1422 Vol. 12, 1422–1428, December 2003 Cancer Epidemiology, Biomarkers & Prevention Fatty Acids and Risk of Prostate Cancer in a Nested Case-Control Study in Male Smokers Satu Ma¨nnisto¨,1,3 Pirjo Pietinen,1 Mikko J. Virtanen,1 serum or dietary ␣-linolenic acid or any other Irma Salminen,2 Demetrius Albanes,5 unsaturated fatty acid and prostate cancer risk, but high Edward Giovannucci,3,4,6 and Jarmo Virtamo1 serum linoleic acid was associated with lower risk in men ␣ Departments of 1Epidemiology and Health Promotion, and 2Health and supplemented with -tocopherol. High serum myristic Functional Capacity, National Public Health Institute, Helsinki, Finland; acid associated with an increased risk of prostate cancer. Departments of 3Nutrition and 4Epidemiology, Harvard School of Public Health, Boston, Massachusetts; 5National Cancer Institute, NIH, Bethesda, Maryland; and 6Department of Medicine, Harvard Medical School, Boston, Introduction Massachusetts Migrant studies and ecologic evidence that incidence rates of clinical prostate cancer vary geographically much more than Abstract that of latent prostate cancer suggest that environmental factors play an important role at least in late prostatic carcinogenesis There is some evidence that ␣-linolenic acid might be (1). Some dietary factors especially have been observed to positively related to prostate cancer risk. Associations increase prostate cancer risk (2). between serum fatty acid composition as well as fatty The evidence on an association between fat intake and acid intakes and prostate cancer risk were examined in prostate cancer risk is mainly based on epidemiological studies. the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Most case-control studies have associated high intakes of ani- Study. The cohort included 29,133 male smokers aged mal fat or saturated fatty acids with an increased risk of prostate 50–69 years. During 5–8 years of follow-up, 246 prostate cancer, but only a few of them have adjusted fat intake for cancer cases were diagnosed. One control was selected energy (3). High total fat intake was associated with the risk of and matched by age (؎ 1 month) for each case from the advanced prostate cancer in the Health Professionals Fol- cohort subjects alive and free of prostate cancer at the low-Up Study (4). Of fatty acids, the prostate cancer risk was time the case was diagnosed. This study included 198 three times higher for men in the highest quintile of ␣-linolenic case-control pairs with baseline serum sample available intake compared with those in the lowest quintile. In the Phy- for both. Fatty acids of serum cholesterol esters were sicians’ Health Study, high plasma concentration of ␣-linolenic measured as a percentage of total fatty acids, using acid was related to a higher prostate cancer risk (5). Compa- capillary gas chromatography. Intakes of fatty acids were rable data from animal studies are limited because of the lack assessed from a validated self-administered dietary of suitable animal models and unclear relevance to the human questionnaire. Serum and dietary fatty acids had no disease (6). consistent association with prostate cancer risk. Serum We examined associations between different dietary fatty ␣-linolenic acid was not related to prostate cancer risk. acids and serum fatty acid concentration, and prostate cancer Twofold risk was found in the highest quartile of serum risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention myristic acid compared with the lowest quartile (odds Study (the ATBC study). ratio, 1.93; 95% confidence interval, 1.02–3.64). ␣- Tocopherol supplementation modified the association between serum linoleic acid and prostate cancer risk (P Materials and Methods for interaction 0.03); odds ratio was 0.17 (95% confidence Study Design and Subjects. The subjects of this study were interval, 0.04–0.68) in the highest quartile of serum participants of the ATBC study, a randomized placebo-con- linoleic acid compared with the lowest quartile in men trolled trial, of which the main aim was to examine whether who received ␣-tocopherol, whereas no association was ␣ ␤ ␣ daily supplementation with -tocopherol (AT), -carotene found in men who did not receive -tocopherol. In (BC), or both would prevent lung cancer or other cancer in male conclusion, we found no overall association between smokers. The study design as well as participant characteristics and methods have been described in detail earlier (7, 8). A questionnaire asking about smoking habits and willing- Received 5/8/02; revised 6/17/03; accepted 8/22/03. ness to participate in the ATBC study was mailed to the total Grant Support: National Cancer Institute Contract N01-CN-45035, Academy of male population aged 50–69 and living in southwestern Fin- Finland (#49637), Finnish Cultural Foundation, and Finnish Food Research land (n ϭ 290,406) between 1985 and 1988 (8). In all, 79% of Foundation. the men replied and 