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Many phytochemicals in fruits and vegetables have been shown to have cancer-inhibitory effects in animal studies. These effects on cancer, however, have not been clearly demonstrated in human studies. This study investigated the association between fruit and vegetable intakes and the risk of adenomatous polyps. Participants were part of the Tennessee Colorectal Polyp Study. Eligible participants aged 40-75 years were recruited from patients undergoing colonoscopy at two medical centers in Nashville, Tennessee, U.S.A. from 2003 to 2005. Cases had at least one adenoma, and controls were polyp-free. Dietary intake was assessed using a self-administered food frequency questionnaire. Associations between dietary intakes and adenoma risk were evaluated using unconditional logistic regression with restricted cubic function. In multivariate analyses of 764 cases and 1,517 controls, increased intakes of total fruits, berries, fruit juice, and green leafy vegetables were associated with reduced adenoma risk. The odds ratio (OR) for upper tertile intake versus lower was 0.66 (95% Confidence Interval (CI) = 0.51-0.86) for total fruits, 0.64 (95% CI = 0.47-0.87) for berries, 0.72 (95% CI = 0.56-0.92) for fruit juice, and 0.74 (95% CI=0.58-0.96) for green vegetables. This study provides additional evidence that high total fruit intake and certain fruit and vegetable intakes may be associated with a reduced risk of colorectal adenomas.
Fruits and vegetables contain a wide-variety of potential cancer-inhibitory nutrients and other phytochemicals. Substantial evidence has indicated a biological link between dietary constituents and carcinogenesis (1,2). Nonetheless, results from individual previous epidemiologic studies on the associations of fruit and vegetable intakes with colorectal cancer have been inconsistent, and a recent summary report suggests fruits and vegetables may have only limited protective effects on colorectal cancer (3). Many case-control studies reported inverse associations with the intake of certain fruits and vegetables (4-9), while most prospective cohort studies showed much weaker or even no associations with these foods (10-14). Colorectal adenomas as established precursors of colorectal cancers have drawn research interest. Intervention studies have been conducted with diets high in fruits and vegetables on adenoma recurrence (15-18) because recurrence allows a shorter trial and reduced sample size (19). However, these randomized intervention trials did not find significant benefits for higher fruit and vegetable intakes in reducing the risk of adenoma recurrence (15,17,18) or rectal mucosal cell proliferation rates (20).
Many factors may contribute to the inconsistency and contradiction (21). One possible biological explanation is that dietary components may affect an early stage of carcinogenesis, and, thus, may only have an impact on primary adenomas, not adenoma recurrence (19,22). In support of this possibility, previous epidemiologic studies have found that intakes of total fruits (22-25) and total vegetables (26-28) were associated with a reduced adenoma risk. These studies also suggested that intakes of certain fruits or vegetables, such as citrus fruits (22), legumes (22,28), dry beans (16), and green leafy vegetables (22,27) might be strongly protective against colorectal adenoma. However, no associations have been reported in some other studies (29-31).
In this article, we examine whether intakes of fruits and vegetables were related to a reduced risk of primary colorectal adenomas in a large colonoscopy-based case-control study, with a special interest in the intakes of subgroups of fruits and vegetables.
Participants were part of the Tennessee Colorectal Polyp Study (TCPS), an on-going colonoscopy-based case-control study being conducted in Nashville, Tennessee. Eligible participants, aged between 40 and 75 years, were identified from patients scheduled for colonoscopy at the Vanderbilt Gastroenterology Clinic and the Veteran’s Affairs Tennessee Valley Health System Nashville campus between February 1, 2003 and December 31, 2005. Excluded from our study were participants who had genetic colorectal cancer syndromes, or a prior history of inflammatory bowel disease, adenomatous polyps, or any cancer other than non-melanoma skin cancer. Among 4,617 eligible participants, 3,083 provided a written informed consent (67%). Among them, 2,678 (87%) completed a telephone interview. Participants were recruited prior to colonoscopy and most were undergoing colonoscopy for screening purposes (52%). On the basis of the clinical colonoscopy and pathology findings, recruited participants were designated as polyp-free controls, cases with adenomatous polyps, or cases with other polyp types. In order to be designated as a control, the consented participant must have had a complete colonoscopy reaching the cecum and was polyp-free at colonoscopy. Included in this analysis are the 874 adenomatous polyp cases and 1,773 polyp-free controls. The study was approved by the Institutional Review Board of Vanderbilt Medical Center for the use of human subjects in research.
