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American Journal of Epidemiology Advance Access originally published online on May 9, 2007
American Journal of Epidemiology 2007 166(2):181-195; doi:10.1093/aje/kwm063
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American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Dietary Fatty Acids and Colorectal Cancer: A Case-Control Study

Evropi Theodoratou1, Geraldine McNeill2, Roseanne Cetnarskyj1,3, Susan M. Farrington4, Albert Tenesa4, Rebecca Barnetson4, Mary Porteous3, Malcolm Dunlop4 and Harry Campbell1,4

1 Public Health Sciences, University of Edinburgh, Edinburgh, United Kingdom
2 Environmental and Occupational Medicine Department, University of Aberdeen, Aberdeen, United Kingdom
3 South East Scotland Genetic Service, Western General Hospital, Edinburgh, United Kingdom
4 Colon Cancer Genetics Group, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom

Correspondence to Professor Harry Campbell, Public Health Sciences, College of Medicine and Vet Medicine, University of Edinburgh, Teviot Place, Edinburgh, Midlothian EH8 9AG, United Kingdom (e-mail: Harry.Campbell{at}ed.ac.uk).

Received for publication October 20, 2006. Accepted for publication January 22, 2007.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Fatty acid effects on colorectal cancer risk were examined in a national prospective case-control study in Scotland (1999–2006), including 1,455 incident cases and 1,455 matched controls. Three conditional logistic regression models adjusted for energy (residual method) and for other risk factors were applied in the whole sample and were stratified by sex, cancer site, age, and tumor staging. Total and trans-monounsaturated fatty acids and palmitic, stearic, and oleic acids were dose-dependently associated with colorectal cancer risk, but these effects did not persist after further energy adjustment. Significant dose-dependent reductions in risk were associated with increased consumption of omega-3 polyunsaturated fatty acids (highest vs. lowest quartile of intake: odds ratio = 0.63, 95% confidence interval: 0.50, 0.80; p < 0.0005 for trend) and of eicosapentaenoic (odds ratio = 0.59, 95% confidence interval: 0.47, 0.75; p < 0.0005 for trend) and docosahexaenoic (odds ratio = 0.63, 95% confidence interval: 0.50, 0.80; p < 0.0005 for trend) acids. These associations persisted after including energy with the nutrient-energy-adjusted term or total fatty acid intake (energy adjusted). The observed different effects of different types of fatty acids underline the importance of type of fat in the etiology and prevention of colorectal cancer.

case-control studies; colorectal neoplasms; fatty acids; fatty acids, omega-3; fatty acids, unsaturated; logistic models; Scotland; stearic acids

Abbreviations: CI, confidence interval; MUFA, monounsaturated fatty acid; OR, odds ratio; PUFA, polyunsaturated fatty acid


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Colorectal cancer is the third most common cancer in both men (14.7 percent of cases) and women (11.3 percent) in Scotland and the second most frequent cancer-related cause of death for men (11 percent of cancer-related deaths) and the third most frequent for women (9 percent) (1). Colorectal cancer etiology is complex, involving both genetic and environmental factors. However, 50–80 percent of cases of colorectal cancer are considered due to environmental factors, such as dietary habits (2). High intake of dietary fruits and vegetables and low intake of fat have been associated with a decreased risk of several cancers, including colorectal cancer (3). Various compounds found in plant foods have been suggested as candidates for these observed effects, with the most important to date being fiber and folate. Results from the European Prospective Investigation into Cancer and Nutrition study indicated a 40 percent reduction in risk associated with the highest versus the lowest quartile of fiber in food (4–6) after adjusting for folate intake. Results from a meta-analysis of the association between folate consumption and colorectal cancer risk were consistent with a small protective effect of folate against colorectal cancer (7). Despite high fat intake being associated with increased risk of cancer, there are some indications that different types of fat have different effects (2).

Fats (triglycerides) consist of fatty acids that are saturated or unsaturated (monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs)). PUFAs are further divided into omega-3 ({omega}3) and omega-6 ({omega}6) PUFAs. Results from ecologic studies indicate that diets high in animal fat (rich in saturated fatty acids) are associated with increased risk of colorectal cancer in contrast to diets high in fish and fish products (rich in {omega}3 PUFAs), which are associated with reduced risk (8). Animal and cell-line studies have suggested that the effect of fats depends not only on their quantity but also on composition of fatty acids, which might explain the differences in the observed associations (9). Several hypothesized mechanisms regarding the role of specific fatty acids in the development of colon cancer have been described. For example, it has been shown that MUFAs and trans-fatty acids promote human colon growth (9). Additionally, {omega}3 and {omega}6 PUFAs have different effects due to their enzymatic competition for their metabolic conversion in eicosanoids, which affect many physiologic processes (10, 11).

