Lisa Verberne
a b
c
d
, Anna Bach-Faig , Genevieve Buckland & Lluís Serra-Majem
a c
a
Department of Clinical Sciences, University of Las Palmas de Gran Canaria, Las Palmas de
Gran Canaria, Spain
b
Wageningen University, Division of Human Nutrition, Wageningen, Netherlands
c
Mediterranean Diet Foundation, Barcelona, Spain
d
Unit of Nutrition, Environment, and Cancer, Cancer Epidemiology Research Programme,
Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain
Published online: 04 Oct 2010.
To cite this article: Lisa Verberne , Anna Bach-Faig , Genevieve Buckland & Lluís Serra-Majem (2010): Association Between
the Mediterranean Diet and Cancer Risk: A Review of Observational Studies, Nutrition and Cancer, 62:7, 860-870
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Nutrition and Cancer, 62(7), 860–870
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Copyright ISSN: 0163-5581 print / 1532-7914 online
DOI: 10.1080/01635581.2010.509834
Association Between the Mediterranean Diet and Cancer
Risk: A Review of Observational Studies
Lisa Verberne
Department of Clinical Sciences, University of Las Palmas de Gran Canaria, Las Palmas de Gran
Canaria, Spain and Wageningen University, Division of Human Nutrition, Wageningen, Netherlands
Anna Bach-Faig
Mediterranean Diet Foundation, Barcelona, Spain
Genevieve Buckland
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Unit of Nutrition, Environment, and Cancer, Cancer Epidemiology Research Programme, Catalan
Institute of Oncology (ICO-IDIBELL), Barcelona, Spain
Lluı́s Serra-Majem
Department of Clinical Sciences, University of Las Palmas de Gran Canaria, Las Palmas de Gran
Canaria, Spain and Mediterranean Diet Foundation, Barcelona, Spain
The aim of this article was to summarize the evidence concerning the association between Mediterranean dietary pattern and
cancer risk in observational epidemiological studies. All the studies that met the following criteria were reviewed: human cohort and
case-control studies that examined the effect of the Mediterranean
diet as an entire food pattern (the combined effect of individual
components of the Mediterranean diet) and whose results were
published in English. Out of the 12 reviewed studies (7 cohort and
5 case-control), 10 studies (6 cohort and 4 case-control) provided
some evidence that the Mediterranean diet was associated with a
reduced risk of cancer incidence or mortality. Although the reviewed studies varied according to certain study characteristics,
such as being set in different populations and studying different
cancer outcomes, the existing evidence from observational studies
collectively suggests that there is a “probable” protective role of the
Mediterranean diet toward cancer in general. Specific results for
several outcomes such as different cancer sites deserve additional
evidence. This favorable effect of the Mediterranean diet on cancer
reduction is of public health relevance, given the tendency of modern societies to shift toward a more U.S. and Northern European
dietary pattern.
Submitted 27 February 2010; accepted in final form 16 July 2010.
Address correspondence to Lluı́s Serra-Majem, Department of
Clinical Sciences, University of Las Palmas de Gran Canaria,
P.O. Box 550, 35080 Las Palmas de Gran Canaria, Spain.
Phone: +34928453476/+34928453477. Fax: +34928453475. E-mail:
[email protected]
INTRODUCTION
Cancer is currently one of the most important public health
issues; each year approximately 11 million new cases of cancer and almost 7 million cancer deaths are recorded globally,
and projections expect this to double by 2030 (1). Despite the
heavy global cancer burden, few cancers are due to an inherited
high susceptibility, and environmental factors (that are largely
modifiable) play a major role in the cancer etiology. As a consequence, a large proportion of cancers are in principle preventable.
Historically, the incidence of overall cancer was lower in
Mediterranean countries compared to northern European countries, the United Kingdom, and the United States (2). This
difference has been linked to the Mediterranean food pattern
consumed in the Mediterranean countries. Although there are
variations in the components of the traditional Mediterranean
diet (MD) between and within countries, the diet is generally
characterized by abundant plant foods (fruit, vegetables, cereals, potatoes, beans, nuts, and seeds); fresh fruit as the typical
daily dessert; olive oil as the principal source of fat; dairy products (principally cheese and yogurt); fish, poultry, and eggs
consumed in low to moderate amounts; red meat consumed in
low amounts; and wine consumed in low to moderate amounts,
normally with meals. As a result, this dietary pattern is low in
saturated fat (less than or equal to 7–8% of energy), with total fat ranging from <25% to >35% of energy throughout the
Mediterranean region (3).
The classic reductionist approach of studying individual
foods or nutrients has been limited by the fact that food
860
CANCER AND THE MEDITERRANEAN DIET
861
62 articles identified through database search (Pubmed and
Scopus)
45 articles excluded on basis of title/abstract
17 articles
2 articles included after consulting references
of selected articles
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19 articles
9 cohort studies
10 case-control
studies
2 articles excluded
after reading whole
article
5 articles excluded
after reading whole
article
7 cohort studies
included
5 case-control
studies included
FIG. 1. Selection of articles.
components are not consumed in isolation, and their health effects are often synergistic (4). As a result, it has been difficult to
isolate their individual health benefits. Therefore, in the past two
decades, scientists have started focusing on measuring multiple
dietary exposures simultaneously, such as the health benefits of
the MD as a prudent dietary pattern. (4). Component and cluster
analysis (5) and many a priori MD indexes (6) have been used
to study the relationship between the MD pattern and health parameters such as mortality or chronic disease risk relationships.
