Topic Highlight Open Access
Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Feb 21, 2013; 19(7): 1011-1019
Published online Feb 21, 2013. doi: 10.3748/wjg.v19.i7.1011
Dietary flavonoid intake and risk of stomach and colorectal cancer
Hae Dong Woo, Jeongseon Kim
Hae Dong Woo, Jeongseon Kim, Molecular Epidemiology Branch, Division of Cancer Epidemiology and Prevention, Research Institute, National Cancer Center, Gyeonggi-do 410-769, South Korea
Author contributions: Woo HD and Kim J conducted the literature review; Woo HD analyzed the data and wrote the manuscript; Kim J interpreted the data, and critically reviewed and edited the manuscript.
Correspondence to: Jeongseon Kim, PhD, Molecular Epidemiology Branch, Division of Cancer Epidemiology and Prevention, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, South Korea. jskim@ncc.re.kr
Telephone: +82-31-9202570 Fax: +82-31-9202579
Received: September 19, 2012
Revised: January 22, 2013
Accepted: February 5, 2013
Published online: February 21, 2013

Abstract

Stomach and colorectal cancers are common cancers and leading causes of cancer deaths. Because the alimentary tract can interact directly with dietary components, stomach and colorectal cancer may be closely related to dietary intake. We systematically searched published literature written in English via PubMed by searching for terms related to stomach and colorectal cancer risk and dietary flavonoids up to June 30, 2012. Twenty-three studies out of 209 identified articles were finally selected for the analysis. Log point effect estimates and the corresponding standard errors were calculated using covariate-adjusted point effect estimates and 95%CIs from the selected studies. Total dietary flavonoid intake was not associated with a reduced risk of colorectal or stomach cancer [odds ratio (OR) (95%CI) = 1.00 (0.90-1.11) and 1.07 (0.70-1.61), respectively]. Among flavonoid subclasses, the intake of flavonols, flavan-3-ols, anthocyanidins, and proanthocyanidins showed a significant inverse association with colorectal cancer risk [OR (95%CI) = 0.71 (0.63-0.81), 0.88 (0.79-0.97), 0.68 (0.56-0.82), and 0.72 (0.61-0.85), respectively]. A significant association was found only between flavonols and stomach cancer risk based on a limited number of selected studies [OR (95%CI) = 0.68 (0.46-0.99)]. In the summary estimates from case-control studies, all flavonoid subclasses except flavones and flavanones were inversely associated with colorectal cancer risk, whereas neither total flavonoids nor any subclasses of flavonoids were associated with colorectal cancer risk in the summary estimates based on the cohort studies. The significant association between flavonoid subclasses and cancer risk might be closely related to bias derived from the case-control design. There was no clear evidence that dietary flavonoids are associated with reduced risk of stomach and colorectal cancer.

Key Words: Flavonoids, Flavonols, Flavones, Flavanones, Flavan-3-ols, Anthocyanidins, Proanthocyanidins, Cancer risk, Meta-analysis



INTRODUCTION

Stomach and colorectal cancer are common cancers and leading causes of cancer deaths[1]. Because the alimentary tract can interact directly with dietary components, stomach and colorectal cancer may be closely related to dietary intake. The consumption of meat, especially of red and processed meats that produce N-nitrosamine, was positively associated with stomach and colorectal cancer risk in a previous meta-analyses[2-4]. However, fruit and vegetable intakes were inversely associated with colorectal cancer risk in people with high intakes of red and processed meat[5], and inverse association between vitamin C intake and stomach cancer risk was stronger in high red and processed meat intake group[6]. High fruit and vegetable intakes are associated with beneficial health effects, and these effects have been partly attributed to the high flavonoid content of these foods. Flavonoids are polyphenolic compounds that are abundant in fruits and vegetables. The beneficial health effects of flavonoids have been attributed to their free radical scavenging properties. In addition to their antioxidant properties, flavonoids have antiviral, antiallergic, antiinflammatory, and antitumor activities[7,8]. Flavonoids are generally classified as flavonols, flavones, flavanones, flavanols, isoflavones or anthocyanidins based on their chemical structure[9-11]. The antioxidant activities of the dietary flavonoids and their subclasses vary due to the differences in their chemical structures. Flavonols, the most common flavonoids in foods, include kaempferol, myricetin, quercetin, and isorhamnetin. Among them, quercetin is abundant in onions and apples, and has been studied extensively due to its high bioavailability and strong antioxidant effects. Flavones, such as apigenin and luteolin, are abundant in green leafy spices (e.g., parsley, thyme, and celery), and the flavanones naringenin, hesperetin, and eriodictyol are found in citrus fruits. Flavanols, often referred to as flavan-3-ols, include catechin, gallocatechin, and epicatechin, which are abundant in teas, red wine, and apples. Isoflavones, especially genistein, are found in soy foods and have been studied widely due to their antitumor properties. Anthocyanidins are found in cherries, strawberries, and red wine.