A meta-analysis of case-control studies found no energy-independent associations between the three major fat subclasses (saturated fatty acids, MUFAs, or PUFAs) and colorectal cancer (12). However, few observational studies have assessed the effect of specific fatty acids on colorectal cancer, and the majority focused on {omega}3 PUFAs (this information is described in a supplementary table, which is referred to as "Web table 1" in the text and is posted on the Journal's website (http://aje.oupjournals.org/)). We identified five cohort (13–17) and six case-control (18–23) studies that tested the association between risk of colorectal cancer and {omega}3 PUFAs (this information is described in a supplementary figure, which is referred to as "Web figure 1" in the text and is also posted on the Journal's website). The results of a recent systematic review of clinical trials and cohort studies for the effect of {omega}3 PUFAs on cardiovascular risk and cancer indicated that these fatty acids have no effect on either disease (24). However, the design of the systematic review had several limitations (25). With respect to cancer, most of the studies had very small numbers of cancer cases and did not distinguish between types of cancer. The two largest studies (26, 27) were originally designed to examine the effect of {omega}3 PUFAs on cardiovascular mortality and did not have cancer as a primary study outcome. We also identified three cohort (13, 14, 16) and three case-control (18–20) studies that assessed the effect of specific saturated fatty acids, MUFAs, and {omega}6 PUFAs and two case-control studies examining the effects of trans-fatty acids (20, 28).

The objective of the present case-control study was to examine associations between colorectal cancer and dietary intake of total fatty acids; seven subgroups (saturated fatty acids, MUFAs, PUFAs, {omega}6 PUFAs, {omega}3 PUFAs, trans-fatty acids, and trans-MUFAs); and nine individual fatty acid compounds (palmitic and stearic acids (saturated fatty acids); oleic acid ({omega}9 PUFAs); linoleic acid, {gamma}-linolenic acid, and arachidonic acids ({omega}6 PUFAs); and {alpha}-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid ({omega}3 PUFAs)).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study population
Our 1999–2006 study included 1,455 cases and 1,455 matched controls from a case-control study of colorectal cancer (Study Of Colorectal Cancer in Scotland, SOCCS). We aimed to recruit prospectively all incident cases of adenocarcinoma of the colorectum in patients aged 16–79 years presenting to surgical units in Scottish hospitals. The main exclusions were patient death before ascertainment, patient too ill to participate, case represented a recurrence of colorectal cancer, or patient unable to give informed consent because of learning difficulties or other medical conditions. We sought to minimize ascertainment bias from loss due to death on the ward or soon after diagnosis by basing research staff in the main surgical centers throughout Scotland so that ascertainment occurred as soon after admission as possible and clinically appropriate.

Recruitment took place typically within 2–3 months of diagnosis to limit survival bias. We recruited approximately 45 percent of all incident cases of colorectal cancer that occurred in Scotland over the study period. During the same period, controls were drawn at random from a population-based register (community health index) and were invited to participate. Cases and controls were matched on age (±1 year), sex, and region of residence. More than 99 percent of the study participants were White Caucasians. We were unable to approach some cases when patients died shortly after diagnosis or were too ill to receive study information. Participation rates among those approached were approximately 58 percent for cases and an estimated 57 percent for population-based controls. For these persons, questionnaires were completed by 82 percent of cases and 97 percent of controls recruited. The lower completion rate among cases is due to cases being readmitted to the hospital or otherwise being too ill to cooperate fully in the study. Ethical approval was obtained from the MultiCentre Research Ethics Committee for Scotland and relevant Local Research Ethics committees, Caldicott guardians (senior National Health Service staff appointed to protect patient information), and National Health Service management committees; and all participants provided written informed consent.

Lifestyle and dietary data
The subjects completed one questionnaire with lifestyle and cancer information, reporting their status 1 year prior to diagnosis or recruitment. Participants were asked about their general medical history, physical activity, and smoking status. Additionally, subjects were asked to report any regular intake of aspirin and nonsteroidal antiinflammatory drugs. Reported height, weight, and waist circumference were recorded. Participants were also asked to report some demographic, socioeconomic, and race/ethnicity data. Finally, women were asked about their menstrual and reproductive history and type of hormone replacement therapy and hormonal contraception, if used.

