Cancer Epidemiology Biomarkers & Prevention Vol. 14, 2056-2058, August 2005
© 2005 American Association for Cancer Research
Dietary Folate, Alcohol Consumption, and Risk of Ovarian Cancer in an Italian Case-Control Study
Claudio Pelucchi1,
Monia Mereghetti1,
Renato Talamini3,
Eva Negri1,
Maurizio Montella4,
Valerio Ramazzotti5,
Silvia Franceschi6 and
Carlo La Vecchia1,2
1 Istituto di Ricerche Farmacologiche "Mario Negri"; 2 Istituto di Statistica Medica e Biometria, Università degli Studi di Milano, Milan, Italy; 3 Servizio di Epidemiologia e Biostatistica, Centro di Riferimento Oncologico, Aviano, Italy; 4 Servizio di Epidemiologia, Istituto Tumori "Fondazione Pascale," Naples, Italy; 5 Servizio Integrato di Epidemiologia e Sistemi Informativi, Istituto Regina Elena-Istituti Fisioterapici Ospedalieri, Rome, Italy; and 6 IARC, Lyon, France
Requests for reprints: Claudio Pelucchi, Istituto di Ricerche Farmacologiche "Mario Negri," Via Eritrea 62, 20157 Milan, Italy. Phone: 39-02-390-141; Fax: 39-02-33200231. E-mail: pelucchi{at}marionegri.it
 |
Introduction
|
|---|
An increasing number of studies are focusing on the potential association between dietary folate intake and risk of various cancers (1), particularly of the colorectum and breast (2, 3). A low folate status can induce misincorporation of uracil into DNA, leading to chromosome breaks in humans and hence increasing cancer risk (4). Alcohol may increase folate requirements in the body and cause relative folate deficiencies (2). Although several findings on the relation between folate intake and ovarian cancer risk are inconsistent (5-9), recent results from two prospective studies, including 266 and 147 incident cases of epithelial ovarian cancer, have suggested an interaction of folate and alcohol in ovarian carcinogenesis [i.e., folate would be inversely related to ovarian cancer risk in alcohol drinkers (5, 6), and alcohol in those with high folate intake (7)]. With the aim to provide further data on the issue, we assessed the relation between dietary folate, alcohol consumption, and ovarian cancer risk in a multicentric case-control study conducted in Italy (10).
|
Materials and Methods
|
|---|
The study was conducted in four Italian areas between 1992 and 1999 (10). Cases were 1,031 women admitted to the major teaching and general hospitals in the areas under surveillance with incident, histologically confirmed epithelial ovarian cancer. Controls were 2,411 women admitted to the same network of hospitals for acute, nonmalignant, and nongynecologic conditions, unrelated to hormonal diseases or to long-term modifications of diet.
A standard questionnaire was given by centrally trained interviewers during hospital stay, including detailed information on personal characteristics, lifestyle habits, a problem-oriented medical history, history of cancer in relatives, menstrual and reproductive factors, and use of oral contraceptives and hormone therapy. A food frequency questionnaire was developed to assess the usual diet during the 2 years preceding diagnosis (for cases) or hospital admission (for controls). The food frequency questionnaire included 78 foods, food groups, or dishes divided into six sections: first courses, second courses, side dishes, fruits, desserts, and beverages. For a few seasonal vegetables and fruits, duration of consumption was elicited.
Energy and nutrient intakes, including folate, methionine, and vitamin B6, were computed from the food frequency questionnaire using an Italian food composition database (11). A separate section investigated alcohol consumption in detail.
Data Analysis
Odds ratios (OR) and 95% confidence intervals (95% CI) were derived using unconditional multiple logistic regression models, including terms for age, study center, year of interview, education, parity, body mass index, alcohol consumption, use of oral contraceptives, physical activity, and energy intake (excluding energy from alcoholic beverages). After adjustment for nonalcohol energy intake, our study had 80% power to detect a 35% reduced risk (i.e., an OR 
0.65) for the highest compared with the lowest quintile of folate intake (
= 0.05).
|
Results
|
|---|
Table 1 reports the distribution of cases and controls, ORs and 95% CIs of ovarian cancer according to quintiles of folate intake of all women together, by histologic subtype and in separate strata of alcohol consumption, methionine, and vitamin B6 intake. Compared with the lowest quintile of dietary folate, the ORs of ovarian cancer were 1.10, 0.99, 1.02 and 0.98 for subsequent quintiles of intake. When further lifestyle, reproductive, and dietary covariates were controlled for, the ORs were 1.14, 1.12, 1.23, and 1.26. For the highest level of folate, the ORs of serous, mucinous, and other subtypes of ovarian cancer were 1.10, 0.41, and 0.85, respectively. In the stratum of non- and low-alcohol drinkers, the OR for an increase in folate intake equal to an SD was 0.93 (95% CI, 0.76-1.14). In the stratum of moderate/high drinkers, the corresponding OR was 1.02 (95% CI, 0.86-1.23), whereas when we considered folate intake in the stratum of hard drinkers only (5th quintile, i.e., >26 g/d), the OR was 1.14 (95% CI, 0.85-1.54). Ovarian cancer risk for folate intake was somewhat higher in strata of low methionine and vitamin B6 (OR, 1.18 and 1.15, respectively) than in strata of high methionine and vitamin B6 (OR, 0.79 and 0.88, respectively).
|
Discussion
|
|---|
Strengths of this investigation are its large size, the use of a validated and reproducible food frequency questionnaire (12-14), the low percentage of refusals of the subjects contacted, and the specific interest of the Italian population that has relatively high levels of alcohol (mostly wine) consumption (15). Our results do not indicate a major role of folate in ovarian cancer risk, nor a relevant interaction of folate with alcohol or with methionine or vitamin B6. These findings are in broad agreement with the available evidence from various studies, which in turn indicated inverse (5), absent (9), and direct (7, 8) relation of folate with ovarian cancer risk.