Dietary assessment was conducted within 13 days after the colonoscopy. Dietary intake in the past 12 months prior to colonoscopy was ascertained using a validated 108-item semi-quantitative food frequency questionnaire (FFQ) which was developed at Vanderbilt University specifically to capture diet in the Southern United States ((32)). Briefly, food items were identified from NHANES-III database using relevant groups. In a comparison of the pilot FFQ data with NHANES-III data, the energy-adjusted intakes were very similar (0.96, 0.92 and 1.01 for total fat, protein, and carbohydrate, respectively). Response categories were “never, rarely, 1/mo, 2-3/mo, 1/wk, 2-3/wk, 4-6/wk, 1/d, or 2+/d”. Participants were also asked about their usual serving size, small, medium, or large. Fruits and vegetables were classified according to their botanical taxonomy and phytochemical content to identify the fruits and vegetables that may be potentially rich sources of vitamins or bioactive components (33) (Supplemental Table 1). Fruit and vegetable intakes were normalized with the usual portion size and expressed in servings/wk. The FFQ was completed by 764 cases and 1,525 controls. Participants with 14 or more missing items in the FFQ or with total caloric intake outside the range of 3349-17585 kJ/d for males and 2512-14654 kJ/d for females were excluded from the analysis. The final data for the analysis consisted of 764 cases and 1,517 controls.
Chi-square statistics and Wilcoxon rank sum test were used to evaluate case-control differences. Both restricted cubic spline (RCS) regression and categorical regression were used with unconditional logistic regression model to examine the association between dietary intake and adenoma risk, Energy intake adjustment was performed by entering energy intake into the model (34). . Intakes of fruits or vegetables were mutually adjusted for in the modeling. Other potential confounders including other dietary factors were selected for evaluation in accordance with previous studies (22,25-28,31). The final model adjusted for age, sex, race, study location, body mass index (BMI), smoking status, regular alcohol consumption (5 or more drinks/wk for at least twelve months in a row), non-steroidal anti-inflammatory use, physical exercise, educational attainment, household income, family history of colorectal cancer in a first-degree relative, and red/processed meat intake (including hamburgers, cheeseburgers, beef, pork and their regular products). The collinearity among the covariates was also analyzed. P values of less than 0.05 (two-sided) were interpreted as being statistically significant. All calculations and computations were performed using R package version 2.4.0 (35).
Selected demographic characteristics and risk factors of the participants were compared between cases and controls. Compared to controls, adenoma cases were older, and more likely to be male, smokers, alcohol drinkers, physically inactive, and of lower educational attainment and lower social economic status. Cases also had higher daily intakes of total energy and red/processed meat, and had lower BMI. A similar proportion of cases and controls underwent colonoscopy for screening purposes (Table 1). No strong correlations were found among the covariates, and the distributions of all the intakes were markedly skewed (data not shown).
The overall estimates of the two methods were similar, thus, we only report the results from the spline regression (Table 2, Supplemental Figure 1). Colorectal adenoma risk was inversely related to increased intakes of total fruits, berries, fruit juice, and green leafy vegetables. An additional analysis of fruit juice found that total fruits, fruits excluding fruit juice, and fruit juice alone were all significantly inversely associated with adenoma risk (data not shown).