A semiquantitative food frequency questionnaire (Scottish Collaborative Group, version 6.41) was completed by participants (http://www.foodfrequency.org). Its validity for ranking macro- and micronutrients in younger adults has been described elsewhere (29). The food frequency questionnaire consisted of 150 food items; participants were asked to describe the amount and frequency of each food on the list that they ate a year prior to diagnosis or recruitment. Participants were also asked to give full details, including brand name, of up to two fats or oils used for home cooking, up to two fat spreads used on bread, and whether they spread their bread with a thin, medium, or thick layer (with medium illustrated in a photograph). On the questionnaire, oil(s) used for home cooking were added as the fat in foods, which are usually home cooked in Scotland. Two additional fields were included: one for participants to report any other foods eaten regularly and not included in the 150-food list and one to report any vitamin, mineral, or food supplements taken. Frequencies of consumption of the specified measures of each food were converted into nutrients by using an in-house calculation program based on the weights of these measures and the nutrient composition of representative foods derived from the United Kingdom food composition tables (30–36). Nutrient information on supplements was collected from manufacturers' product information and added to the daily nutrient intake. Supplements that contributed to the daily intake of fatty acids included cod or halibut liver oil (35.6 percent of the total number of supplements taken), evening primrose oil (5.8 percent), and fish oils (2.5 percent).

The quality of completion of both questionnaires was checked weekly. Forms with more than a maximum acceptable number of blank entries were returned to participants for additional information.

Fatty acid data
Fatty acid data were obtained from both the United Kingdom food composition tables (30–36) and the FOODBASE database (Institute of Brain Chemistry, London, United Kingdom), a nutrient database for fatty acids. Although the FOODBASE database contained some errors, all values were manually checked and corrected. The data that were calculated included intake of total fatty acids, saturated fatty acids, MUFAs, PUFAs, {omega}6 PUFAs, {omega}3 PUFAs, trans-fatty acids, and trans-MUFAs. Data were also obtained for the fatty acids palmitic and stearic (saturated fatty acids); oleic ({omega}9 PUFA); linoleic, {gamma}-linolenic, and arachidonic ({omega}6 PUFAs); and {alpha}-linolenic, eicosapentaenoic acid, and docosahexaenoic acid ({omega}3 PUFAs). Fatty acid intake from supplements was added to dietary individual, subclass, and total fatty acid intake after energy adjustment. The list of fatty acids included in the analysis was determined prior to the analysis after investigating their distributions in this study population and their correlation coefficients and was also based on the quality of the compositional information for that compound.

Statistical analysis
We used the statistical package Intercooled Stata version 7.2 (Stata Corporation, College Station, Texas). Spearman rank correlation coefficients were calculated to test the correlation between each individual fatty acid. Pearson's {chi}2 test and the t test were used to test the difference between cases and controls in terms of categorical and continuous confounding variables. We used the Wilcoxon rank-sum test to test for differences in crude fatty acid intake.

Conditional logistic regression models were used to estimate the strength of association between colorectal cancer risk and fatty acid quartiles (based on the combined distributions of cases and controls). Fatty acid intake was adjusted for total energy intake by using the residual method (37). The core statistical model (model I) was corrected for family history of colorectal cancer (low, medium, and high risk), smoking (yes vs. no), body mass index (weight (kg)/height (m)2, continuously), physical activity (total hours of cycling and any other sport activities, four categories), total fiber intake (grams/day, continuously), alcohol intake (grams/day, continuously), and regular intake of nonsteroidal antiinflammatory drugs (yes vs. no). The associations were tested in two additional models (model II and III). In model II, in addition to the confounding factors in model I, total energy intake was included as a covariate, as suggested by Willett and Stampfer (37) to reduce the random error. In model III, the associations were further adjusted for total fatty acid intake (energy adjusted).