A reduced risk of cardiovascular disease associated with flavonoid intake has been observed in many epidemiological studies[12,13]. Flavonoids have been suggested to reduce the risk of cardiovascular disease by modulating various mechanisms[14]. However, the association between cancer risk and dietary flavonoid intake has less supportive evidence from epidemiological studies, and the results have been inconsistent. To date, meta-analyses have focused mainly on dietary flavonoids and cardiovascular disease[12,13] or tea flavonoids and lung cancer[15,16]. Thus, we performed a meta-analysis of summary data to calculate the effect estimates of dietary flavonoid intake, including individual subclasses of flavonoids, on stomach and colorectal cancer risk.

DIETARY FLAVONOID INTAKE AND RISK OF STOMACH AND COLORECTAL CANCER

English-language studies were systemically searched using PubMed with the phrase “cancer risk and (stomach or gastric or colorectal or colon or bowel or rectal) and (flavonoid or flavonol or quercetin or kaempferol or myricetin or isorhamnetin or flavone or luteolin or apigenin or flavanone or eriodictyol or hesperetin or naringenin or flavan-3-ol or catechin or epicatechin or theaflavin or anthocyanidin or cyanidin or delphinidin or malvidin or pelargonidin or peonidin or petunidin or proanthocyanidin or isoflavone)” up to June 30, 2012. The inclusion criteria were as follows: (1) original articles with a case-control or cohort design; (2) articles reporting intake of either total flavonoids or subclasses of flavonoids and stomach or colorectal cancer; (3) articles with at least 3 categories of dietary flavonoid intake; and (4) studies reporting adjusted odds ratios (OR) or relative risks (RR) with 95%CIs for the risk of stomach or colorectal cancer in subjects with the highest dietary flavonoid intake compared with those with the lowest intake of dietary flavonoids.

The retrieved studies were reviewed independently by two investigators (Woo HD and Kim J). Data on authors, publication year, types of flavonoids, cancer sites, country in which the study was performed, number of cases and controls, categories of flavonoids or subclasses of flavonoids, subclasses included in the calculation of total flavonoids, and adjusted OR/RR and 95%CI were collected for the meta-analysis. The multivariate-adjusted values for OR/RR and 95%CI were selected for the meta-analysis to reduce the effects of potential confounding variables. If there was additional adjustment for fruit and vegetable intake, the adjusted values were selected.

All statistical analyses were performed using the STATA software package (version 10; Stata Corp, College Station, TX, United States). Log point effect estimates and the corresponding standard errors were calculated using the covariate-adjusted point effect estimates and 95%CI from selected studies and weighted by the inverse variance to calculate the summary estimates[17]. The heterogeneity across studies was measured using the Q-test based on the χ2 statistic. Heterogeneity was considered statistically significant when P < 0.1 for the Q-test and was quantified using the I2 test as described by Higgins et al[18]. Based on the heterogeneity of the included studies, fixed or random effects models were selected to calculate the pooled effect measures. Sensitivity analyses were performed to test the robustness of the results of the combined effects.

A total of 209 studies were identified, and 160 studies were excluded based on the titles and abstracts. The full texts of the remaining 49 studies were reviewed, and 25 studies were excluded for the following reasons: 7 studies were not related to dietary flavonoid intake or any of the flavonoid subclasses; 5 studies presented only recurrence or survival analysis data; 5 studies were not related to stomach or colorectal cancer: 4 studies did not report cancer risk; 2 studies were review articles; and 2 studies reported plasma concentrations instead of dietary flavonoid intake.

