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Nutrition and Cancer

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Dietary Folate, Alcohol Consumption, and Risk of Non-

Hodgkin Lymphoma
a a b c d
Jerry Polesel , Luigino Dal Maso , Carlo La Vecchia , Maurizio Montella , Michele
e d a f
Spina , Anna Crispo , Renato Talamini & Silvia Franceschi
a
Unità di Epidemiologia e Biostatistica, Centro di Riferimento Oncologico , Aviano, Italy
b
Laboratorio di Epidemiologia , Istituto di Ricerche Farmacologiche “M. Negri,” , Milan,
Italy
c
Istituto di Statistica Medica e Biometria , Università degli Studi di Milano , Milan, Italy
d
Servizio di Epidemiologia , Istituto Tumori “Fondazione Pascale,” , Naples, Italy
e
Divisione di Oncologia Medica A, Centro di Riferimento Oncologico , Aviano, Italy
f
International Agency for Research on Cancer , Lyon, France
Published online: 05 Dec 2007.

To cite this article: Jerry Polesel , Luigino Dal Maso , Carlo La Vecchia , Maurizio Montella , Michele Spina , Anna Crispo ,
Renato Talamini & Silvia Franceschi (2007) Dietary Folate, Alcohol Consumption, and Risk of Non-Hodgkin Lymphoma,
Nutrition and Cancer, 57:2, 146-150, DOI: 10.1080/01635580701274202

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 NUTRITION AND CANCER, 57(2), 146–150
Copyright

C 2007, Lawrence Erlbaum Associates, Inc.

Dietary Folate, Alcohol Consumption, and Risk of

Non-Hodgkin Lymphoma

Jerry Polesel, Luigino Dal Maso, Carlo La Vecchia, Maurizio Montella, Michele Spina,
Anna Crispo, Renato Talamini, Silvia Franceschi

Abstract: Dietary deficiency of folate and other micronutri- sequent DNA methylation (1). Deficiency of folate and other
ents involved in the one-carbon metabolism (i.e., vitamins B vitamins has been associated to several diseases, including
Downloaded by [University of Illinois Chicago] at 03:56 21 November 2014

B2 , B6 , B12 , and methionine) have been related to sev-
eral diseases, including cancers, but results on non-Hodgkin
lymphoma (NHL) are controversial. A hospital-based case-
control study was conducted in Italy, in 1999–2002. Cases
were 190 incident, histologically confirmed NHL aged 18–84
years. Controls were 484 subjects admitted to hospitals for
acute, non-neoplastic diseases supposed to be unrelated to
alcohol consumption or to diet modification. Dietary habits,
including alcohol drinking, were assessed by a validated
food-frequency questionnaire. Nutrient intakes were com-
puted using the Italian food composition database. Odds
ratios (ORs) and corresponding 95% confidence intervals
for tertiles of nutrients’ intake were computed using the
energy-adjusted residual models. No significant association
emerged between NHL risk and intakes of folate (OR = 0.9),
vitamin B2 (OR = 0.9), vitamin B6 (OR = 0.8), and me-
thionine (OR = 0.7). However, a significant inverse associa-
tion was observed for all the nutrients examined among ab-
stainers and former drinkers, whereas no relations between
one-carbon nutrients and NHL risk emerged among current
alcohol drinkers. Our findings support the possibility of an
antagonist effect of alcohol on the one-carbon metabolism
in NHL etiology. However, the lack of an overall effect for
one-carbon nutrients and the small sample size suggested
caution in interpreting our results.
heart disease and cancer (2,3). Inverse relations have been
reported for cancers of the colon and rectum (4), breast (5),
and prostate (6). Dietary deficiency of the so-called one-
carbon nutrients (i.e., folate, B vitamins, and methionine)
may lead to an altered one-carbon metabolism; subsequently,
it may induce chromosomal instability and may lead to abnor-
mal DNA methylation (1) involved in lymphomagenesis (7).
However, the evidence of such nutrients having a protective
effect on non-Hodgkin lymphoma (NHL) is still controver-
sial (8–10).
A recent collaborative re-analysis of 9 case-control studies
(11) reported a moderate inverse relation between alcohol
and NHL risk. Alcohol plays an antagonist effect on one-
carbon metabolism, and high alcohol–low folate profile has
been associated with high risks of breast cancer (12) and
colorectal cancer (4), but the evidence for NHL is scanty (9).
To provide further insights on the role of folate and alco-
hol intake in NHL etiology, in particular on the interaction
between alcohol and the nutrients involved in the one-carbon
metabolism, we analyzed data from a case-control study con-
ducted in Italy. The high proportion of alcohol drinkers, and
the wide range intake of alcohol and considered nutrients in
the study population, allowed the evaluation of the role of
alcohol in the one-carbon metabolism.
Material and Methods

