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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,.

NUTRITION AND CANCER, 57(2), 146–150 C 2007, Lawrence Erlbaum Associates, Inc. Copyright 

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 micronutrients involved in the one-carbon metabolism (i.e., vitamins B2 , B6 , B12 , and methionine) have been related to several diseases, including cancers, but results on non-Hodgkin lymphoma (NHL) are controversial. A hospital-based casecontrol 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 computed 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 methionine (OR = 0.7). However, a significant inverse association was observed for all the nutrients examined among abstainers 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.

sequent DNA methylation (1). Deficiency of folate and other B vitamins has been associated to several diseases, including 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 onecarbon 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 abnormal DNA methylation (1) involved in lymphomagenesis (7). However, the evidence of such nutrients having a protective effect on non-Hodgkin lymphoma (NHL) is still controversial (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 onecarbon 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 alcohol 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 conducted 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 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 supplies the one-carbon unit for methionine synthesis and sub-

Between January 1999 and July 2002, we conducted a 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 Unit`a 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, Universit`a 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. Histological specimens were classified according to the International 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 follicular NHL, 14 (7%) were T-cell NHL, 46 (24%) were of miscellaneous subtypes, and 6 (3%) were of unknown histological subtypes. Controls were patients between 18 and 84 yr old (median 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 incomplete 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 entire 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 questionnaire to cases and controls during their hospital stay. Study subjects were asked to report information on sociodemographic indicators, lifestyle factors, smoking and drinking 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 sweeteners; (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 corresponding duration were elicited. Weekly number of drinks of various alcoholic beverages was questioned. Taking into account the different ethanol concentration, 1 drink corresponded 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 correlation 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 satisfactory (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 nutrient 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 continuum, plus terms for study center, education (

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