Sensitivity tests were conducted for the remaining 24 studies of total flavonoids and each subclass of flavonoids. One study showing substantial influence on the summary estimates in the sensitivity tests was excluded[19]. Thus, 23 studies, comprising 13 case-control studies and 10 cohort studies, were finally selected to estimate the overall effects of total dietary flavonoid or flavonoid subclass intake on stomach and colorectal cancer risk (Table 1)[20-42]. Begg’s funnel plot and Egger’s test were used to evaluate the publication bias in studies of total flavonoids and each subclass of flavonoids. Egger’s test showed no significant bias.

Table 1 Selected studies on dietary flavonoids and risk of stomach and colorectal cancer.
Ref.Cancer siteCountryStudy periodCase/control (n/n)Dietary assessment methodReported flavonoidsIncluded subclasses for total flavonoidsIntake comparison High vs low (mg/d)1Controlled confounders
Garcia-Closas et al[20]StomachSpain1987-1989354/354Diet historyQ, K, MQ4 vs Q1 mean (SD), Q: 7.1 (6.5), K: 1.2 (1.9), M: 0.65 (1.17)Total energy intake, intake of nitrites, nitrosamines, vitamin C, total carotenoids (α-carotene, β-carotene, lutein, and lycopene) and other specific favonoids (quercetin, kaempferol, myricetin, and luteolin)
Lagiou et al[21]StomachGreece1981-1984110/100FFQF1, F2, F3, F4, An, IF1: per 10.0, F2: per 0.3, F3: per 19.8, F4: per 135.1, An: per 40.4, I: per 2.0.Age, gender, total energy intake, place of birth, BMI, height, years of education, smoking habits and duration of smoking, alcohol consumption, and fruit and vegetable consumption
Cotterchio et al[22]ColorectumCanada1997-20001095/1890FFQI> 1.097 vs < 0.289.Age, sex, and total energy intake
Rossi et al[23]ColorectumItaly1992-19961953/4154FFQT, F1, F2, F3, F4, An, IF1, F2, F3, F4, An, IT: > 191.1 vs < 75.3, F1: > 28.5 vs < 13.2, F2: > 0.7 vs < 0.3, F3: > 67.0 vs < 12.5, F4: > 88.5 vs < 20.8, An: > 31.7 vs < 5.3, I: > 33.9 vs < 14.4Age, sex, energy intake, study center, family history of colorectal cancer, education, alcohol consumption, BMI, and occupational physical activity
Theodoratou et al[24]ColorectumScotland-1456/1456FFQF1, F2, F3, F4, Q, H, N, C, EF1: > 36.75 vs < 16, F2: > 1.9 vs < 0.5, F3: > 45.2 vs < 16.7, F4: > 162.1 vs < 42.6, Q: > 22.9 vs < 11.7, H: > 21.1 vs < 3.95, N: > 19.7 vs < 3.8Total energy intake, family history of colorectal cancer, total fiber intake, alcohol intake, NSAID intake, smoking, BMI, physical activity, and fruit and vegetable intake
Akhter et al[25]ColorectumJapan2004-2005721/697FFQI> 62.41 vs < 24.77Age, sex, total energy intake, screening period, family history of colorectal cancer, cigarette smoking, alcohol consumption, BMI, physical activity, supplement use and non-steroidal anti-inflammatory drug use
Kyle et al[26]ColorectumUnited Kingdom1998-2000261/404FFQF1, F3, F4F1: > 40.4 vs < 19.3, F3: > 32.2 vs < 2.73, F4: > 188.8 vs < 67.1Age, energy, family history, non-steroidal anti-inflammatory drugs, aspirin, Mn, riboflavin, vitamin C, folate
Rossi et al[27]StomachItaly1997-2007230/547FFQF1, F2, F3, F4, An, I, PF1: > 32.3 vs < 13.2, F2: > 0.7 vs < 0.3, F3: > 56.8 vs < 12.9, F4: > 79.2 vs < 21.6, An: > 21.5 vs < 6.2, I: > 34.3 vs < 15.0, P: > 373.0 vs < 339.6Age, sex, education, year of interview, BMI, tobacco smoking, and total energy intake
Rossi et al[28]ColorectumItaly1992-19961953/4154FFQP> 486.6 vs < 202.5Age, sex, study center, family history, education, alcohol consumption, BMI, physical activity and energy intake
Budhathoki et al[29]ColorectumJapan2003-2003816/815FFQI74.4 vs 15.5 (median)Age, sex, total energy intake, resident area, parental colorectal cancer, smoking, alcohol use, BMI, type of job, and leisure time physical activity