Our findings were confirmed after inclusion in the regression models of several lifestyle, reproductive, and dietary covariates, and at various levels of alcohol drinking. With reference to histologic subtypes of ovarian cancer (16), no association emerged for serous, endometrioid, and clear-cell tumors. However, the inverse relation of dietary folate with mucinous ovarian cancers was consistent with previous findings from the Swedish Mammography Cohort (5), but still uncertain because of the small number of mucinous cases in both studies.
Among possible explanations of the inconsistent findings of the studies, there are potential bias of epidemiologic studies. Case-control studies are generally more liable to bias than prospective ones. However, findings from a companion case-control study of breast cancer, where an inverse association with folate intake (stronger in high alcohol drinkers) was observed (17), are reassuring for the control group that we investigated, because the breast and ovarian studies were conducted on similar populations and shared a number of control subjects too.
In addition, differences in folate intake and alcohol consumption between various populations should be taken into account. In fact, the estimated median intake of folate widely differed between our study (248 µg/d) and the Swedish (178 µg/d) and the Iowa studies (331 µg/d; refs. 5–7). Further, the pattern of alcohol drinking in our investigation was peculiar for this population because we observed a large proportion of nondrinkers (40.6% of controls) as well as of hard drinkers (22.0% of controls had an intake of >25 g/d).
Notwithstanding these considerations, our findings from one of the largest data sets of ovarian cancer collected to date, as well as the overall epidemiologic evidence, do not support a role of folate and alcohol in ovarian carcinogenesis (18).
|
Acknowledgments
|
|---|
We thank M.P. Bonifacino for editorial assistance.
|
Footnotes
|
|---|
Grant support: Italian Association for Cancer Research and the Italian League against Cancer.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 3/21/05;
revised 4/26/05;
accepted 6/14/05.
|
References
|
|---|
- Lucock M. Is folic acid the ultimate functional food component for disease prevention? BMJ 2004;328:211–4.[Free Full Text]
- Giovannucci E, Rimm EB, Ascherio A, Stampfer MJ, Colditz GA, Willett WC. Alcohol, low-methionine–low-folate diets, and risk of colon cancer in men. J Natl Cancer Inst 1995;7:265–73.
- Shrubsole MJ, Jin F, Dai Q, et al. Dietary folate intake and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Res 2001;61:7136–41.[Abstract/Free Full Text]
- Blount BC, Mack MM, Wehr CM, et al. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci U S A 1997;94:3290–5.[Abstract/Free Full Text]
- Larsson SC, Giovannucci E, Wolk A. Dietary folate intake and incidence of ovarian cancer: the Swedish Mammography Cohort. J Natl Cancer Inst 2004;96:396–402.[Abstract/Free Full Text]
- Larsson SC, Wolk A. Wine consumption and epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev 2004;13:1823–4.[Free Full Text]
- Kelemen LE, Sellers TA, Vierkant RA, Harnack L, Cerhan JR. Association of folate and alcohol with risk of ovarian cancer in a prospective study of postmenopausal women. Cancer Causes Control 2004;15:1085–93.[CrossRef][Medline]
- Salazar-Martinez E, Lazcano-Ponce EC, Gonzalez Lira-Lira G, Escudero-De los Rios P, Hernandez-Avila M. Nutritional determinants of epithelial ovarian cancer risk: a case-control study in Mexico. Oncology 2002;63:151–7.[CrossRef][Medline]
- McCann SE, Freudenheim JL, Marshall JR, Graham S. Risk of human ovarian cancer is related to dietary intake of selected nutrients, phytochemicals and food groups. J Nutr 2003;133:1937–42.[Abstract/Free Full Text]
- Tavani A, Gallus S, La Vecchia C, et al. Physical activity and risk of ovarian cancer: an Italian case-control study. Int J Cancer 2001;91:407–11.[Medline]
- Salvini S, Parpinel M, Gnagnarella P, Maisonneuve P, Turrini A. Banca dati di composizione degli alimenti per studi epidemiologici in Italia. Milan: Istituto Europeo di Oncologia; 1998.
- Franceschi S, Barbone F, Negri E, et al. Reproducibility of an Italian food frequency questionnaire for cancer studies. Results for specific nutrients. Ann Epidemiol 1995;5:69–75.[CrossRef][Medline]
- Decarli A, Franceschi S, Ferraroni M, et al. Validation of a food-frequency questionnaire to assess dietary intakes in cancer studies in Italy. Results for specific nutrients. Ann Epidemiol 1996;6:110–8.[CrossRef][Medline]
- Ferraroni M, Decarli A, Franceschi S, et al. Validity and reproducibility of alcohol consumption in Italy. Int J Epidemiol 1996;25:775–82.[Abstract/Free Full Text]
- La Vecchia C. Alcohol in the mediterranean diet: Benefits and risks. Int J Vitam Nutr Res 2001;71:210–3.[Medline]
- Bertone-Johnson ER. Epidemiology of ovarian cancer: a status report. Lancet 2005;365:101–2.[Medline]
- Negri E, La Vecchia C, Franceschi S. Re: Dietary folate consumption and breast cancer risk. J Natl Cancer Inst 2000;92:1270–1.[Free Full Text]
- Tavani A, Gallus S, Dal Maso L, et al. Coffee and alcohol intake and risk of ovarian cancer: an Italian case-control study. Nutr Cancer 2001;39:29–34.[CrossRef][Medline]
Top
Introduction
Materials and Methods
