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)

Franceschi, Silvia

La Vecchia, Carlo

Mereghetti, Monia

Montella, Maurizio

Negri, Eva

Pelucchi, Claudio

Ramazzotti, Valerio

Talamini, Renato

English

Montclair State University Digital Commons

Montclair State University Montclair State University Digital Commons Department of Public Health Scholarship and Creative Works Department of Public Health Summer 8-2005 Dietary Folate, Alcohol Consumption, and Risk of Ovarian Cancer in an Italian Case-Control Study Claudio Pelucchi Istituto di Ricerche Farmacologiche Monia Mereghetti Istituto di Ricerche Farmacologiche Renato Talamini Servizio di Epidemiologia e Biostatistica, Centro di Riferimento Oncologico Eva Negri Istituto di Ricerche Farmacologiche Maurizio Montella Servizio di Epidemiologia, Istituto Tumori Fondazione Pascale See next page for additional authors Follow this and additional works at: https://digitalcommons.montclair.edu/public-health-facpubs  Part of the Clinical Epidemiology Commons, Community Health and Preventive Medicine Commons, Dietetics and Clinical Nutrition Commons, Environmental Public Health Commons, Epidemiology Commons, Health Services Administration Commons, Health Services Research Commons, International Public Health Commons, Life Sciences Commons, Maternal and Child Health Commons, Occupational Health and Industrial Hygiene Commons, Other Chemicals and Drugs Commons, Other Public Health Commons, Public Health Education and Promotion Commons, and the Women's Health Commons MSU Digital Commons Citation Pelucchi, Claudio; Mereghetti, Monia; Talamini, Renato; Negri, Eva; Montella, Maurizio; Ramazzotti, Valerio; Franceschi, Silvia; and La Vecchia, Carlo, "Dietary Folate, Alcohol Consumption, and Risk of Ovarian Cancer in an Italian Case-Control Study" (2005). Department of Public Health Scholarship and Creative Works. 95. https://digitalcommons.montclair.edu/public-health-facpubs/95 This Article is brought to you for free and open access by the Department of Public Health at Montclair State University Digital Commons. It has been accepted for inclusion in Department of Public Health Scholarship and Creative Works by an authorized administrator of Montclair State University Digital Commons. For more information, please contact digitalcommons@montclair.edu. Authors Claudio Pelucchi, Monia Mereghetti, Renato Talamini, Eva Negri, Maurizio Montella, Valerio Ramazzotti, Silvia Franceschi, and Carlo La Vecchia This article is available at Montclair State University Digital Commons: https://digitalcommons.montclair.edu/public-health-facpubs/95 Null Results in BriefDietary Folate, Alcohol Consumption, and Risk ofOvarian Cancer in an Italian Case-Control StudyClaudio Pelucchi,1 Monia Mereghetti,1 Renato Talamini,3 Eva Negri,1 Maurizio Montella,4Valerio Ramazzotti,5 Silvia Franceschi,6 and Carlo La Vecchia1,21Istituto di Ricerche Farmacologiche ‘‘Mario Negri’’; 2Istituto di Statistica Medica e Biometria, Università degli Studi di Milano, Milan,Italy; 3Servizio di Epidemiologia e Biostatistica, Centro di Riferimento Oncologico, Aviano, Italy; 4Servizio di Epidemiologia, IstitutoTumori ‘‘Fondazione Pascale,’’ Naples, Italy; 5Servizio Integrato di Epidemiologia e Sistemi Informativi, Istituto Regina Elena-IstitutiFisioterapici Ospedalieri, Rome, Italy; and 6IARC, Lyon, FranceIntroductionAn increasing number of studies are focusing on thepotential association between dietary folate intake and riskof various cancers (1), particularly of the colorectum andbreast (2, 3). A low folate status can induce misincorporationof uracil into DNA, leading to chromosome breaks inhumans and hence increasing cancer risk (4). Alcohol mayincrease folate requirements in the body and cause relativefolate deficiencies (2). Although several findings on therelation between folate intake and ovarian cancer risk areinconsistent (5-9), recent results from two prospectivestudies, including 266 and 147 incident cases of epithelialovarian cancer, have suggested an interaction of folate andalcohol in ovarian carcinogenesis [i.e., folate would beinversely related to ovarian cancer risk in alcohol drinkers(5, 6), and alcohol in those with high folate intake (7)]. Withthe aim to provide further data on the issue, we assessed therelation between dietary folate, alcohol consumption, andovarian cancer risk in a multicentric