Ekström et al[30]Stomach (cardia and non cardia)Sweden1989-1995C81, Non; 420 /1116FFQQ> 11.89 vs < 3.88Age, sex, socioeconomic status, number of siblings, BMI, smoking and energy and salt intake
Zamora-Ros et al[31]ColorectumSpain1996-1998424/401FFQT, F1, F2, F3, F4, An, I, PF1, F2, F3, F4, An, I, P, ThT: > 167.9 vs < 68.9, F1: > 11.5 vs < 5.1, F2: > 2.1 vs < 0.7, F3: > 17.7 vs < 3.7, F4: > 12.9 vs < 4.9, An: > 10.6 vs < 3.3, I: > 0.17 vs < 0.07, P: > 112.3 vs < 40.9Age, sex, energy intake, BMI, alcohol and fiber intake, red and processed meat intake, tobacco consumption, physical activity, regular drugs, and family history of colorectal cancer
Djuric et al[32]ColorectumUnited States2003-20051163/1501FFQQ> 10.29 vs < 4.33Age, sex, physical activity at age 30-39, BMI, family history of colorectal cancer, highest education achieved, and nonsteroidal antiinflammatory drug use (NSAID) use, red meat, and total calcium intake
Follow-up (yr)Case (n)
Hirvonen [33]Colorectum, StomachFinland6.1 (median)C 133S 111Diet historyTF1, F216.3 vs 4.2 (median)Age and supplementation group
Knekt et al[34]Colorectum, StomachFinland30 (maximum)C 90S 74Diet historyT, Q, K, M, H, NF1, F2, F3T: > 39.5 (F), 26.9 (M) vs < 8.5 (F), 4.3 (M), Q: > 4.7 (F), 3.9 (M) vs < 1.8 (F), 1.5 (M), K: > 0.9 (F), 0.8 (M) vs < 0.2 (F), 0.1 (M), M: > 0.2 (F), 0.11 (M) vs < 0.03 (F), 0.06 (M), H:> 26.8 (F), 15.4 (M) vs < 3.2 (F), 0 (M), N: > 7.7 (F), 4.7 (M) vs < 0.9 (F), 0 (M)Age, sex, geographic area, occupation, smoking, and BMI
Lin et al[35]ColorectumUnited States-878FFQT, Q, K, MF1, F2Q5 vs Q1 (NHS: > 31.1 vs < 9.6, HPFS: > 30.5 vs < 10.7)Age, BMI, family history of colorectal cancer, history of colorectal polyps, prior sigmoidoscopy screening, physical activity, smoking status, red meat intake, alcohol consumption, total energy intake, total calcium intake, total folate intake, total fiber intake, aspirin use, and multivitamin use
Akhter et al[36]ColorectumJapan7.6 (mean)886FFQIQ4 vs Q1Age, public health center area, history of diabetes mellitus, BMI, leisure time physical activity, cigarette smoking, alcohol drinking, and intake of vitamin D, dairy products, meat, fruit, vegetable, and fish, (F) + menopausal status and current use of female hormones
Mursu et al[37]ColorectumFinland16.2 (mean)55Food recordingT, F1, F2, F3, F4, AnF1, F2, F3, F4, AnQ4 vs Q1T: 416.3 vs 265.0 (mean)Age and examination years, BMI, smoking status, pack-years of smoking, physical activity, intakes of alcohol, total fat and saturated fat, and energy adjusted intake of fiber, vitamin C and E
Simon et al[38]ColorectumNetherlands13.31271FFQT, F4F1, F2T: > 36 vs < 16 (M), F4: > 84.3 vs < 44.4 (M), T: > 38.3 vs < 18.4 (F), F4: > 95.9 vs < 51.6 (F)Age, family history of colorectal cancer, smoking status, alcohol intake, occupational physical activity at longest held job, BMI and processed meat intake
Ward et al[41]ColorectumUnitd States9 (mean)221Food recordingIContinuousAge, height, weight, family history of colorectal cancer, smoking status, aspirin use, physical activity, and average daily intake of fat, energy, calcium, alcohol, and red and processed meats, (F) + oral contraceptive use, menopausal status, menopausal hormone therapy use, parity, breastfeeding, and surgical removal of ovaries
Hara et al[42]StomachJapan1249FFQIQ4 vs Q1 (median), 42.3 vs 9.2 (M), 41.8 vs 9.4 (F)Age, public center area, BMI, smoking status, ethanol intake, family history of gastric cancer, vegetable, fruit, fish, salt, and total energy intake