In addition to the whole sample analysis, odds ratios and 95 percent confidence intervals were calculated in stratified subgroups according to cancer type, sex, age, and tumor staging. Finally, we used Review Manager software (version 4.2; developed at the Nordic Cochrane Centre, part of The Cochrane Collaboration) to perform a meta-analysis of four published case-control studies (18, 19, 22, 23) to compare the effect of high versus low intake of {omega}3 PUFAs on colorectal cancer risk.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
We found no significant differences between the cases and the controls in terms of sex, body mass index, daily fiber intake, daily alcohol intake, smoking, physical activity, and area deprivation index, but there was a significant difference in age (p = 0.031) and family history of colorectal cancer (p < 0.0005) (table 1). Compared with cases, controls reported a significantly lower total daily energy intake (p = 0.001) and also more regular use of nonsteroidal antiinflammatory drugs (p = 0.001) and supplements (p < 0.00005).


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  		TABLE 1. Demographic characteristics and lifestyle factors for the study population,* Scotland, 1999–2006

 
Evaluation of the fatty acid composition of the diet of our study population showed that the most abundant fatty acids were oleic, palmitic, and linoleic (table 2). A number of different foods contributed to the intake of these fatty acid subclasses and specific fatty acids (table 2), and results from the Wilcoxon rank-sum test showed that consumption of total fatty acids, saturated fatty acids, MUFAs, n-3 PUFAs, trans-fatty acids, and trans-MUFAs and of the individual fatty acids palmitic, stearic, oleic, eicosapentaenoic, and docosahexaenoic significantly differed between cases and controls (table 2).


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  		TABLE 2. Main dietary sources and description of fatty acid subclasses for 1,455 cases and 1,455 matched controls, Scotland, 1999–2006

 
Table 3 presents the results of the three multiple logistic regression models regarding the relation between quartiles of fatty acid intake and risk of colorectal cancer as odds ratios, 95 percent confidence intervals, and p values for trend for colorectal cancer regarding intake of total fatty acids, each of the seven subgroups, and each of the individual compounds. For model I, intake of total fatty acids and trans-MUFAs as well as of the individual fatty acids palmitic, stearic, and oleic showed a strong and dose-dependent effect on colorectal cancer risk (p for trend = 0.047, p for trend = 0.012, p for trend = 0.027, p for trend = 0.001, and p for trend = 0.004, respectively), with approximately a 30–50 percent increase in risk for those with high intakes versus low intakes (odds ratio (OR) = 1.22, 95 percent confidence interval (CI): 0.96, 1.54; OR = 1.38, 95 percent CI: 1.09, 1.74; OR = 1.31, 95 percent CI: 1.03, 1.67; OR = 1.54, 95 percent CI: 1.21, 1.97; and OR = 1.42, 95 percent CI: 1.11, 1.80, respectively). Intake of {omega}3 PUFAs and of eicosapentaenoic and docosahexaenoic fatty acids was inversely and dose-dependently associated with colorectal cancer (p for trend < 0.0005, p for trend < 0.0005, and p for trend < 0.0005, respectively), with approximately a 40 percent reduction in risk for those with high intakes versus low intakes (OR = 0.63, 95 percent CI: 0.50, 0.80; OR = 0.59, 95 percent CI: 0.47, 0.75; and OR = 0.63, 95 percent CI: 0.50, 0.80, respectively). The {omega}3/{omega}6 ratio was also inversely associated with colorectal cancer (high vs. low quartile, OR = 0.62, 95 percent CI: 0.49, 0.79; p for trend < 0.0005).


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  		TABLE 3. Intake of fatty acid subclasses and of specific fatty acids and risk of colorectal cancer in the whole study sample, Scotland, 1999–2006{dagger},{ddagger}

 
To correct any potential multiple testing error, we readjusted the p-value level from 0.05 to 0.0035 by applying the Bonferroni correction for 14 independent tests (eight independent tests in this analysis and six in a previous analysis of flavonoids (38) in the same study population). After we applied the Bonferroni correction, the associations of {omega}3 PUFAs, eicosapentaenoic acid, docosahexaenoic acid, and stearic acid remained significant. Additionally, in models II and III, the effect of only {omega}3 PUFAs, eicosapentaenoic acid, docosahexaenoic acid, and {omega}3/{omega}6 remained constant and significant. In distinct contrast, there were no associations of PUFAs, {omega}6 PUFAs, linoleic acid, {gamma}-linolenic acid, arachidonic acid, and {alpha}-linolenic acid with colorectal cancer risk in either model (p for trend = 0.88, p for trend = 0.79, p for trend = 0.75, p for trend = 0.47, p for trend = 0.57, and p for trend = 0.67, respectively, in model I).