Adenoma risk decreases as total fruit intake increases from low to moderate, but the risk does not decrease further with an additional increase of total fruit intake (Figure 1). The spline regression falls apart at the upper tertile of categorical model, indicating an underestimated reduction of the risk for upper versus lower tertile. The spline regression also found a nonlinear association for total fruit intake (Figure 1). In addition, spline regression had narrower 95% CIs relative to categorical regression (data not shown).
In this study, we found intakes of total fruits, particularly berries and fruit juices, and green leafy vegetables were inversely associated with risk for colorectal adenomas. Fruit and vegetable intake has been associated with a decreased risk for colorectal adenomas in some (24-28,36,37) but not all previous studies (29-31). Interestingly, three of the four previously noted cohort studies reported high intake of total fruits reduced adenoma risk (22,23,38). In the Nurses’ Health Study (NHS), fruit consumption was inversely related to the risk of colorectal adenomas, whereas high intake of vegetables did not substantially change the risk (22). In the Health Professionals’ Follow-up Study (HPFS) conducted in men, frequent consumption of fruits, but not vegetables, was associated with reduced prevalence of adenomas (38). Another follow-up study also observed that higher intake of fruits reduced the growth of colorectal adenoma (23). Most recently in a case-control study, a diet high in fruits and low in meats reduced colorectal adenoma risk (24). Overall, the findings from these previous studies support the results from our study, suggesting a stronger protective effect of total fruits than total vegetables against colorectal adenomas.
A recent pooled analysis of 14 cohort studies indicated that fruit and vegetable intake was not strongly associated with colon cancer risk (39). Our findings in a colorectal adenoma study, a precursor to colorectal cancer, may suggest the roles of fruits and vegetables and their components differ according to the timing in carcinogenesis. For example, antioxidants may have cancer-inhibitory effects in the early stage of carcinogenesis (40,41). When used at a later stage, antioxidants might actually stimulate the growth of tumors through the enhanced survival of tumor cells (41). Unlike fruits, vegetables are often consumed in cooked dishes, and cooking processes could cause significant loss of antioxidant activity (42).
Fruits are usually consumed as whole units while vegetables are usually consumed as part of mixed dishes. Thus, recall and quantification of fruit intake may be easier, and, thus, more accurate than for vegetable intake (22). This could result in a stronger association of adenoma risk with fruit intake than with vegetable intake. Validation studies of FFQ versus 24-hour dietary recall did show weaker correlations for vegetables compared with fruits (43). However, a follow-up study using a 5-day dietary record found fruit intake, not vegetable intake, was significantly associated with adenoma growth rate (23). Thus, measurement error in vegetable intake might not account for the difference.
No study has evaluated the association between adenoma risk and berry intake alone (23). A number of studies have suggested the potential chemopreventive properties of berries (44,45). Berries possess much more potent antioxidant activity compared with other fruits and vegetables (45). A clinical trial found that berry powder caused an approximate 50% regression rate of rectal polyps (44).
Two case-control studies have looked at the relationship between fruit juice drinking and adenoma risk with a protective result in one study and no association in the other (27,31). Unlike our study, fruit juice was excluded from the total fruits in these two studies. The disparity between our results and previous reports may be ascribable to the differences in fruit availability and/or eating habits from different regions (46). Furthermore, juice processing squeezes antioxidants into the juice whereas peeling of fruits results in a substantial loss of these compounds (46).
To date, four studies have examined intake of green leafy vegetables; two showed protective effects (22,27) and two observed no associations (30,31). The protective effects by green leafy vegetables in our study were very similar to the NHS (22). Our finding may also suggest that only some subgroups of vegetables are protective or more protective than others since the protection by total vegetable intake was not significant (16). Folate’s central function is in maintaining DNA integrity; it is rich in green leafy vegetables, and has benefits in cancer prevention when administered prior to the existence of preneoplastic lesions (19). However, studies have found increased colorectal neoplasia when folate is administered after lesions are present (47). A recent clinical trial also failed to observe risk reduction by folate supplementation for participants with a recent history of colorectal adenomas (48).