The summary estimates for the risk of cancer in subjects with the highest dietary flavonoid intake, compared with that in subjects with the lowest flavonoid intake, are presented in Table 2. The heterogeneity was low in the overall results, but heterogeneity was found in several summary estimates of the studies that included mostly case-control design. Total dietary flavonoids were not associated with a reduced risk of colorectal or stomach cancer [OR (95%CI) = 1.00 (0.90-1.11) and 1.07 (0.70-1.61), respectively]. However, flavonol, flavan-3-ol, anthocyanidin, and proanthocyanidin intakes showed a significant inverse association with colorectal cancer risk among flavonoid subclasses [OR (95%CI) = 0.71 (0.63-0.81), 0.88 (0.79-0.97), 0.68 (0.56-0.82), and 0.72 (0.61-0.85), respectively]. A significant association was found only for flavonol intake and stomach cancer risk in a limited number of selected studies [OR (95%CI) = 0.68 (0.46-0.99)].

Table 2 Summary estimates of dietary flavonoids and stomach and colorectal cancer risk.
CombinedColorectumStomach
Heterogeneity
Heterogeneity
Heterogeneity
na
RR
95%CI
I2
Pb
n
RR
95%CI
I2
Pb
n
RR
95%CI
I2
Pb
Total flavonoids111.000.91-1.1115.0%0.30191.000.90-1.1128.2%0.19421.070.70-1.610%0.464
Cohort91.050.93-1.180%0.51771.040.92-1.189.6%0.3552----
Case-control-----20.810.50-1.2967.9%0.078c0
Female-----30.930.84-1.040%0.8900
Male51.050.96-1.150%0.51441.050.96-1.1518.6%0.2981
Flavonols70.710.63-0.8010.7%0.34850.710.63-0.8137.0%0.17520.680.46-0.990%0.586
Case-control60.700.62-0.790%0.75540.700.62-0.790%0.5102----
Female-----20.840.75-0.930%0.3610
Male-----30.870.79-0.9645.4%0.1600
Quercetin80.810.68-0.9744.1%0.085c40.900.80-1.0342.2%0.15940.660.51-0.850%0.472
Kaempferol40.950.65-1.3755.2%0.082c21.120.91-1.380%0.97920.730.31-1.7171.8%0.060c
Myricetin41.150.87-1.510%0.96521.150.80-1.670%0.60721.130.75-1.710%0.935
Flavones60.840.74-0.9644.8%0.10740.830.63-1.0964.4%0.038c20.760.54-1.080%0.635
Case-control50.820.66-1.0255.0%0.064c30.830.61-1.1487.9%0.016c2----
Female-----20.940.84-1.040%0.3530
Male-----30.920.84-1.020%0.4770
Flavanones71.040.86-1.2744.5%0.094c51.080.95-1.2228.2%0.23420.720.49-1.0738.3%0.203
Case-control61.050.85-1.3053.3%0.057c41.080.95-1.2346.4%0.1442----
Female-----21.010.89-1.140%0.7340
Male-----30.990.89-1.110%0.5830
Hesperidin31.120.90-1.400%0.67521.150.91-1.450%0.5871
Naringenin31.110.89-1.380%0.73221.130.90-1.420%0.5391
Flavan-3-ols90.880.80-0.9716.3%0.29770.880.79-0.9730.1%0.19820.910.66-1.260%0.335
Cohort-----30.910.76-1.0826.9%0.2540
Case-control60.870.77-0.9824.7%0.24940.860.76-0.9846.6%0.1322----
Female-----30.940.87-1.0254.7%0.1100
Male-----41.070.99-1.1523.5%0.2700
Anthocyanidines50.750.64-0.8921.9%0.27530.680.56-0.820%0.86821.030.73-1.430%0.509
Case-control40.760.64-0.9037.9%0.18520.680.56-0.830%0.6682----
Proanthocyanidines30.550.35-0.8774.4%0.020c20.720.61-0.850%0.3721
Isoflavones140.900.80-1.0154.4%0.008c100.890.77-1.0265.1%0.003c40.910.78-1.065.5%0.206
Cohort70.980.85-1.1244.0%0.09851.020.90-1.1543.1%0.13520.880.74-1.0548.7%0.163
Case-control70.780.70-0.8737.5%0.14350.760.68-0.8536.2%0.18021.020.73-1.440%0.430
Female70.950.81-1.1147.7%0.075c60.930.78-1.1154.3%0.052c1
Male60.890.82-0.9635.7%0.17050.900.83-0.9942.0%0.1411