Introduction Between January 1999 and July 2002, we conducted a

Folate is a water-soluble vitamin, which is involved in
DNA methylation and DNA synthesis. Together with other
micronutrients (i.e., vitamins B2 , B6 , B12 ), folate plays an
important role in the one-carbon metabolism, where it sup-
plies the one-carbon unit for methionine synthesis and sub-
case-control study on NHL and hepatocellular carcinoma
(HCC) in Pordenone, northern Italy, and in Naples, southern
Italy (13,14). Cases were patients between 18 and 84 yr old
(median age: 58 yr) with incident, histologically confirmed
NHL. They were admitted to the National Cancer Institute,
Aviano, the “Santa Maria degli Angeli” General Hospital,

Jerry Polesel, Luigino Dal Maso, and Renato Talamini are affiliated with Unità di Epidemiologia e Biostatistica, Centro di Riferimento Oncologico, Aviano,
Italy. Carlo La Vecchia is affiliated with Laboratorio di Epidemiologia, Istituto di Ricerche Farmacologiche “M. Negri,” Milan, Italy, and Istituto di Statistica
Medica e Biometria, Università degli Studi di Milano, Milan, Italy. Maurizio Montella and Anna Crispo are affiliated with Servizio di Epidemiologia, Istituto
Tumori “Fondazione Pascale,” Naples, Italy. Michele Spina is affiliated with Divisione di Oncologia Medica A, Centro di Riferimento Oncologico, Aviano,
Italy. Silvia Franceschi is affiliated with the International Agency for Research on Cancer, Lyon, France.
 Pordenone, the “Pascale” National Cancer Institute, and four
General Hospitals, Naples.
Out of 225 NHL patients enrolled in the study (13), 35
cases without comprehensive information on dietary habits
were excluded, thus leaving 190 HIV-negative cases. Histo-
logical specimens were classified according to the Interna-
tional Classification of Diseases for Oncology (15), which
was updated to include categories in the Revised European–
American Lymphoma (REAL)/World Health Organization
(WHO) classification (16,17). One pathologist from each
study area reviewed histological diagnoses (13). The largest
proportion of cases (n = 93, 49%) was diffuse large B-cell
lymphoma (DLBCL), whereas 31 cases (16%) were follic-
ular NHL, 14 (7%) were T-cell NHL, 46 (24%) were of
miscellaneous subtypes, and 6 (3%) were of unknown histo-
logical subtypes.
Controls were patients between 18 and 84 yr old (median
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age: 63), admitted for a wide spectrum of acute conditions to
the same hospitals where NHL cases had been interviewed.
Specifically excluded from the control group were patients
admitted for malignant diseases, conditions related to alcohol
and tobacco consumption, hepatitis, haematologic, allergic,
autoimmune diseases, and any chronic diseases that might
have changed lifestyle habits. Overall, 504 controls were
enrolled (13); 20 patients were excluded because of incom-
plete dietary questionnaire, thus leaving 484 controls. Of
these, 27% were admitted to the hospital for trauma; 24% for
non-traumatic orthopaedic diseases, 22% for acute surgical
conditions, 15% for eye diseases, and 12% for a variety of
other illnesses. Controls were more often males and were
older than cases as age matching was conducted according
to the gender and age distribution of cancer cases in the en-
tire case-control study, which also included HCC (14). No
significant differences in nutrients’ intake emerged among
the controls subgroups, as well as for alcohol intake.
Trained interviewers administered a structured ques-
tionnaire to cases and controls during their hospital stay.
Study subjects were asked to report information on socio-
demographic indicators, lifestyle factors, smoking and drink-
ing habits. A validated food frequency-questionnaire (FFQ)
was employed to assess the usual diet during the 2 years
before diagnosis or hospital admission for the controls (18).
Briefly, the FFQ included 63 foods, food groups or recipes
divided into 7 sections: (i) milk, hot beverages, and sweeten-
ers; (ii) bread, cereals, and first courses; (iii) second courses
(e.g., meat and other main dishes); (iv) side dishes (e.g.,