Most of the studies have used a priori indexes or scores that are
conceptually similar to define and evaluate the adherence to the
MD pattern among the study populations.
There has been a decrease in the adherence to the MD in
Mediterranean countries in the past half century (7) as well as
an increase in sedentary lifestyles among other lifestyle factor
changes. It is not clear how these changing dietary and lifestyle
patterns could influence cancer risk of these areas.
In addition, it is difficult to study the health effects of the MD,
since it is not only a dietary pattern but also represents a way of
life and a cultural model. It is also difficult to separate out the
specific effect of a single component of the MD in relation to
a disease. There is increasing epidemiological evidence of the
health benefits of the MD, which have been summarized in several literature reviews (8–12). Although the MD is historically
most famous for its cardio-protective effect, there is increasing
research on its relationship with cancer. This article will systematically review observational studies that assess the adherence
to a MD as a single exposure in relation to risk of cancer.
No isolated study or study type can provide evidence that
any factor is a cause of, or is protective against, any disease (1).
Thus, as the World Cancer Research Fund (WCRF) and American Institute for Cancer Research (AICR) state, the causation
of diseases can be more accurately deduced if they are based
on a variety of epidemiological studies. In order to objectively
evaluate diet–cancer risk relationships, systematic reviews such
as this are needed, and they should be used to provide evidencebased dietary guidelines that support public health recommendations and policies.
METHODS
The literature review focused on observational studies that
have investigated the association between adherence to a MD
and cancer. A systematic search was conducted in PubMed and
862
United States; Nurses
Health Study
Sweden; Uppsala Health
Care Region
United States; National
Institutes of Health (NIH);
AARP
Greece; EPIC study
Lagiou et al.
2006 (15)
Mitrou et al.
2007 (16)
Benetou et al.
2008 (17)
M/F
M/F
F
F
Country/Study Population
Sex
Belgium, Denmark, France, M/F
Greece, Hungary, Italy, the
Netherlands, Portugal,
Spain, Switzerland, Finland;
HALE project
Fung et al. 2006
(14)
Author/Year of
Publication
Knoops et al.
2004 (13)
20–86 yr
50–71 yr
30–49 yr
30–55 yr
Age at Entry
70–90 yr
7.9 yr
10 yr
12 yr
18 yr
Follow-up
10 yr
851/25,623
5,985/380,296
280/42,237
3,580/71,058
Cases/Total
233/2,152
Outcome
Overall cancer mortality
Results
–HR of adhering to a MD
(≥4 points): 0.90 (95% CI
= 0.70–1.17)
–HR of a combination of 4
low factors: adhering to a
MD, moderate OH
consumption, at least 30 min
of PA/day and nonsmoking:
0.31 (95% CI = 0.19–0.50)
Breast cancer risk
–ER+: RR of Q5 vs.
9-item MDSc: (+): 1.
Vegetable (without potatoes). (postmenopausal)
Q1:1.05 (95% CI =
2. Legumes. 3. Fruit. 4. Nuts.
0.91–1.18), P for trend =
5. Whole grain cereals. 6.
0.23 –ER−: RR.
MUFA/SFA. 7. Fish. (−): 8.
–ER−: RR of Q5 vs. Q1: 0.79
Red and processed meat
(95% CI = 0.60–1.03), P
(+m). 9. OH.
for trend = 0.03.
Overall cancer
–HR of high vs. low MDS:
9-items MDSb: (+): 1.
Vegetables. 2. Legumes. 3.
mortality; main cancers: 0.80 (95% CI = 0.57–1.13),
Fruits and nuts. 4. Cereals. 5. breast and lung
P = 0.200 For a 2 point
Fish and seafood. 6.
increase in score: –Subjects
MUFA/SFA. (−): 7. Meat. 8.
<40 yr: T3 vs. T1 1.07
Dairy (+m). 9. OH.
(95% CI = 0.79–1.43)
–Subjects ≥40 yr: T3 vs. T1
0.84 (95% CI = 0.71–1.01)
b
Overall cancer mortality –HR of high vs. low (MDSc)
8-items MDS : (+): 1.
MUFA/SFA. 2. Legumes. 3.
–Men: 0.83 (95% CI =
Grains. 4. Fruits and nuts. 5.
0.76–0.91), P < 0.001
Vegetables (without potatoes).
–Women: 0.88 (95% CI =
8. Fish. (−): 6. Meat. 7. Dairy.
0.78–1.00), P = 0.04
9-item MDSc: (+): 1.
(similar results with the
Vegetable (without potatoes).
MDSc indexes).
2. Legumes. 3. Fruit. 4. Nuts.
5. Whole grains. 6. Fish. 7.
MUFA/SFA. (−): 8. Red and
processed meat. (+m): 9. OH.
9- items MDSb: (+): 1.
Overall cancer incidence –HR of high vs. low MDS:
Vegetables. 2. Legumes. 3.