Subgroup analyses by study design or sex were conducted for each subclass of flavonoids. In case-control studies, all flavonoid subclasses except flavones and flavanones were inversely associated with colorectal cancer risk. However, neither total flavonoids nor any subclasses of flavonoids were associated with colorectal cancer risk in the cohort studies. Colorectal cancer showed a statistically significant association for the summary estimate of flavonols in both female and male subjects [OR (95%CI) = 0.84 (0.75-0.93) and 0.87 (0.79-0.96), respectively] and isoflavones in male subjects [OR (95%CI) = 0.90 (0.83-0.99)]. A reduced risk of colorectal cancer was not observed for the subclasses of flavonols.

The preventative effects of flavonoids on stomach and colorectal cancer risk were estimated by pooling the estimates based on the published observational studies. Total dietary flavonoid intake was not associated with a reduced risk of stomach and colorectal cancer, but several subclasses of flavonoids, mostly in case-control studies, showed protective effects against stomach and colorectal cancer risk.

Flavonoids could affect cancer risk through their antiinflammatory and antitumor activities. Flavonoids exert their antiinflammatory activities by inhibiting cycloxygenase-2 (COX2) in colon cancer cells, and this is associated with a reduced risk of colorectal cancer[43]. Plant flavonoids induce apoptosis and suppress the growth of colon cancer cells by inhibiting the COX2- and Wnt/epidermal growth factor receptor/nuclear factor-κB-signaling pathways, which play crucial roles in colorectal cancer[44]. Quercetin inhibits tyrosine kinase activity, thus downregulating cell proliferation[45]. The antitumor effects of flavonoids have not been demonstrated conclusively, but it has been suggested that the free radical scavenging properties of flavonoids are closely related to beneficial effects on cancer risk, as flavonoids are more effective antioxidants than vitamin C, vitamin E and carotenoids[46]. Hydroxylation at the 3-position on the C ring, the increased number of hydroxyl groups in ring B, and a saturated 2-3 bond on the C ring showed enhanced scavenging activities[47,48].

Reduced risks of colorectal cancer were observed in the summary estimates for flavonols, flavan-3-ols, anthocyanidins, and proanthocyanidins in the present study, as well as in subgroup analyses. The intake of total dietary flavonols and dietary quercetin were associated with a significant reduction of stomach cancer risk. These results might be attributed to the antiinflammatory and antitumor effects of those nutrients. However, no reduced risk of stomach and colorectal cancer was observed in the summary estimates of total dietary flavonoids, including the subgroup analyses by sex and study design, in the present meta-analysis. The subclasses of flavonoids included in the calculations of total flavonoids were different across studies, as shown in Table 1. All studies included flavonols and flavones among the total dietary flavonoids, but flavan-3-ols, proanthocyanidins, which can contribute a considerable proportion of the total flavonoid intake, were not considered in most studies. These discrepancies can lead to highly heterogeneous results. However, the overall results were homogenous in terms of the effects of total flavonoids, except for the summary estimate of case-control studies, which showed moderate heterogeneity. Thus, dietary flavonoid intake might not be truly associated with stomach or colorectal cancer risk. Furthermore, dietary intake of quercetin, kaempferol, and myricetin showed no significant association with colorectal cancer risk, whereas total dietary flavonols showed statistically significant results for both cancer types. These results might be closely related to the design of the selected studies. The studies that investigated total flavonoids as well as the flavonols quercetin, kaempferol and myricetin were mostly cohort designs, while the studies that investigated total flavonols were mostly case-control designs. Case-control studies are more subject to recall bias, resulting in either an underestimate or overestimate of the risk estimates. Especially in stomach and colorectal cancer, patients might have intestinal discomfort prior to diagnosis, resulting in changes in dietary habits. Similar results were found in a meta-analysis of fruit and vegetable consumption[49]. A statistically significant association between the risk of stomach and colorectal cancer and fruit and vegetable consumption was observed only in the summary estimate of case-control studies. This summary risk estimate was highly heterogeneous, unlike that of the cohort studies, suggesting that bias might be introduced in case-control studies. Another explanation for the lack of association in cohort studies is the typically short follow-up times. In a meta-analysis of association between fruit and vegetable consumption and gastric cancer risk[50], a significant association was observed only in the meta-analyses of studies with more than 10 years of follow-up. Meta-regression also revealed that longer follow-up time was associated with lower risk of gastric cancer. The mean follow-up times were more than 10 years for all cohort studies reporting total dietary flavonoid intake in our study, except for Hirvonen et al[33]. A meta-analysis performed after excluding this study did not change the results. Thus, the hypothesis of an inverse association between dietary flavonoids and risk of stomach and colorectal cancer cannot be supported by our results.