vegetables); (v) fruits; (vi) sweets, desserts, and soft drinks;
(vii) alcoholic beverages. For vegetables and fruits subject
to seasonal variation, consumption in season and their cor-
responding duration were elicited. Weekly number of drinks
of various alcoholic beverages was questioned. Taking into
account the different ethanol concentration, 1 drink corre-
sponded approximately to 125 ml of wine, 330 ml of beer,
and 30 ml of hard liquor (i.e., approximately 12 g of ethanol).
Non-drinkers were subjects who abstained from drinking
lifelong. In order to exclude drinking habit modification due
to early symptoms of the disease, former drinkers were those
Vol. 57, No. 2
who quit drinking at least 2 yr before the interview. In the
present study vitamin supplementation was less than 4%
among cases (n = 8) and 2% among controls (n = 9), so that
it was not considered in the analysis. The FFQ was tested for
reproducibility by comparing the results of two subsequent
FFQ administrations (median lag = 5.4 mo): Pearson cor-
relation coefficient (ρ) for nutrients intake ranged between
0.51 to 0.80 (19). Likewise, the validity of the FFQ, tested
comparing FFQ results with a 7-day dietary diary, was satis-
factory (ρ = 0.29 to 0.96) (20). Daily intake of energy and
nutrients were computed using the Italian food composition
database (21). Odds ratios (OR), and their corresponding
95% confidence intervals (CI), for increasing levels of nutri-
ent intakes compared to the lowest one, were computed using
unconditional multiple logistic regression models (22). The
model included terms for 5-yr age categories and age in con-
tinuum, plus terms for study center, education (<7, 7–11, or
≥12 years), and total energy intake (energy from alcohol in-
cluded). Adjustment for energy was made using the residual
method (23) and nutrients were entered in the model as ter-
tiles of intake based on the distribution of controls alone. The
test for trend was based on the likelihood-ratio test between
the models with and without a linear term for each nutrient’s
tertile, coded using the nutrient’s median value within the
tertile among controls (22). Heterogeneity of risk estimates
across strata was evaluated by Wald χ 2 test (24).
Results
Table 1 shows distribution of NHL cases and controls
according to sex, age, and selected variables. Cases were
younger than controls and reported higher education, which
is largely attributable to differences in age and birth co-
horts. Former alcohol drinkers showed the same risk as ab-
stainers (OR = 1.0), as did moderate alcohol drinkers (<7
drinks/week vs. abstainers, OR = 0.7, 95% CI: 0.5–1.2) and
heavy drinkers (OR = 0.9, 95% CI: 0.5–1.5).
No significant association emerged between NHL risk and
intakes of folate (OR = 0.9, 95% CI: 0.6–1.4), vitamin B2
(OR = 0.9, 95% CI: 0.6–1.4), vitamin B6 (OR = 0.8, 95%
CI: 0.5–1.2), and methionine (OR = 0.7, 95% CI: 0.5–1.1)
(Table 2). No differences emerged between genders, as well
as among different histological subtypes (e.g., diffuse large
B-cell, follicular, and other NHL).
In order to investigate the possible antagonist effect of al-
cohol on the association between determinants of one-carbon
metabolism and NHL risk, analyses were further conducted
in separate strata according to drinking habits (Table 2).
Among abstainers and former drinkers, a consistently inverse
association with NHL risk emerged for all nutrients: folate
(OR = 0.4, 95% CI: 0.2–0.9), vitamin B2 (OR = 0.3, 95% CI:
0.1–0.7), vitamin B6 (OR = 0.5, 95% CI: 0.2–1.1), and me-
thionine (OR = 0.4, 95% CI: 0.2–0.9). No significant differ-
ences emerged between abstainers and former drinkers, nor
between moderate and heavy drinkers (data not shown). Con-
versely, no association emerged between folate and other nu-
trients and NHL risk in current drinkers (Table 2), suggesting
147
 Table 1. Distribution of 190 Cases of non-Hodgkin Lymphoma and 484 Controls, Odds Ratio (OR), and Corresponding 95%
Confidence Intervals (CI)a for Selected Socio-Demographic Factors, Total Energy Intake, and Drinking Habits. Italy,
1999–2002
Cases Controls
N (%) N (%) OR (95% CI)