A total of 1,028 participants reported consumption of supplement products, and intake was significantly associated with disease status. We identified the exact nutrient composition of these dietary supplements and added the supplement nutrients to the dietary ones. In addition, we adjusted for supplement intake by adding this covariate in a fourth model (data not shown), which had no effect on the direction and strength of the associations.

Odds ratios, 95 percent confidence intervals, and p values for trend for colorectal cancer risk were estimated as before for groups stratified by sex (table 4), cancer site (colon or rectal), and age and tumor staging (data not shown), for both model I and model II analysis. In general, {omega}3 PUFAs, eicosapentaenoic acid, docosahexaenoic acid, and {omega}3/{omega}6 appear to have a strong inverse and dose-dependent effect on colorectal cancer risk, which did not vary by any stratification. In contrast, intakes of total fatty acids, of MUFAS and trans-MUFAs, and of oleic acid were associated with colorectal cancer in females but not in males (table 4). However, the effect of only trans-MUFAs remained significant after we used the Bonferroni-corrected p value. The effect of fatty acids did not vary among the stratified groups by either type of cancer or stage of diagnosis or age (data not shown).


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  		TABLE 4. Intake of fatty acid subclasses and of specific fatty acids and risk of colorectal cancer by sex, Scotland, 1999–2006{dagger},{ddagger}

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In addition to validity data collected for macro- and micronutrients in a Scottish population (29), biomarker studies suggest that phytoestrogen and flavonoid intakes as reported on this food frequency questionnaire are correlated with independent measures of intake (39, 40). Furthermore, intake of fatty acids from dietary supplements was separately identified and added to the nutrient intake of fatty acids. Many different foods contributed to the intake of the seven fatty acid subclasses under study, so results were not determined by one major food category, and fatty acid intake in this population varied widely (table 2).

We found that, compared with matched controls, patients with colorectal cancer consumed lower amounts of {omega}3 PUFAs and individual eicosapentaenoic acid and docosahexaenoic acid. These associations persisted after controlling for a number of confounding factors and overall energy intake in addition to the residual adjustment in multivariate logistic regression models. There was a dose-response relation with reduction in risk associated with each increasing quartile of consumption, with trend tests being highly significant even after adjustment for multiple tests. We explored the effect of fish, oily fish (the main source of {omega}3 PUFAs), and white fish intake on colorectal cancer. Although ecologic and laboratory studies suggest that consumption of oily fish is inversely associated with colorectal cancer, results from epidemiologic studies are inconsistent (17, 23). In our population, the comparison of highest versus lowest quartile intakes of total fish showed an odds ratio for colorectal cancer risk of 0.76 (95 percent CI: 0.60, 0.96; p for trend = 0.009) and of oily fish an odds ratio of 0.66 (95 percent CI: 0.53, 0.82; p for trend < 0.0005). There was no association between white fish intake and colorectal cancer (p for trend = 0.679).

In contrast, we found no associations between intake of {omega}6 PUFAs and colorectal cancer risk. The reasons for these differences can be explained by the different biologic action of {omega}6 PUFAs, which have been found to increase the concentration of promoters in colon carcinogenesis (8). In contrast, {omega}3 PUFAs are rapidly incorporated into cell membranes and effect several anticarcinogenic biologic responses (41–43). Additionally, {omega}3 and {omega}6 PUFAs are converted into eicosanoids by using the same enzymatic systems. Eicosanoids derived from {omega}3 have anticarcinogenic properties, whereas the {omega}6 ones have procarcinogenic effects (11). Therefore, changes in the {omega}3/{omega}6 ratio may contribute to the early stages of carcinogenesis.

Total fatty acids, trans-MUFAs, and palmitic, stearic, and oleic acids were dose-dependently associated with colorectal cancer, but these effects did not persist in model II and model III analyses (after applying the Bonferroni correction). Some evidence supports a gender effect for selected fatty acids. The associations of MUFAs, trans-fatty acids, trans-MUFAs, and oleic acid were significant just in the female group in both model I and model II analysis. These results are in accordance with one case-control study (28) but not with two other case-control studies (20, 44) that studied sex-specific effects. However, a possible reason is that men may be less aware of their habitual diet and less able to estimate portion size (29).