54,000 smoked at least five cigarettes per 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 day, and 42,000 of smokers were willing to participate in the accordance with 18 U.S.C. Section 1734 solely to indicate this fact. trial. Participants were excluded if they had a previous history Notes: Dr. Ma¨nnisto¨conducted this work while visiting at Harvard School of of cancer or a disease limiting long term participation, or if they Public Health. used vitamin E, vitamin A, or BC supplements in excess of Requests for reprints: Satu Ma¨nnisto¨, National Public Health Institute, Depart- ment of Epidemiology and Health Promotion, Mannerheimintie 166, 00300 predefined doses. In addition, some of the men who were Helsinki, Finland. Fax: 358-9-4744-8591; E-mail: [email protected]. initially interested in participation refused their participation Downloaded from cebp.aacrjournals.org on September 28, 2021. © 2003 American Association for Cancer Research. Cancer Epidemiology, Biomarkers & Prevention 1423 before randomization. Thus, 29,133 men were randomly as- urated fatty acids, and 0.73 for polyunsaturated fatty acids. The signed to receive AT (50 mg/day), BC (20 mg/day), both energy-adjusted correlation coefficients between the question- agents, or placebo. Follow-up continued for 5–8 years (median, naire and the diet records were 0.39, 0.62, 0.38, and 0.69, 6.1 years), until April 30, 1993. The ATBC study was approved respectively. by the Institutional Review Boards of both the National Public Laboratory Analysis. We analyzed serum cholesterol esters, Health Institute in Finland and the United States National which reflect fatty acid intakes of a few days (15). Lipids were Cancer Institute. extracted from serum samples by a modification of Folch et al. At the first visit, each man completed questionnaires on (16), and cholesterol esters were separated from the fat extract general background characteristics and medical, smoking, and by TLC. The cholesterol ester fatty acids were trans-esterified occupational histories. Height and weight were measured, and by acidic methanol (17). The fatty acid composition was de- serum samples were collected and stored at Ϫ70°C for future termined by a HRGC 412 Micromat gas chromatography analyses. (HNU-Nordion Instruments, Finland) with a 25-m long NB-351 A total of 246 prostate cancer cases were diagnosed during fused silica capillary column (diameter, 0.32 mm and phase the trial period. They were ascertained using the Finnish Cancer layer, 0.20 ␮m; HNU-Nordion Instruments). Split injection was Registry and the Register of Causes of Death. All of the cases used, and helium was used as carrier gas. The temperature was were reviewed independently by two oncologists to confirm the programmed from 170°Cto230°C. The percentage composi- diagnosis and stage, and two pathologists checked the original tion of fatty acid methyl esters normalized to 100% was cal- histological and cytological specimens. One control was se- culated from 14:0 to 22:6 with a Sunicom Workstation (Hel- lected for each prostate cancer case from the participants of the sinki, Finland). Between-series variation of the larger gas ATBC study. The controls were required to be alive and free of chromatography peaks (the amount of the fatty acid over 3%) prostate cancer at the date when the case was diagnosed. They was 2.4–8% and that of smaller peaks (the amount of the fatty were also individually matched with the case by age (Ϯ1 acid under 2%) 9–12% with exception for docosahexaenoic month) and by trial supplementation group. Complete data sets acid, C22:6n-3 (25%). were available for both in 198 matched case-control pairs (28 Statistical Methods. The case-control differences were tested cases and 30 controls had missing data either on dietary factors, using either paired t tests or paired ␹2 tests. The odds ratios serum samples, or adjusting factors). (ORs) were calculated with conditional logistic regression. All Prostate tumors were classified by following the criteria of of the models were adjusted for area of residence (urban/rural), the American Joint Committee on Cancer (9) to stage 0 and education, body mass index, alcohol consumption, and number stage I clinically inapparent (latent) tumors, and to stage II, III, of years of smoking. In addition, dietary variables were ad- and IV clinically apparent tumors. Of the 198 prostate cancer justed for energy. Because the unadjusted results were similar cases, 42 cases (21.2%) were classified as stage 0 or I tumors, to those of the multivariate models, the unadjusted results were and 155 (78.3%) were classified as stage II, III, or IV tumors. presented. Quartiles for grouped analyses were calculated in One subject could not be staged. The data were separately full data with cases and controls combined. Tests for trends analyzed for men having stage 0 or stage I tumors, and for men were calculated using Wald tests with linear contrasts.