Gender
Males 101 (53.2) 330 (68.2)
Females 89 (46.8) 154 (31.8)
Age (yr)
<45 43 (22.6) 102 (21.1)
45–54 34 (17.9) 55 (11.4)
55–64 57 (30.0) 116 (24.0)
≥65 56 (29.5) 211 (43.6)
Center
Pordenone/Aviano 95 (50.0) 260 (53.7)
Naples 95 (50.0) 224 (46.3)
Education (yr)
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<7 77 (40.5) 238 (49.2)

7–11 60 (31.6) 124 (25.6)
≥12 53 (27.9) 122 (25.2)
Energy intake (kCal)
<1998 67 (35.3) 162 (33.5) 1b
1998–2469 59 (31.1) 162 (33.5) 0.94 (0.61–1.45)
≥2470 64 (33.7) 160 (33.1) 1.19 (0.75–1.88)
χ 2 for trend P = 0.46
Drinking habits
Abstainers 48 (25.3) 83 (17.2) 1b
Former drinkers 18 (9.5) 42 (8.7) 0.99 (0.49–2.00)
Current drinkers
<7 drinks/week 56 (29.5) 153 (31.6) 0.74 (0.45–1.22)
≥7 drinks/week 68 (35.8) 206 (42.6) 0.88 (0.51–1.52)
χ 2 for trend P = 0.96

a: Adjusted for age (in quinquennia and continuous term), gender, center (Aviano/Pordenone, Naples), and education (<7 yr, 7–11 yr, ≥12 yr).
b: Reference category.

a modifying effect of drinking habits. These findings were
consistent across strata of gender; however, considering the
small sample size not fully supporting additional stratifica-
tion other than by drinking habits, such considerations could
be speculative.
Discussion
The present study did not provide evidence of an overall
direct role of folate and other one-carbon nutrients in the
etiology of NHL, but did support the possibility of an antag-
onist effect of alcohol on the one-carbon metabolism in NHL
etiology (4,25).
The results of the present study agree with the findings
from a cohort study (8), which reported null associations be-
tween NHL risk and folate from food. Conversely, an Ameri-
can case-control study (9) reported a moderate protection for
vitamin B6 , vitamin B12 , and methionine. Likewise, results
on one-carbon-nutrients containing foods were controversial
(8,18,26–33).
A recent pooled analysis (11) reported a lower NHL risk
among alcohol drinkers, especially among current drinkers,
but the risks did not decrease for increasing alcohol intake.
An immunemodulatory effect of alcohol was suggested, as
moderate alcohol intake might improve cellular and humoral
immune responses (11). The present study did not find a sig-
nificant association between alcohol consumption and NHL
risk, but point estimates were compatible with the study by
Morton and colleagues (11).
In the present study, a modifying effect of alcohol emerged
on the relation between NHL risk and one-carbon nutrients,
with risk estimates consistently lower than unity among ab-
stainers and former drinkers for all the considered nutrients.
Former drinkers (i.e., people who quit at least 2 yr before
the interview) showed the same risk profile of abstainers for
each nutrient, suggesting that recent alcohol consumption,
better than past cumulative exposure, is important in the in-
teraction with one-carbon nutrients. Lim and colleagues (9)
had investigated the issue, reporting null results. However,
the difference in the prevalence of abstainers (41% among
controls in comparison to 17% in the present study), as well
as in the average alcohol intake among drinkers (79.1 g/wk
vs. 227.2 g/wk among controls, respectively) may partly ex-
plain these differences, suggesting that the antagonist effect
of alcohol on one-carbon metabolism requires high levels
of alcohol to be detected. Moreover, the different FFQs used
for dietary intake assessment should be accounted among the
possible causes of inconsistencies between studies.