(nonmelanoma skin
–Total: 0.78 (95% CI =
Fruits and nuts. 4. Cereals. 5. cancer excluded). Main 0.64–0.94) –Men: 0.83
Fish. (−): 6. MUFA/SFA.
cancers: –Men: Lung
(95% CI = 0.63–1.09)
(−): 7. Meat. 8. Dairy. (+m): and prostate –Women:
–Women: 0.73 (95% CI =
9. OH.
Breast and large bowel
0.56–0.96)
MD Definition (components)
8 items MDSb (+): 1.
MUFA/SFA. 2. Legumes,
nuts, and seeds. 3. Grains. 4.
Fruit. 5. Vegetables and
potatoes. 8. Fish. (−): 6.
Meat. 7. Dairy.
TABLE 1
Overview cohort studiesa
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Age, years of education,
smoking, BMI, height, PA,
supplement use, total energy
intake, consumption of eggs,
confectionary, and
nonalcoholic beverages
Age, race, total energy intake,
BMI, education, marital
status, PA, hormone therapy,
smoking
Age, BMI, PA, age at
menopause, hormone therapy,
smoking, energy intake,
family history, weight change
since age 18 yr, supplement
use, history of benign breast
disease.
Age at enrolment, height,
BMI, smoking, PA, education,
energy intake, potato intake,
egg intake, polyunsaturated
lipid intake, sweet and sugar
intake, nonalcoholic beverage
intake
Adjustments
OH, PA, smoking, age, sex,
years of education, BMI,
study, region, center,
occupation, waist
circumference, marital status,
and energy intake.
863
Europe (United
Kingdom, France,
Denmark, Sweden,
Germany, Italy, Spain,
The Netherlands,
Norway, Greece)
Buckand et al.
2009 (19)
M/F
M/F
35–70 yr
50–71 yr
8.9 yr
5 yr
449/485,044
3,110/492,382
9-items MDSb: (+):
1.Whole grains. 2.
Vegetables. 3. Fruit. 4.
Fish. 5. Legumes. 6.
Nuts. (-): 7. MUFA/SFA.
8. Red meat and
processed. (+m): 9. OH.
9-item MDSd: (+): 1.
Fruit, nuts, and seeds. 2.
Vegetables (without
potatoes). 3. Legumes. 4.
Fish and seafood (fresh
or frozen, excluding fish
products and preserved
fish). 5. Cereals. 6. Olive
oil. (-): 7. Meat. 8.
Dairy. (+m): 9. OH.
–RR of Q1 vs. Q5: –Men:
0.72 (95% CI = 0.63–0.83)
–Women: 0.89 (95% CI =
0.72–1.11)
–HR of high vs. low MDS:
0.67 (95% CI = 0.47–0.94),
P = 0.020. No evidence of
heterogeneity between
subsites or subtypes.
Colorectal cancer
Gastric adenocarcinoma
Subsites: Cardia,
noncardia Subtypes:
Intestinal and diffuse
Age, center (strata), sex,
BMI, education level,
smoking, energy intake
Age, ethnicity, education,
BMI, smoking, PA,
menopausal hormone
therapy, and energy intake
e
a
Abbreviations are as follows: MD, Mediterranean Diet; M, male; F, female; MDS, Mediterranean Diet Score created by Trichopoulou et al. (b) and variations of it (c,d and
); MUFA/SFA, ratio of monounsaturated to saturated fat; Meat, meat and meat products; Dairy, milk and dairy products; (+), positive components; (-), negative components;
(+m), components positive in moderation; HR, hazard ratio; OH, alcohol consumption; PA, physical activity; CI, confidence interval; BMI, body mass index; P, P for trend; ER+,
estrogen receptor positive, ER–, estrogen receptor negative; RR, relative risk; Q: quartile; T, tertile; AARP, American Association of Retired Personas; EPIC, European Prospective
Investigation into Cancer.
United States; NIH
AARP Diet and Health
Study
Reedy et al. 2008
(18)
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864
United States;
F
The Four Corners
Breast Cancer
United States;
M/F
The Prostate,
Lung, Colorectal
and Ovarian
Cancer Screening
Trial
Murtaugh et al.
2008 (23)
Dixon et al. 2007
(24)
55–74 yr
25–79 yr
25–74 yr
35–79 yr
Age
1. <78 yr (median age: 57
yr); 2. <77 yr (median
age: 60 yr); 3. <79 yr
(median age: 61 yr)
3,592/3,3971
Hispanic: 757/867;
non-Hispanic:
1,524/1,598
1,248/1,148
488/461
Cases/Controls
1. 598/1,491;
2. 304/743;
3. 460/1,088
Cancer Outcome
1. Oral/pharyngeal cancer;
2. Esophageal cancer;
3. Laryngeal cancer
Breast cancer
Distal colorectal adenoma
8-item MDSb: (+):
1. Vegetables. 2. Legumes.
3. Fruit and nut. 4. Cereals.
5. Fish. 6. MUFA/SFA. (−):
7. Meat. 8. Dairy. (+m):
9. OH.
Via factor analysis: MD
pattern included high factor
loadings for liquor
consumption, poultry,
seafood, vegetables, salad
greens, and high-fat salad
dressings.