case-control studyconducted in Italy (10).Materials and MethodsThe study was conducted in four Italian areas between 1992and 1999 (10). Cases were 1,031 women admitted to the majorteaching and general hospitals in the areas under surveillancewith incident, histologically confirmed epithelial ovariancancer. Controls were 2,411 women admitted to the samenetwork of hospitals for acute, nonmalignant, and nongyneco-logic conditions, unrelated to hormonal diseases or to long-term modifications of diet.A standard questionnaire was given by centrally trainedinterviewers during hospital stay, including detailed informa-tion on personal characteristics, lifestyle habits, a problem-oriented medical history, history of cancer in relatives,menstrual and reproductive factors, and use of oral contra-ceptives and hormone therapy. A food frequency questionnairewas developed to assess the usual diet during the 2 yearspreceding diagnosis (for cases) or hospital admission (forcontrols). 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. Fora few seasonal vegetables and fruits, duration of consumptionwas elicited.Energy and nutrient intakes, including folate, methionine,and vitamin B6, were computed from the food frequencyquestionnaire using an Italian food composition database(11). A separate section investigated alcohol consumption indetail.Data Analysis. Odds ratios (OR) and 95% confidenceintervals (95% CI) were derived using unconditional multiplelogistic regression models, including terms for age, studycenter, year of interview, education, parity, body mass index,alcohol consumption, use of oral contraceptives, physicalactivity, and energy intake (excluding energy from alcoholicbeverages). After adjustment for nonalcohol energy intake, ourstudy had 80% power to detect a 35% reduced risk (i.e., an ORV 0.65) for the highest compared with the lowest quintile offolate intake (a = 0.05).ResultsTable 1 reports the distribution of cases and controls, ORs and95% CIs of ovarian cancer according to quintiles of folateintake of all women together, by histologic subtype and inseparate strata of alcohol consumption, methionine, andvitamin B6 intake. Compared with the lowest quintile ofdietary folate, the ORs of ovarian cancer were 1.10, 0.99, 1.02and 0.98 for subsequent quintiles of intake. When furtherlifestyle, reproductive, and dietary covariates were controlledfor, the ORs were 1.14, 1.12, 1.23, and 1.26. For the highestlevel of folate, the ORs of serous, mucinous, and othersubtypes 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 was0.93 (95% CI, 0.76-1.14). In the stratum of moderate/highdrinkers, the corresponding OR was 1.02 (95% CI, 0.86-1.23),whereas when we considered folate intake in the stratum ofhard drinkers only (5th quintile, i.e., >26 g/d), the OR was1.14 (95% CI, 0.85-1.54). Ovarian cancer risk for folate intakewas somewhat higher in strata of low methionine andvitamin B6 (OR, 1.18 and 1.15, respectively) than in strataof high methionine and vitamin B6 (OR, 0.79 and 0.88,respectively).DiscussionStrengths of this investigation are its large size, the use ofa validated and reproducible food frequency questionnaire2056Cancer Epidemiol Biomarkers Prev 2005;14(8). August 2005Cancer Epidemiol Biomarkers Prev 2005;14(8):2056 – 8Received 3/21/ 05; revised 4/26/ 05; accepted 6/14/ 05.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.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@marionegri.itCopyright D 2005 American Association for Cancer Research.doi:10.1158/1055-9965.EPI-05-0192Research. on November 9, 2020. © 2005 American Association for Cancercebp.aacrjournals.org Downloaded from (12-14), the low percentage of refusals of the subjects contacted,and the specific interest of the Italian population that hasrelatively high levels of alcohol (mostly wine) consumption(15). Our results do not indicate a major role of folate inovarian cancer risk, nor a relevant interaction of folate withalcohol or with methionine or vitamin B6. These findings are inbroad agreement with the available evidence from variousstudies, which in turn indicated inverse (5), absent (9), anddirect (7, 8) relation of folate with ovarian cancer risk.Our findings were confirmed after inclusion in theregression models of several lifestyle, reproductive, anddietary 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 folatewith mucinous ovarian