Although this meta-analysis provided little evidence of an inverse association between stomach and colorectal cancer risk and flavonoid intake, several mechanisms supported by in vitro and animal studies remain biologically plausible. Antitumor effects were shown for quercetin, luteolin, and myricetin[51-54], and polyphenols extracted from apple and olive oil had a chemopreventive effect in colon cancer cell lines or mice[55-57] and antioxidant activities in gastric mucosa[58,59]. Most subclasses of flavonoids were inversely associated in the present meta-analyses, although some bias might have been introduced. Thus, it is thought that dietary flavonoids are inversely associated with stomach or colorectal cancer risk, but this association is very small, making it difficult to detect. The United States Department of Agriculture (USDA) database for food flavonoids has been updated several times since 2003[60]. Most total dietary flavonoids are flavan-3-ols (82.5%), as estimated by USDA database and 24 h dietary records provided by United States adults[61]. The second greatest contributor was flavanones (7.6%), followed by flavonols (6.8%), anthocyanidins (1.6%), flavones (0.8%), and isoflavones (0.6%). However, the bioavailability of these compounds might be different. For example, tea flavonoids showed low absorption rates, whereas quercetin and isoflavones showed strong bioavailability. The main source of dietary flavonoid subclasses in Scotland in a database by Kyle et al[62] was tea[24], whereas the main sources of total flavonoids in Spain[31], calculated using the USDA database[60], were fruits (65.1%), followed by wine (14.4%), legumes (6.3%), and vegetables (4.2%). The methods used to estimate total flavonoids from dietary intake are poorly established[61]. Levels of exact individual flavonoid intake from food should be determined to confirm the true association between flavonoids and stomach and colorectal cancer risk.

The main limitation of this study is the small number of publications included. Especially in the case of stomach cancer, summary estimates could not be calculated in several subgroup analyses due to the limited number of studies. Because a significant association was found in the analyses of case-control studies which were subject to bias, the inverse association between subclasses of dietary flavonoid intake and cancer risk may be overestimated.

CONCLUSION

There was no clear evidence that dietary flavonoids are associated with reduced risk of stomach and colorectal cancer in the present meta-analysis. However, there is a possibility that there may be a weak association with stomach and colorectal cancer based on consistent associations for subclasses of flavonoids. The association of flavonoids with stomach and colorectal cancer could be relatively small and thus might only be detected with better methods of estimating true dietary flavonoid intake.