148 Nutrition and Cancer 2007

 Table 2. Odds Ratios (OR) and 95% Confidence Intervals (CI)a for non-Hodgkin Lymphoma and Daily Intake of Individual
Dietary One-carbon Determinants and Alcohol. Italy, 1999–2002
Overall Abstainers and former drinkers Current drinkers
Nutrient Ca Co OR (95% CI) Ca Co OR (95% CI) Ca Co OR (95% CI)

Folate (µg)
<263 61 162 1b 23 31 1b 38 131 1b
263 to <330 62 161 0.98 (0.63–1.51) 23 44 0.57 (0.25–1.31) 39 117 1.02 (0.60–1.75)
≥330 67 161 0.92 (0.59–1.42) 20 50 0.40 (0.17–0.94) 47 111 1.16 (0.68–1.99)
χ 2 for trend P = 0.71 P = 0.03 P = 0.61
χ 2 for heterogeneityc = 2.35; P = 0.11
Vitamin B2 (mg)
<1.28 61 162 1b 23 31 1b 38 131 1b
1.28 to <1.65 66 161 1.03 (0.67–1.60) 24 43 0.62 (0.27–1.40) 42 118 1.29 (0.74–2.22)
≥1.65 63 161 0.89 (0.57–1.41) 19 51 0.28 (0.11–0.70) 44 110 1.32 (0.76–2.32)
χ 2 for trend P = 0.60 p < 0.01 P = 0.35
χ 2 for heterogeneityc = 8.05; p < 0.01
Vitamin B6 (mg)
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<1.94 65 162 1b 25 35 1b 40 127 1b

1.94 to <2.36 68 161 0.97 (0.63–1.49) 19 49 0.36 (0.15–0.85) 49 112 1.36 (0.81–2.28)
≥2.36 57 161 0.75 (0.48–1.18) 22 41 0.47 (0.20–1.10) 35 120 0.85 (0.49–1.48)
χ 2 for trend P = 0.21 P = 0.12 P = 0.56
χ 2 for heterogeneityc = 3.17; P = 0.07
Methionine (g)
<1.64 63 162 1b 19 25 1b 44 137 1b
1.64 to <2.02 75 161 1.12 (0.73–1.71) 25 47 0.63 (0.27–1.46) 50 114 1.35 (0.82–2.26)
≥2.02 52 161 0.72 (0.45–1.13) 22 53 0.39 (0.16–0.93) 30 108 0.85 (0.48–1.50)
χ 2 for trend P = 0.16 P = 0.03 P = 0.68
χ 2 for heterogeneityc = 2.04; P = 0.18

Ca = Cases; Co = Controls.
a : Adjusted for age (in quinquennia and continuous term), gender, center (Aviano/Pordenone, Naples), education (<7 yr, 7–11 yr, ≥12 yr), and total energy

intake (continuous term).

b : Reference category.
c : Between strata of drinking habits.