Results from both cohort and case-control studies are inconsistent regarding the effect of {omega}3 PUFAs (Web table 1). Several environmental and genetic factors may influence the relation between fatty acids and colorectal cancer, which may account for the reported inconsistency. In the Nurses' Health Study, an inverse association between {omega}3 PUFAs and risk of large adenomas was found, and the authors concluded that possibly high intake of these fatty acids may reduce the progression of small to large adenomas (15). In two other cohort studies, neither fish nor {omega}3 PUFAs were found to be associated with colorectal cancer (14, 17). Of the three largest case-control studies (18, 20, 22), two (20, 22) found an inverse association between {omega}3 PUFAs and colorectal cancer, whereas the third one (18) found no significant effect. When we examined the effect of high intake of {omega}3 PUFAs in a combined data set of five case-control studies (18, 19, 22, 23), we found a significant decreased risk (combined OR = 0.87, 95 percent CI: 0.77, 0.99) (Web figure 1).

The external validity of this study may be limited by underrepresentation of cases who were very ill when presenting to the hospital. In addition, we cannot be sure of the validity of the estimate of nutrient intakes with this food frequency questionnaire in this age group because existing validity studies were carried out among younger subjects (29, 40). However, any measurement error would be most likely to attenuate observed associations. Additionally, recognized limitations of case-control studies using food frequency questionnaires include recall bias, misclassification bias due to imprecise measures of dietary intake, and residual confounding after attempts to control for confounders. We tried to limit these problems by close matching of and adoption of identical study procedures for cases and controls, use of a food frequency questionnaire that had been validated (29, 45), use of images of portion sizes and careful instructions to improve accuracy of reporting diet, and adoption of a recall period 1 year before diagnosis or recruitment date to reduce recall bias. The choice of this referent period possibly helped the participants to focus on their diets before diagnosis. In addition, the results for the {omega}3 PUFAs seem to be distinct from the ones for the other groups and were consistent in all statistical models. If there was a general bias effect, we would expect to see it across the whole range of the fatty acids and would not have found this difference for the {omega}3 PUFAs.

In conclusion, this large case-control study investigated an a priori hypothesis that different fatty acids have different effects on colorectal cancer. Given the evidence of anticarcinogenic or procarcinogenic effects from in vitro and animal in vivo studies, this test of the hypothesis was given high priority to minimize problems with multiple testing. Moderately strong inverse and dose-dependent associations were found in multivariate logistic regression models between colorectal cancer risk and intake of {omega}3 PUFAs and its main compounds, eicosapentaenoic acid and docosahexaenoic acid. The effects remained constant and significant after further energy adjustment and stratification. In addition, after the results of four published case-control studies were combined, the protective effect of the {omega}3 PUFAs remained constant and significant. Even if these results are in accordance with results of previous epidemiologic and laboratory studies, confirmation of these findings is still required in further large-scale studies.


   ACKNOWLEDGMENTS
 
This study was supported by Medical Research Council (MRC), Chief Scientist Office (CSO), and Cancer Research UK (CRUK) grants to M. Dunlop, H. Campbell, and M. Porteous. E. Theodoratou was also supported by a studentship from the Greek State Scholarship Foundation.

The authors thank and acknowledge the contribution and support of M. Edwards and G. Barr for recruitment supervision and data management and Drs. N. Anderson and J. Kyle for their assistance with data interpretation and analysis.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