The evidence from all these studies may suggest that there may be a critical timing window for the prevention of adenoma initiation and progression by supplementation (19). This hypothesis could also explain the results from intervention studies and randomized clinical trials in which adenoma recurrence, not primary adenoma, were used as the endpoint (15-18). The undetected early precursor lesions may have already been present in the subjects’ mucosa in these studies (48). Therefore, the time course may not be long enough for specific dietary components to function (19). This possibility could contribute to the NHS finding in which the risk reduction by fruits and vegetables was more pronounced in incident adenomas relative to prevalent adenomas (22). This potential time period issue is also supported by the observation that fruit intake had no significant effects on colorectal carcinoma risk in both the NHS and the HPFS (49) but fruit intake reduced adenoma risk in the same two cohorts (22,38).
Since there are many bioactive components in fruits and vegetables with varied functions and concentrations, the effects of these components on the initiation and progression of colorectal adenoma or cancer may also differ. Thus, these constituents from fruits, berries, and green leafy vegetables may work either independently or jointly to explain our observed findings.
In this study, spline regression provided more complete information about the association in addition to a more appropriately estimated OR and better fit for skewed data. By contrast, regression of average risk on average exposures as with categorical regression can inaccurately present the exposure effects if those effects are nonlinear within categories (50) as demonstrated in our study.
The present study has several strengths. Participants were excluded with prior history of adenomatous polyps, a condition that may relate to a change in dietary habits. The present study included only controls undergoing a full colonoscopy throughout colon and rectum; thus, the potential contamination of cases in the control group is not a major concern. The FFQ was developed specifically to capture diet in the Southern United States. Furthermore, most participants were recruited before the colonoscopy that defined their case or control status. Thus, controls were not any less likely to participate in the study than cases. There are also some concerns or limitations in the study. Dietary intake was assessed a few days after the diagnosis; therefore, recall bias may be a concern. The maximum intake frequency included on the FFQ was 2 or more times per day. It is possible that, if a higher threshold exists, we were unable to distinguish it. However, only a very small fraction of participants reported such high consumption for a particular item. Additionally, the ability to distinguish higher intake levels would not have changed the observed findings but, instead, would have improved the effect size. In the study, controls were slightly more likely to undergo a colonoscopy due to family history. However, there were no appreciable differences in effect estimates in stratified analysis by colonoscopy indication. Selection bias is another potential concern, but we have found that age, sex, study site, and the reasons for the colonoscopy did not differ substantially between persons who did or did not consent to participate in the study. Although we adjusted for many confounding factors, residual confounding may still arise when there were measurement errors in confounding factors (16,22).
In conclusion, the findings from this study suggest that an increase in total fruit intake and certain fruit and vegetable intake may reduce the risk for colorectal adenomas. The inverse associations between intake of berries and green leafy vegetables and adenoma risk are relatively new and should be evaluated in other study populations.
The authors thank Ms. Brandy Venuti for helpful technical comments in the preparation of this manuscript and Ms. Terri Scott for assistance with the graphics. The project described was supported by grants P50CA95103 and R01CA97386 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.
Publisher's Disclaimer: This is an un-copyedited author manuscript that has been accepted for publication in The Journal of Nutrition, copyright © American Society for Nutrition (ASN). This manuscript may not be duplicated or reproduced, other than for personal use or within the rule of ‘Fair Use of Copyrighted Materials’ (section 107, Title 17, US Code) without permission of the copyright owner, the ASN. The final copyedited article, which is the version of record, can be found at http://www.nutrition.org/publications/. The ASN disclaims any responsibility or liability for errors or omissions in this version of the manuscript or in any version derived from it by the National Institutes of Health or other parties.
1Supported by grants from NIH: P50CA95103 and R01CA97386.