Alcohol consumption could impair folate intake and
bioavailability by means of several mechanisms (25). Heavy
alcohol drinkers suffer of primary malnutrition (i.e., inade-
quate dietary intake of nutrient), including folate deficiency.
Moreover, ethanol could diminish intestinal absorption and
block release of folate from hepatocyte (4). Finally, an in-
creased renal excretion of folate among alcohol drinkers was
suggested (25).
Alcohol also plays a direct role in the intracellular
one-carbon metabolism, inhibiting methionine synthase and
its ramifications and thus reducing the concentration of
some metabolites, which are critical for DNA methy-
lation (25). DNA methylation is related to genetic in-
stability, including chromosomal imbalance, which was
linked to the pathogenesis of lymphoproliferative disor-
ders such as NHL (34). In addition, alcohol may in-
hibit the transcription of several enzymes involved in the
one-carbon metabolism, as well as their enzyme activity
(25).
The present study, as most hospital-based case-control
studies, may suffer some limitation (22). Sample size is one
of the principal limitations. The small number of cases and
controls did not allow a categorization of exposure finer than
in tertiles, as well as additional stratification other than by
drinking habits. Moreover, hospital controls may differ from
the general population in relation to dietary habits, and thus
selection bias cannot be totally ruled out. However, great
attention was paid in excluding all diagnoses that might have
been associated to or had determined special dietary habits in
control subjects. When excluding each subgroup of control
patients, the results did not change substantially, suggesting
that the selection bias, if any, was negligible. Most likely, the
administration of the questionnaire to cases and controls by
the same interviewers, under similar conditions in a hospital
setting, and the almost complete participation of identified
cases and controls, minimized information bias. Adjustments
for sex, age, center, and education were made to address
potential confounding.
The great proportion of current and former drinkers, and
high levels of alcohol intake, have to be counted among the
strengths of the present study, as they allowed investigating
the modification effect of alcohol on the relation between
one-carbon nutrients and NHL risk. Moreover, the rare vi-
tamins supplementation in Italy gives the opportunity to in-
vestigate the relationship between one-carbon nutrients and
NHL risk in a population whose nutrient intake is almost
totally due to food. Finally, the availability of a detailed and
validated FFQ (19,20) and of the Italian Food Composition
Database (21) allowed accurate computation of daily intake
of micronutrients.

Vol. 57, No. 2 149

 In conclusion, our findings support the possibility of an
antagonist effect of alcohol on the one-carbon metabolism
in NHL etiology. The lack of an overall effect of one-carbon
nutrients on NHL risk, but not among abstainers and former
drinkers, suggested that any potentially beneficial effect of
such nutrients may be counteracted by alcohol intake. How-
ever, the small sample size suggested caution in the interpre-
tation of our results. Larger investigations are recommended
to guarantee sufficient power to investigate the issue in strata
of alcohol intake and according to NHL subtype.
Acknowledgments and Notes
This work was supported by grants from A.I.R.C. (Italian Association for
Cancer Research) and the Italian League Against Cancer. The authors wish
to thank Drs. A. Pinto, V. Canzonieri, and M. Crovatto for the collaboration
to the study, Mrs. O. Volpato for study coordination, Drs. G. Laconca, M.
Grimaldi, and S. Desicato for their help in data collection. We are also deeply
Downloaded by [University of Illinois Chicago] at 03:56 21 November 2014
thankful to Drs. R. Mele, A. Grandi, L. Forner, P. Ascierto, R. Magri, and R.
Di Lauro for providing hospital control patients. Address correspondence to
Jerry Polesel, Unità di Epidemiologia e Biostatistica, Centro di Riferimento
Oncologico, Via F. Gallini, 2, 33081 Aviano (PN), Italy; Tel:+39-0434-
659354. FAX:+39-0434-659222. E-mail: polesel@cro.it
Submitted 2 June 2006; accepted in final form 16 October 2006.
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