Endometrial cancer
9-item MDSb: (+):
1. MUFA/SFA. 2. Grains.
3. Legumes. 4. Fruits.
5. Vegetables. 6. Fish. (−):
7. Meat. 8. Dairy. (+m):
9. OH 11-item Goulet (24)
score and a variant of it (9):
(+): 1. Cereals. 2. Legumes.
3. Fruits. 4. Vegetables.
5. Olive oil. (−): 6. Meat.
7. Dairy. 8. Poultry. 9. Red
meat. 10. Eggs. 11. Sweets.
Incident breast cancer
10-item MDSc: (+):
1.Vegetables. 2. Legumes.
3. Fruit/nuts. 4. Cereals.
5. Fish and seafood.
6. MUFA/SFA. (−):
7. Meat. 8. Dairy. 9.
Carbohydrates. 10. OH.
MD Definition
(components)
8-item MDSb: (+):
1. MUFA/SFA. 2. Cereals.
3. Legumes. 4. Fruits.
5. Vegetables. (−): 6. Meat.
7. Dairy. (+m): 8. OH.
Age, race/ethnicity, use of
oral contraceptives, parity,
energy intake, PA, use of
hormone therapy, BMI
Adjustments
Age, sex, study center,
education, smoking, BMI,
total energy intake
Age, specific ethnicity,
education, birthplace, years
of residence in the United
States, PA, marital status,
parity, age at menarche, type
of menopause, age at
menopause, BMI and
energy intake
OR of Q4 vs. Q1 = 0.76 (95% Age, medical center,
CI = 0.63–0.92), P trend <
education, ethnicity,
0.01
menopausal status, family
history, smoking, total
activity, energy intake,
dietary fibre, dietary
calcium, height, parity,
BMI, Hormone exposure
–OR of high MD adherence
Center, age, energy intake,
(≥6 points) vs. low (≤2
ethnic origin, education,
points): –Men: 0.79 (95% CI BMI, PA, smoking, aspirin
= 0.68–0.92), P trend < 0.001 use, ibuprofen use, calcium
–Women: 0.99 (95% CI =
supplement use, and
0.81–1.23), P trend = 0.302
hormone replacement
therapy
RR of scoring ≥8 vs. 0–3:
0.65 (95% CI = 0.44–0.95), P
= 0.009. RR = 0.7
(0.48–1.04), P trend = 0.033
after fully adjustment
Results
–With 1 point increase MDS:
1. OR = 0.77 (95% CI =
0.71–0.83). 2. OR = 0.72
(95% CI = 0.65–0.81). 3. OR
= 0.71 (95%CI = 0.65–0.78),
P < 0.001.
OR for a modified scoring
method based on the 3
indexes, for the Q5 vs. Q1:
0.92 (95% CI = 0.59–1.4)
a
Abbreviations are as follows: MD, Mediterranean diet; M, male; F, female; MDS, Mediterranean Diet Score created by Trichopoulou et al. (b) and variations of it (c); (+),
positive components; MUFA/SFA, ratio of monounsaturated to saturated fat; (−), negative components; Meat, meat and meat products; Dairy, milk and dairy products; (+m),
components positive in moderation; OH, alcohol consumption; OR, odds ratio; CI, confidence interval; BMI, body mass index; Q, quartile; PA, physical activity; RR, relative risk.
F
United States,
Asian Americans
Wu et al. 2009
(22)
F
Sex
1. M/F;
2. M/F;
3. M/F
United States
Country
Italy
Dalvi et al. 2007
(21)
Author/Year of
Publication
Bosetti et al.
2003 (20)
TABLE 2
Overview case control studiesa
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CANCER AND THE MEDITERRANEAN DIET
Scopus. In PubMed, the following MesH terms were used: diet,
Mediterranean, neoplasms, cohort studies, and case control
studies. The search was limited to human studies and restricted
to articles in English. In Scopus, an advanced search was conducted within title, abstract, and keywords. The search terms
used were Mediterranean diet, cancer, case control, and cohort.
This initial search resulted in 62 articles. The search was
then refined to include articles only if they examined the effect
of the MD pattern as a single exposure, and thus the combination of its components on cancer risk, and excluded research on
the isolated effect of individual components or nutrients within
the MD. This resulted in an initial exclusion of 45 articles after
reading the titles and abstracts of these articles (Fig. 1). Two
additional publications were then identified through the bibliography cited in the original search, giving a total of 19 articles,
10 case-control studies, and 9 cohort studies. After reading the
full text of these articles, 5 case-control studies were excluded; 4
only assessed components of the MD as exposure, and the other
article was actually a review. Of the cohort studies, 2 articles
were excluded because of the existence of multiple articles for
the same study.
Key methodological features of the cohort and case-control
studies that could influence the outcome have been detailed in
Tables 1 and 2: characteristics of study sample (country of origin, age, gender, and size of the sample), length of follow-up (in
cohorts), definition of the MD (components), and confounding
variables.