  1. Cancer in Scotland: Scottish Cancer Registry. (2006) Edinburgh, Scotland: National Health Service, National Services Scotland. (www.isdscotland.org; http://www.isdscotland.org/isd/1425.html).
  2. Roynette CE, Calder PC, Dupertuis YM, et al. n-3 polyunsaturated fatty acids and colon cancer prevention. Clin Nutr (2004) 23:139–51.[CrossRef][Web of Science][Medline]
  3. Food, nutrition and the prevention of cancer: a global prospective (1997) Washington, DC: American Institute for Cancer Research, World Cancer Research Fund.
  4. Bingham SA, Day NE, Luben R, et al. Dietary fibre in food and protection against colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC): an observational study. Lancet (2003) 361:1496–501.[CrossRef][Web of Science][Medline]
  5. Bingham S. The fibre-folate debate in colo-rectal cancer. Proc Nutr Soc (2006) 65:19–23.[CrossRef][Web of Science][Medline]
  6. Bingham SA, Norat T, Moskal A, et al. Is the association with fiber from foods in colorectal cancer confounded by folate intake? Cancer Epidemiol Biomarkers Prev (2005) 14:1552–6.[Abstract/Free Full Text]
  7. Sanjoaquin MA, Allen N, Couto E, et al. Folate intake and colorectal cancer risk: a meta-analytical approach. Int J Cancer (2005) 113:825–8.[CrossRef][Web of Science][Medline]
  8. Reddy BS. Omega-3 fatty acids in colorectal cancer prevention. Int J Cancer (2004) 112:1–7.[CrossRef][Web of Science][Medline]
  9. Nkondjock A, Shatenstein B, Maisonneuve P, et al. Specific fatty acids and human colorectal cancer: an overview. Cancer Detect Prev (2003) 27:55–66.[CrossRef][Web of Science][Medline]
  10. MacLean CH, Newberry SJ, Mojica WA, et al. Effects of omega-3 fatty acids on cancer risk: a systematic review. JAMA (2006) 295:403–15.[Abstract/Free Full Text]
  11. Larsson SC, Kumlin M, Ingelman-Sundberg M, et al. Dietary long-chain n-3 fatty acids for the prevention of cancer: a review of potential mechanisms. Am J Clin Nutr (2004) 79:935–45.[Abstract/Free Full Text]
  12. Howe GR, Aronson KJ, Benito E, et al. The relationship between dietary fat intake and risk of colorectal cancer: evidence from the combined analysis of 13 case-control studies. Cancer Causes Control (1997) 8:215–28.[CrossRef][Web of Science][Medline]
  13. Bostick RM, Potter JD, Kushi LH, et al. Sugar, meat, and fat intake, and non-dietary risk factors for colon cancer incidence in Iowa women (United States). Cancer Causes Control (1994) 5:38–52.[CrossRef][Web of Science][Medline]
  14. Lin J, Zhang SM, Cook NR, et al. Dietary fat and fatty acids and risk of colorectal cancer in women. Am J Epidemiol (2004) 160:1011–22.[Abstract/Free Full Text]
  15. Oh K, Willett WC, Fuchs CS, et al. Dietary marine n-3 fatty acids in relation to risk of distal colorectal adenoma in women. Cancer Epidemiol Biomarkers Prev (2005) 14:835–41.[Abstract/Free Full Text]
  16. Terry P, Bergkvist L, Holmberg L, et al. No association between fat and fatty acids intake and risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev (2001) 10:913–14.[Free Full Text]
  17. Kobayashi M, Tsubono Y, Otani T, et al. Fish, long-chain n-3 polyunsaturated fatty acids, and risk of colorectal cancer in middle-aged Japanese: the JPHC study. Nutr Cancer (2004) 49:32–40.[CrossRef][Web of Science][Medline]
  18. Slattery ML, Potter JD, Duncan DM, et al. Dietary fats and colon cancer: assessment of risk associated with specific fatty acids. Int J Cancer (1997) 73:670–7.[CrossRef][Web of Science][Medline]
  19. Kojima M, Wakai K, Tokudome S, et al. Serum levels of polyunsaturated fatty acids and risk of colorectal cancer: a prospective study. Am J Epidemiol (2005) 161:462–71.[Abstract/Free Full Text]
  20. Nkondjock A, Shatenstein B, Maisonneuve P, et al. Assessment of risk associated with specific fatty acids and colorectal cancer among French-Canadians in Montreal: a case-control study. Int J Epidemiol (2003) 32:200–9.[Abstract/Free Full Text]
  21. Ravasco P, Monteiro-Grillo I, Marques VP, et al. Nutritional risks and colorectal cancer in a Portuguese population. Nutr Hosp (2005) 20:165–72.[Medline]
  22. Tavani A, Pelucchi C, Parpinel M, et al. n-3 polyunsaturated fatty acid intake and cancer risk in Italy and Switzerland. Int J Cancer (2003) 105:113–16.[CrossRef][Web of Science][Medline]