cancers was consistent with previousfindings from the Swedish Mammography Cohort (5), but stilluncertain because of the small number of mucinous cases inboth studies.Among possible explanations of the inconsistent findings ofthe studies, there are potential bias of epidemiologic studies.Case-control studies are generally more liable to bias thanprospective ones. However, findings from a companion case-control study of breast cancer, where an inverse associationwith folate intake (stronger in high alcohol drinkers) wasobserved (17), are reassuring for the control group that weinvestigated, because the breast and ovarian studies wereconducted on similar populations and shared a number ofcontrol subjects too.In addition, differences in folate intake and alcoholconsumption between various populations should be takeninto account. In fact, the estimated median intake of folatewidely differed between our study (248 Ag/d) and the Swedish(178 Ag/d) and the Iowa studies (331 Ag/d; refs. 5–7). Further,the pattern of alcohol drinking in our investigation waspeculiar for this population because we observed a largeproportion of nondrinkers (40.6% of controls) as well as ofhard drinkers (22.0% of controls had an intake of >25 g/d).Notwithstanding these considerations, our findings fromone of the largest data sets of ovarian cancer collected to date,as well as the overall epidemiologic evidence, do not support arole of folate and alcohol in ovarian carcinogenesis (18).AcknowledgmentsWe thank M.P. Bonifacino for editorial assistance.References1. Lucock M. Is folic acid the ultimate functional food component for diseaseprevention? BMJ 2004;328:211 – 4.2. 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 – 73.3. 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 – 41.4. Blount BC, Mack MM, Wehr CM, et al. Folate deficiency causes uracilmisincorporation into human DNA and chromosome breakage: implica-tions for cancer and neuronal damage. Proc Natl Acad Sci U S A 1997;94:3290 – 5.5. Larsson SC, Giovannucci E, Wolk A. Dietary folate intake and incidence ofovarian cancer: the Swedish Mammography Cohort. J Natl Cancer Inst2004;96:396 – 402.6. Larsson SC, Wolk A. Wine consumption and epithelial ovarian cancer.Cancer Epidemiol Biomarkers Prev 2004;13:1823 – 4.Table 1. ORs and 95% CIs of ovarian cancer according to dietary folate intake; Italy, 1992-1999Quintile of folate intake* m2trend Continuous ORc1st 2nd 3rd 4th 5thAll womenCases/controls 159:480 209:491 209:466 218:483 236:491OR (95% CI)b 1 1.10 (0.82-1.49) 0.99 (0.72-1.35) 1.02 (0.73-1.43) 0.98 (0.67-1.44) 0.09 (P = 0.76) 0.99 (0.87-1.13)OR (95% CI)x 1 1.14 (0.83-1.56) 1.12 (0.80-1.57) 1.23 (0.85-1.80) 1.26 (0.80-1.97) 0.97 (P = 0.32) 1.10 (0.94-1.29)Histologic subtypeSerous (493 cases)b 1 1.16 (0.77-1.75) 1.05 (0.68-1.62) 1.15 (0.74-1.81) 1.10 (0.66-1.84) 0.07 (P = 0.79) 1.05 (0.88-1.24)Mucinous (81 cases)b 1 0.64 (0.28-1.46) 0.48 (0.20-1.16) 0.59 (0.24-1.44) 0.41 (0.14-1.18) 2.08 (P = 0.15) 0.80 (0.54-1.18)Other (176 cases)b 1 0.59 (0.32-1.08) 0.73 (0.40-1.32) 0.84 (0.45-1.55) 0.85 (0.42-1.74) 0.01 (P = 0.92) 1.03 (0.80-1.32)Alcohol drinking<1.8 g/dCases/controls 84:296 95:258 90:215 84:212 89:207OR (95% CI)b 1 0.88 (0.57-1.34) 0.89 (0.56-1.41) 0.81 (0.49-1.34) 0.73 (0.40-1.32) 0.97 (P = 0.32) 0.93 (0.76-1.14)z1.8 g/dCases/controls 75:184 114:233 119:251 134:271 147:284OR (95% CI)b 1 1.35 (0.87-2.10) 1.03 (0.66-1.62) 1.26 (0.79-2.01) 1.19 (0.70-2.02) 0.10 (P = 0.75) 1.02 (0.86-1.23)Methionine intakek<Median valueCases/controls 94:264 101:272 95:220 123:228 119:221OR (95% CI)b 1 0.96 (0.63-1.46) 0.99 (0.63-1.54) 1.38 (0.87-2.19) 1.33 (0.77-2.28) 2.43 (P = 0.12) 1.18 (0.99-1.42)zMedian valueCases/controls 65:216 108:219 114:246 95:255 117:270OR (95% CI)b 1 1.29 (0.82-2.02) 0.94 (0.59-1.50) 0.72 (0.43-1.20) 0.71 (0.40-1.26) 4.59 (P = 0.03) 0.79 (0.64-0.96)Vitamin B6 intakek<Median valueCases/controls 127:350 129:287 115:234 96:200 71:134OR (95% CI)b 1 1.18 (0.81-1.73) 1.16 (0.76-1.78) 1.22 (0.75-1.99) 1.22 (0.64-2.32) 0.43 (P = 0.51) 1.15 (0.90-1.46)zMedian valueCases/controls 32:130 80:204 94:232 122:283 165:357OR (95% CI)b 1 1.07 (0.62-1.87) 0.84 (0.48-1.46) 0.88 (0.50-1.56) 0.77 (0.41-1.44) 1.31 (P = 0.25) 0.88 (0.73-1.07)*Cut points for quintiles of folate intake among controls were 186, 231, 268, and 316 Ag/d. The lowest quintile was taken as reference category.cFor an