RESULTS
Study Characteristics
A total of 12 studies were identified that met all the search
criteria (13–24). The studies were classified as cohort (13–19) or
case-control (20–24) studies. The methodology and the results
of the studies are summarized in Table 1 and Table 2. All studies
were published between 2003 and 2009. Most of the studies were
carried out in non-Mediterranean populations despite the fact
that the main exposure of interest was the Mediterranean-like
dietary pattern. In fact, most of the studies (7 studies) were from
the United States. Two studies were conducted in Mediterranean
countries—in Greece and in Italy (17,20). The study by Bosetti
et al. (20) conducted in Italy included 3 different case-control
studies. Three studies were carried out in Sweden (15) or in
several European countries including Mediterranean countries
(13,19). In total, 5 studies were conducted in females only and
7 in men and women of which 2 studies showed the results for
men and women separately.
Definition of the MD
Almost all cohort studies included in this review assessed
the adherence to the MD applying the Trichopoulou et al. (25)
Mediterranean diet score (MDS), although in some studies, various modifications were made. In the studies of Fung et al. (14),
865
Buckland et al. (19), and Mitrou et al. (16), potatoes were excluded from vegetable intake. Knoops et al. (13) combined the
group of legumes and nuts to one group, and Buckland et al.
(19) used tertiles as cut-offs instead of medians and olive oil
instead of the dietary lipid ratio.
The case-control studies have used different methods to assess the adherence to the MD. Bosetti et al. (20), Dalvi et al.
(21), Dixon et al. (24), and Wu et al. (22) used the key components of the definition of Trichopoulou et al. (25), although
with some modifications. For instance, Bosetti et al. (20) only
used 8 items, excluding fish. Dalvi et al. (21) added some components such as olive oil, eggs, sweets, and poultry, and Wu et
al. (22) incorporated a low consumption of carbohydrates as a
detrimental component.
Generally, most of these dietary indexes are based on assigning a score according to the daily intake of the components. The
medians of the sample, specific for sex, were used as cut-off
points in most of the studies (25). For beneficial components
presumed to fit the traditional MD (vegetables, legumes, fruits
and nuts, cereal, fish, etc.), subjects whose consumption was
below the median were assigned a value of “0,” and subjects
whose consumption was at or above the median were assigned
a value of “1.” The scoring was inversed for components presumed to be detrimental and not fit the MD pattern (meat and
meat products and dairy products). For ethanol, a value of “1”
was commonly assigned to moderate consumption. In general,
healthy intervals were defined as 10 and 50 g/day for men and 5
and 25 g/day for women. Finally, in general, for lipid intake, a
value of “1” was assigned to individuals with a monounsaturated
to saturated lipids ratio at or above the median.
Main Outcomes
Out of the cohort studies, 4 studies assessed overall cancer (13,15–17), and 3 studies looked specifically at breast (14),
gastric (19), and colorectal (18) cancers. In the Nurses’ Health
study, no significant association of the MD and postmenopausal
breast cancer risk was found (18). However, when the analyses
were separated into estrogen receptor positive and negative tumors, there appeared to be a 7% reduction in breast cancer risk
(P = 0.02) for an increase of 10% in the MD score in the receptor
negative tumor group. In the European Prospective Investigation into Cancer (EPIC) study, a high compared to a low MD
score was associated with a 33% reduction [95% confidence
interval (CI) of 6–53%] in gastric adenocarcinoma (19). In a
cohort study set in the United States (18), a 28% reduced risk of
colorectal cancer was observed in men who consumed a more
Mediterranean-like dietary pattern.
Two out of the four cohort studies that looked at overall cancer found a significant inverse association with the MD (16,17).
A 2-point increase in the MDS resulted in a significant reduction
in overall cancer incidence by 12% in the Greek EPIC cohort
(17) and by 6% in men in the National Institute of Health study
in the United States (16). In an earlier study in the Greek EPIC
cohort, a 2-point increase in the MD score was associated with
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866
L. VERBERNE ET AL.
a 24% reduction in overall cancer mortality, with a 95% CI of
2–41%. The 2 other cohort studies that assessed overall cancer
mortality did not find significant results, but some borderline or
partial evidence (within subgroups) was observed (13,15). For
instance, among women less than 40 yr old at enrollment, there
was no association of the MD with cancer mortality, mainly focusing on breast and lung cancer (15). However, among women
40 to 49 yr old at enrolment who were followed up for approximately 12 yr, a 2-point increase in the MD score was associated
with reduced mortality from cancer of 16% (95% CI = –1 to
29%) (15). In the European HALE study (13), the MD did not
significantly reduce overall cancer mortality. However, the effect
of the MD together with a healthy lifestyle [(moderate alcohol
consumption, nonsmoking, and being physically active) was inversely related to cancer mortality even at ages 70 to 90 yr (HR
of 0.31 (95% CI = 0.19–0.50)].
The cancer outcomes of the case-control studies were breast,
endometrial, oral/pharyngeal, esophageal, colorectal, and laryngeal cancer. The 3 case-control studies from Italy (20) found
strong significant inverse associations between the MD and 3
upper aero-digestive tract cancers. A 1-point increase in the
MDS was associated with a reduced risk of oropharyngeal,
esophageal, and laryngeal cancer by 23% (95% CI = 17–29%),
28% (95% CI = 19–35%), and 29% (95% CI = 22–35%), respectively.