  23. Busstra MC, Siezen CL, Grubben MJ, et al. Tissue levels of fish fatty acids and risk of colorectal adenomas: a case-control study (Netherlands). Cancer Causes Control (2003) 14:269–76.[CrossRef][Web of Science][Medline]
  24. Hooper L, Thompson RL, Harrison RA, et al. Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review. BMJ (2006) 332:752–60.[Abstract/Free Full Text]
  25. He K, Song Y. Risks and benefits of omega 3 fats: a few thoughts on systematic review. (Letter). BMJ (2006) 332:915-a.[Free Full Text]
  26. Burr ML, Ashfield-Watt PA, Dunstan FD, et al. Lack of benefit of dietary advice to men with angina: results of a controlled trial. Eur J Clin Nutr (2003) 57:193–200.[CrossRef][Web of Science][Medline]
  27. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet (1999) 354:447–55.[CrossRef][Web of Science][Medline]
  28. Slattery ML, Benson J, Ma KN, et al. Trans-fatty acids and colon cancer. Nutr Cancer (2001) 39:170–5.[CrossRef][Web of Science][Medline]
  29. Masson LF, McNeill G, Tomany JO, et al. Statistical approaches for assessing the relative validity of a food-frequency questionnaire: use of correlation coefficients and the kappa statistic. Public Health Nutr (2003) 6:313–21.[CrossRef][Web of Science][Medline]
  30. Holland B, Welch AA, Unwin ID, et al. McCance and Widdowson's the composition of foods. (1991) 5th ed. Cambridge, United Kingdom: Royal Society of Chemistry.
  31. Holland B, Welch AA, Buss DH. Vegetables, herbs and spices. Fifth supplement to the 4th edition of McCance and Widdowson's the composition of foods. (1991) Cambridge, United Kingdom: Royal Society of Chemistry.
  32. Holland B, Welch AA, Buss DH. Fruit and nuts. First supplement to the 5th edition of McCance and Widdowson's the composition of foods. (1992) Cambridge, United Kingdom: Royal Society of Chemistry.
  33. Holland B, Welch AA, Buss DH. Vegetable dishes. Second supplement to the 5th edition of McCance and Widdowson's the composition of foods. (1992) Cambridge, United Kingdom: Royal Society of Chemistry.
  34. Holland B, Brown J, Buss DH. Fish and fish products. Third supplement to the 5th edition of McCance and Widdowson's the composition of foods. (1993) Cambridge, United Kingdom: Royal Society of Chemistry.
  35. Chan W, Brown J, Buss DH. Miscellaneous foods. Fourth supplement to the 5th edition of McCance and Widdowson's the composition of foods. (1994) Cambridge, United Kingdom: Royal Society of Chemistry.
  36. Chan W, Brown J, Church SM, et al. Meat products and dishes. Sixth supplement to the 5th edition of McCance and Widdowson's the composition of foods. (1996) Cambridge, United Kingdom: Royal Society of Chemistry.
  37. Willett W, Stampfer MJ. Total energy intake: implications for epidemiologic analyses. Am J Epidemiol (1986) 124:17–27.[Free Full Text]
  38. Theodoratou E, Kyle J, Cetnarskyj R, et al. Dietary flavonoids and colorectal cancer. Cancer Epidemiol Biomarkers Prev (2007) 16:684–93.[Abstract/Free Full Text]
  39. Heald CL, Bolton-Smith C, Ritchie MR, et al. Phyto-oestrogen intake in Scottish men: use of serum to validate a self-administered food-frequency questionnaire in older men. Eur J Clin Nutr (2006) 60:129–35.[CrossRef][Web of Science][Medline]
  40. Kyle J, Masson LF, Grubb DA, et al. Estimating dietary flavonoid intake: comparison of a semi-quantitative food frequency questionnaire with 4-day weighed diet records in a Scottish population. (Abstract). Proc Nutr Soc (2002) 61:69A.
  41. Grimble RF. Nutritional modulation of immune function. Proc Nutr Soc (2001) 60:389–97.[Web of Science][Medline]
  42. Grant WB. Fish consumption, cancer, and Alzheimer disease. Am J Clin Nutr (2000) 71:599–600.[Free Full Text]
  43. Rose DP, Connolly JM. Omega-3 fatty acids as cancer chemopreventive agents. Pharmacol Ther (1999) 83:217–44.[CrossRef][Web of Science][Medline]
  44. McKelvey W, Greenland S, Chen MJ, et al. A case-control study of colorectal adenomatous polyps and consumption of foods containing partially hydrogenated oils. Cancer Epidemiol Biomarkers Prev (1999) 8:519–24.[Abstract/Free Full Text]
  45. Bolton-Smith C, Smith WC, Woodward M, et al. Nutrient intakes of different social-class groups: results from the Scottish Heart Health Study (SHHS). Br J Nutr (1991) 65:321–35.[CrossRef][Web of Science][Medline]

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