increase in folate intake equal to an SD, calculated among controls (83.47 Ag/d).bEstimates from unconditional logistic regression models adjusted for age, study center, year of interview, education, parity, body mass index, alcohol consumption,oral contraceptives use, physical activity, and nonalcohol energy intake.xIncluding all the adjustments above, plus further terms for menopausal status, family history of breast and/or ovarian cancer, age at menarche, first birth andmenopause, hormone replacement therapy use, diabetes, fruit and vegetable consumption, and smoking habit.kEnergy-adjusted intake.Cancer Epidemiology, Biomarkers & Prevention 2057Cancer Epidemiol Biomarkers Prev 2005;14(8). August 2005Research. on November 9, 2020. © 2005 American Association for Cancercebp.aacrjournals.org Downloaded from 7. Kelemen LE, Sellers TA, Vierkant RA, Harnack L, Cerhan JR. Association offolate and alcohol with risk of ovarian cancer in a prospective study ofpostmenopausal women. Cancer Causes Control 2004;15:1085 – 93.8. Salazar-Martinez E, Lazcano-Ponce EC, Gonzalez Lira-Lira G, Escudero-Delos Rios P, Hernandez-Avila M. Nutritional determinants of epithelialovarian cancer risk: a case-control study in Mexico. Oncology 2002;63:151 – 7.9. McCann SE, Freudenheim JL, Marshall JR, Graham S. Risk of human ovariancancer is related to dietary intake of selected nutrients, phytochemicals andfood groups. J Nutr 2003;133:1937 – 42.10. Tavani A, Gallus S, La Vecchia C, et al. Physical activity and risk of ovariancancer: an Italian case-control study. Int J Cancer 2001;91:407 – 11.11. Salvini S, Parpinel M, Gnagnarella P, Maisonneuve P, Turrini A. Banca datidi composizione degli alimenti per studi epidemiologici in Italia. Milan:Istituto Europeo di Oncologia; 1998.12. Franceschi S, Barbone F, Negri E, et al. Reproducibility of an Italian foodfrequency questionnaire for cancer studies. Results for specific nutrients.Ann Epidemiol 1995;5:69 – 75.13. Decarli A, Franceschi S, Ferraroni M, et al. Validation of a food-frequencyquestionnaire to assess dietary intakes in cancer studies in Italy. Results forspecific nutrients. Ann Epidemiol 1996;6:110 – 8.14. Ferraroni M, Decarli A, Franceschi S, et al. Validity and reproducibility ofalcohol consumption in Italy. Int J Epidemiol 1996;25:775 – 82.15. La Vecchia C. Alcohol in the mediterranean diet: Benefits and risks. Int JVitam Nutr Res 2001;71:210 – 3.16. Bertone-Johnson ER. Epidemiology of ovarian cancer: a status report. Lancet2005;365:101 – 2.17. Negri E, La Vecchia C, Franceschi S. Re: Dietary folate consumption andbreast cancer risk. J Natl Cancer Inst 2000;92:1270 – 1.18. Tavani A, Gallus S, Dal Maso L, et al. Coffee and alcohol intake and risk ofovarian cancer: an Italian case-control study. Nutr Cancer 2001;39:29 – 34.Dietary Folate and Ovarian Cancer Risk2058Cancer Epidemiol Biomarkers Prev 2005;14(8). August 2005Research. on November 9, 2020. © 2005 American Association for Cancercebp.aacrjournals.org Downloaded from 2005;14:2056-2058. Cancer Epidemiol Biomarkers Prev   Claudio Pelucchi, Monia Mereghetti, Renato Talamini, et al.   Cancer in an Italian Case-Control StudyDietary Folate, Alcohol Consumption, and Risk of Ovarian  Updated version   http://cebp.aacrjournals.org/content/14/8/2056Access the most recent version of this article at:          Cited articles   http://cebp.aacrjournals.org/content/14/8/2056.full#ref-list-1This article cites 17 articles, 5 of which you can access for free at:      E-mail alerts  related to this article or journal.Sign up to receive free email-alerts  SubscriptionsReprints and   .pubs@aacr.orgDepartment atTo order reprints of this article or to subscribe to the journal, contact the AACR Publications  Permissions  Rightslink site. (CCC)Click on "Request Permissions" which will take you to the Copyright Clearance Center's.http://cebp.aacrjournals.org/content/14/8/2056To request permission to re-use all or part of this article, use this linkResearch. on November 9, 2020. © 2005 American Association for Cancercebp.aacrjournals.org Downloaded from 

Dietary Folate, Alcohol Consumption, and Risk of Ovarian Cancer in an Italian Case-Control Study

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Dietary Folate, Alcohol Consumption, and Risk of Ovarian Cancer in an Italian Case-Control Study

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