For colorectal cancer, a case-control study (24) found that following the current U.S. dietary recommendations or a Mediterranean dietary pattern was associated with a 21% reduced risk
in men.
The 2 case-control studies on breast cancer found a reduced
risk of breast cancer with increasing adherence to a MD (22,23).
A 24% lower incidence of breast cancer was observed among
American Hispanic and non-Hispanic women in the highest
quartile of MD consumption analyzed via factor analysis (23).
Similarly, a 35% lower risk of breast cancer was observed among
Asian American women with highest MD scores (more than 8
points) compared to the lowest (0–3 scores) (22).
One out of the 5 case-control studies found no evidence of
an association between the MD pattern and endometrial cancer
risk among the American adult female population at their level
of consumption of the MD (21). These results were the same
regardless of the MD definition or score used to assess the
adherence to the MD (25,26).
DISCUSSION
Although research on the beneficial role of MD on health
began in the early 1970s in the classic Seven Countries Study
by Keys et al. (27), epidemiological studies have only started
investigating the protective role of the MD on cancer relatively
recently, with most research conduced within the last 5 yr. This
current review summarizes the observational studies to date that
have investigated the role of the Mediterranean dietary pattern
on cancer incidence and mortality. We found that out of the 12
studies reviewed (7 cohort and 5 case-control), 10 studies (6
cohort and 4 case-control) provided some evidence that the MD
was associated with a reduced the risk of cancer incidence or
mortality. Collectively, the evidence from these observational
studies suggests that the MD is a cancer-preventive dietary pattern.
If the strength of evidence for this relationship is assessed
according to criteria set out in the WCRF/AICR 2007 report
(1), it appears most of criteria for a “probable” relationship are
met; 1) the evidence comes from at least two independent cohort studies. In fact, the results from 6 cohort studies have been
summarized in a meta-analysis by Sofi et al. (12), providing a
pooled relative risk of 0.94 (95% CI of 0.92–0.96) for risk of occurrence of or mortality from cancer for each 2-point increase in
the MD score (25). Four case-control studies also provided some
evidence of an association; 2) although there was no substantial unexplained heterogeneity within or between study types
or different populations (i.e., European vs. United States and
Mediterranean vs. non-Mediterranean), the associations varied
somewhat depending on the populations’ characteristics, status, and cancer-sites; 3) there is evidence from good quality
studies that can exclude the possibility that the observed results
are due to random or systematic error. For instance, there are
several large prospective cohort studies with a long follow-up
time (around 10 yr) studying incident and mortality end points,
depending on the study. In addition, 2 of the EPIC studies calibrated the dietary measurements using data from 24-h recalls,
and 4) presence of plausible biological gradient—many of the
studies reported a dose-response relationship, with a greater reduction in risk of cancer as adherence to the MD increased from
low to high. However, there is a lack of evidence from randomized control trials in humans, the main source of evidence to
be able to establish a causal relationship. The number of years
an individual needs to be able to obtain such a beneficial effect
is also unknown, and only 1 intervention study, the Lyon Heart
randomized control trial (28), has investigated the effect of the
Mediterranean-like diet (rich in oleic and alpha-linolenic acid)
and cancer incidence. The results are only suggestive because
of the relatively few numbers of cases (n = 24) that occurred
during the 4-yr follow-up. However, the MD group had significantly lower risk of cancer, RR 0.39 (0.15, 1.01), compared to
the control group (following a Step-1 AHA prudent diet).
Studies that have investigated the effect of the MD on overall
cancer mortality have found some evidence that greater adherence to a MD was associated with a reduced risk of cancer,
ranging from 14% to 27% depending on the increment in MD
measured (16,17). Several studies have assessed specific cancer
sites separately, which is of interest, as different cancer sites
may be etiologically heterogeneous. Although the magnitude of
the effect is related to the increment in the MD measured and the
study type, a high adherence to the MD was associated with reduced risk of breast cancer, ranging from 21–55% (22,23) and a
reduced risk of colorectal cancer ranging from 21–28% was observed only in men (18,24). The range of risk reduction against
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CANCER AND THE MEDITERRANEAN DIET
some respiratory tract, gastric, and oral cancers was around the
20–30% for those individuals whose diet was closest to the MD
pattern (19,20).
Moreover, various aspects of the MD were linked to a decreased risk of several cancers in a review by Trichopoulou and
Vasilopoulou (29). It was estimated that up to 25% of colorectal;
15% of breast; and 10% of prostate, pancreas, and endometrial
cancer incidence could be prevented by following a MD-like
pattern (2).
In this systematic review, the variability in the observed associations and strength of the relationship between adherence to
a MD and risk of cancer could be linked to the inherent variability in study populations, designs, end points (different cancer
sites and incidence vs. mortality), or subtle differences in the
MD definition. Also, secular trends in food supply, which are
causing Mediterranean countries to lose some of their dietary
characteristics, make it difficult to assess the health effect of the
traditional MD in observational studies. Studying the relationship between diet and cancer is complex and requires adjusting
or stratifying by multiple confounding variables and careful interpretation. In addition, unlike coronary heart disease, which
is more of a homogenous end point, cancer is better described
as a constellation of several diseases, with various different risk
factors (WCRF) (1). Therefore, it follows that the extent of the
reduction in risk obtained by following a MD will vary depending on the cancer site.
The cancer-protective effect of the MD also seems to vary according to the population’s characteristics and status: smoking
(16,19), age groups (14,19), premenopausal or postmenopausal
status (14,21), BMI status (16), gender (17,18,24), and so forth.
For instance, more pronounced effects of the MD pattern were
observed among smokers with high adherence to the Mediterranean dietary pattern (16). Additionally, the increased risk of
death associated with obesity may mask the inverse association
of the MD with all-cause mortality (16). There also appears to be
differential results by sex: The results for overall cancer reduction were exposure-dependent and stronger among women in
one study (17) and only significant in men for colorectal cancer
studies (18,24). Moreover, some subtypes of cancers may be differentially associated with diet, such as the breast cancer tumors
with different hormone receptor status (14) or different subsites
or subtypes of gastric cancer (19) compared to estrogen receptor
positive tumors (14). Furthermore, specific cancer subsites may
be etiologically heterogeneous and may be differently affected
by the components and dose of the MD, which could also make
the results difficult to interpret, especially as most studies have
not analyzed the different cancer subsites separately.
The few studies that found no clear evidence or a borderline inverse MD–cancer association had some particular study
and population characteristics that should be discussed in order
to accurately interpret the results (13–15,21). Issues that could
have influenced the results include relatively small sample sizes
(13,21) or relatively few cases (13), the old age group of the
study population (13), or many countries of origin for the small
867
sample (13). The results could also have been influenced by an
overall lower adherence to the MD in the studied population
compared to the reference Mediterranean populations (25), for
instance, in studies set in the United States (21). To more accurately assess this relationship, studies are needed with larger
samples, sufficient dietary heterogeneity with respect to the MD,
and with sufficient variation in cancer incidence so as to include
low-risk populations.
Besides the limitations previously stated, various other limitations in all the reviewed observational studies should be considered when interpreting the results. First, possible measurement error and recall bias should be taken into account, especially in case-control studies. Second, although all the studies
had adjusted for many confounding variables, some residual
confounding in observation studies is almost inevitable by factors not measured in the study or by variables that are adjusted
for but were measured with error (27). For example, the effect of
dietary supplements could be an important confounder in some
populations (21), and some of the studies did not control for
this.
An adjustment for energy intake is also necessary for the evaluation of food and nutrient health effects (30). Although this may
be less imperative for overall patterns analysis, this issue seems
more important in case-control studies in which misreporting
is common, especially among cases. Some attempts have been
made to reduce some of the inherent error in the dietary assessment methods, such as adjusting individual components of the
index by total energy intake (16,19). Third, using MD indexes in
American and Nordic populations (13–16,21–23) might not adequately represent conformity with the traditional MD, as it may
only reflect adherence to some of the MD components that are
also characteristic of a general “prudent” dietary pattern. Some
studies that were concerned that the median intake of the dietary
components might be lower in their study populations compared
to Mediterranean populations made some adjustments—using
alternate cut-off points or the highest intakes (16,19). Moreover,
small sample sizes (21) may limit the precision to be able identify cancer risk factors, and even large samples are normally
only able to estimate approximately 20–30% risk variability.
On the other hand, many of the studies reviewed have important positive qualities that support the observed results. First is
the use of conceptually similar ways to define the dietary pattern,
as many of them include similar components and use an intuitive
and simple score based on the MD score by Trichopoulou et al.
(29), making it easy for comparisons and giving robustness to the
findings. Second, many of the studies had large sample sizes and
reasonably long follow-up of the cohorts, which allows an adequate period and for cancer cases to accumulate. Third, a single
cohort enables the effects of diet and lifestyle to be assessed for
multiple types of cancer and other diseases. In addition, several
cohort studies have calibrated the dietary data using more accurate data from a 24-h recall in a subsample, in order to reduce
dietary measurement error. Validated, interviewer-administered
dietary questionnaires are also frequently used (17). Moreover,
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868
L. VERBERNE ET AL.
comparable results were observed using dietary indexes and factor analysis to examine the relationship of dietary pattern and
cancer (22).
There is substantial evidence that diet plays an important
role in the etiology of cancer. Extensive evidence exists on the
relationship between key components of the MD and cancer
risk (29,31–33). For instance, key findings are that an increased
intake of vegetable and fruit, whole-grain foods, olive oil vs.
other added fats, fish, and diets rich in n-3 PUFA are related to a
reduced cancer risk (20,32,33). Meanwhile non-Mediterranean
aspects such as high consumption of red and processed meat
and alcohol (all types) have been associated with an increased
risk of several types of cancer (1). However, in relation to cancer
risk, the dietary pattern analysis approach as reviewed in this
article is now gaining ground over the single nutrient or food
approach (5).
The evidence of the cancer protective effect of the MD pattern
is generally stronger than the evidence from individual foods,
food groups, or nutrients and cancer risk (1). Some possible
explanations of this could be that interactions and synergisms
exist between the components; individual components could
also have health effects that are undetectable alone but when
integrated with other foods or nutrients in a dietary index, the
health benefits become more pronounced (25). Dietary indexes
can overcome the issues of collinearity or confounding between
components in the score; and, finally, dietary pattern indexes
evaluate only the extremes of cumulative exposure, limiting the
background noise of individual components (34). Thus, all these
issues justify the use of dietary pattern studies to assess cancer
risk reduction (17).
The beneficial effect of the MD on cancer risk may be mediated through several biological mechanisms such as chronic
inflammation and oxidative stress. A MD-like pattern is related
to a high antioxidant capacity and low oxidized LDL-cholesterol
due to its richness in dietary antioxidants such as vitamin C, vitamin E, carotenoids, phenols, and flavonoids (35). Fiber may
potentially offset the carcinogenic effects of N-nitroso compounds (NOC) (exogenous exposure comes from a diet such as
red meat, tobacco, and other environmental sources) by acting
as a nitrite scavengers (36); and the omega-6/3 fatty acids ratio may also play a role, as its constituents potentially prevent
cancer initiation and progression (37,38). Additionally, a high
intake of total meat, red meat, and processed meat (uncommon in traditional MDs) is associated with an increased risk of
some cancers, especially colorectal and gastric cancer (1), which
can be explained by several possible mechanisms including the
potential carcinogenic effects of nitrite and nitrosamines, salt,
and heterocyclic amines and polycyclic aromatic hydrocarbons
(36). Higher adherence to the MD has been linked to decreased
inflammation and coagulation processes through lower levels
of C-reactive proteins, interkeukin-6, homocysteine, fibrinogen
(39), and several other biomarkers of inflammation and endothelial dysfunction (14,40). Several micronutrients and food components (including folate, flavonoids, and carotenoids) showed
inverse relations with cancer risk, but the main component(s)
responsible for the favorable effect of a diet rich in vegetables and fruit remain undefined (41). Tomato has been shown
to be beneficial in cancer prevention, particularly for prostatic
cancer, and lycopene emerges as the most relevant functional
component; a substantial part of the lycopene effects can be
explained by its antioxidant action but also by downregulation mechanisms of the inflammatory response (42,43). Olive
oil is an integral ingredient of the MD, and accumulating evidence suggests that it may have a potential role in lowering the
risk of several types of cancers. The mechanisms by which the
cancer-preventing effects of olive oil can be performed, however, are not completely known. However, a novel hypothesis
is that oleic acid, the monounsaturated fatty acids in olive oil,
is able to specifically regulate cancer-related oncogenes (44).
Recent findings concerning the bioavailability of certain important minor components of olive oil, including efficient antioxidant polyphenols, the triterpene hydrocarbon squalene, and
beta-sitosterol, considered as putative nutritional biomarkers,
have been described in relation to the incidence of cancer (45).
In addition, a MD pattern was shown to cover the average nutrient requirements much better than the Western diet (46), and
this may also contribute to the overall cancer preventive effects.
Increasing our understanding of the biological mechanisms involved in cancer processes will also help to develop preventive
strategies.
Patterns of production and consumption of food products,
physical activity, and lifestyles in general have changed greatly
throughout the past decades. These are mainly consequences
of globalization, industrialization, and urbanization that have
taken place, first in Europe and North America, and increasingly in most developing countries. These transformations are
reflected in changes in cancer incidences and mortality, and
projections estimate that by 2013, 70% of cancer deaths will occur in middle- and low-income countries (1). However, as with
other diseases, the risk of cancer is modified by social, cultural,
economic, and other environmental factors.
As obesity is linked to several cancers (1), the increasing
obesity epidemic will add to the rising cancer trend. Therefore,
the effect of the MD (11) on body weight may have an additional
favorable response to cancer risk reduction (1).
The fact that the MD is associated with reduced risk of cancer does not preclude that other dietary patterns may also be
protective. Actually, traditional diets in general have been associated with a lower risk of cancer (23,47). The WFCR/AICR
Panel agreed that recommendations on specific foods such as
the increase of fruits and vegetables and the decrease of red and
processed meat actually coincide with recommendations toward
a plant-based diet such as the MD or East Asian dietary pattern.
The healthy effects of the traditional pattern may also be related to behavioral or cultural aspects, although some common
components of the traditional diets (e.g., high consumption of
legumes and vegetables, etc.) are also likely to be involved in
their benefits. In contrast, substantial evidence agrees that the
CANCER AND THE MEDITERRANEAN DIET
Western dietary pattern is associated with an increased risk of
several types of cancers (14,23). Therefore, the MD has a favorable effect on reducing cancer risk, which is relevant to the
public health sector given the tendency of modern societies to
shift toward a more Westernized and globalized dietary pattern
(7).
Although the reviewed cohort and case-control studies had
certain district study characteristics, such as being set in different
populations and analyzing different cancer outcomes, the existing evidence suggests a protective role of the Mediterranean
dietary pattern toward cancer in general. Specific results for
several outcomes, such as different cancer sites, deserve additional research. The purpose of this review was to give a general
overview of the situation so as to be able to provide possible
guidelines for cancer prevention.
14.
15.
16.
17.
18.
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19.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the Spanish Ministry
of Health (Instituto de Salud Carlos III) RTIC RD06/0045
RD06/0020, Exp PI07/0130 and La Caixa (Exp BM06-130-0).
None of the authors have any conflict of interest.
20.
21.
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