Footnotes

P- Reviewers Lin J, Passamonti S, Romano M S- Editor Song XX L- Editor Cant MR E- Editor Xiong L

References
1.  Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893-2917.  [PubMed]  [DOI]
2.  Sandhu MS, White IR, McPherson K. Systematic review of the prospective cohort studies on meat consumption and colorectal cancer risk: a meta-analytical approach. Cancer Epidemiol Biomarkers Prev. 2001;10:439-446.  [PubMed]  [DOI]
3.  Larsson SC, Wolk A. Meat consumption and risk of colorectal cancer: a meta-analysis of prospective studies. Int J Cancer. 2006;119:2657-2664.  [PubMed]  [DOI]
4.  Larsson SC, Orsini N, Wolk A. Processed meat consumption and stomach cancer risk: a meta-analysis. J Natl Cancer Inst. 2006;98:1078-1087.  [PubMed]  [DOI]
5.  van Duijnhoven FJ, Bueno-De-Mesquita HB, Ferrari P, Jenab M, Boshuizen HC, Ros MM, Casagrande C, Tjønneland A, Olsen A, Overvad K. Fruit, vegetables, and colorectal cancer risk: the European Prospective Investigation into Cancer and Nutrition. Am J Clin Nutr. 2009;89:1441-1452.  [PubMed]  [DOI]
6.  Jenab M, Riboli E, Ferrari P, Sabate J, Slimani N, Norat T, Friesen M, Tjønneland A, Olsen A, Overvad K. Plasma and dietary vitamin C levels and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST). Carcinogenesis. 2006;27:2250-2257.  [PubMed]  [DOI]
7.  Middleton EEffect of plant flavonoids on immune and inflammatory cell function. Adv Exp Med Biol. 1998;439:175-182.  [PubMed]  [DOI]
8.  Lambert JD, Hong J, Yang GY, Liao J, Yang CS. Inhibition of carcinogenesis by polyphenols: evidence from laboratory investigations. Am J Clin Nutr. 2005;81:284S-291S.  [PubMed]  [DOI]
9.  Beecher GR. Overview of dietary flavonoids: nomenclature, occurrence and intake. J Nutr. 2003;133:3248S-3254S.  [PubMed]  [DOI]
10.  Neuhouser MLDietary flavonoids and cancer risk: evidence from human population studies. Nutr Cancer. 2004;50:1-7.  [PubMed]  [DOI]
11.   Available from: http://www.ars.usda.gov/services/docs.htm?docid=6231.  [PubMed]  [DOI]
12.  Huxley RR, Neil HA. The relation between dietary flavonol intake and coronary heart disease mortality: a meta-analysis of prospective cohort studies. Eur J Clin Nutr. 2003;57:904-908.  [PubMed]  [DOI]
13.  Hooper L, Kroon PA, Rimm EB, Cohn JS, Harvey I, Le Cornu KA, Ryder JJ, Hall WL, Cassidy A. Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2008;88:38-50.  [PubMed]  [DOI]
14.  Schroeter H, Heiss C, Spencer JP, Keen CL, Lupton JR, Schmitz HH. Recommending flavanols and procyanidins for cardiovascular health: current knowledge and future needs. Mol Aspects Med. 2010;31:546-557.  [PubMed]  [DOI]
15.  Sun CL, Yuan JM, Koh WP, Yu MC. Green tea, black tea and breast cancer risk: a meta-analysis of epidemiological studies. Carcinogenesis. 2006;27:1310-1315.  [PubMed]  [DOI]
16.  Tang N, Wu Y, Zhou B, Wang B, Yu R. Green tea, black tea consumption and risk of lung cancer: a meta-analysis. Lung Cancer. 2009;65:274-283.  [PubMed]  [DOI]
17.  Sterne JAC, Bradburn MJ, Egger M. Meta-Analysis in Stata. Altman DG, editors. Systematic Reviews in Health Care: Meta-analysis in Context. London, England: BMJ Publishing Group 2001; 347-369.  [PubMed]  [DOI]
18.  Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557-560.  [PubMed]  [DOI]
19.  Ravasco P, Monteiro-Grillo I, Marqués Vidal P, Camilo ME; Nutritional risks and colorectal cancer in a Portuguese population. Nutr Hosp ; 20: 165-172.  .  [PubMed]  [DOI]
20.  Garcia-Closas R, Gonzalez CA, Agudo A, Riboli E. Intake of specific carotenoids and flavonoids and the risk of gastric cancer in Spain. Cancer Causes Control. 1999;10:71-75.  [PubMed]  [DOI]
21.  Lagiou P, Samoli E, Lagiou A, Peterson J, Tzonou A, Dwyer J, Trichopoulos D. Flavonoids, vitamin C and adenocarcinoma of the stomach. Cancer Causes Control. 2004;15:67-72.  [PubMed]  [DOI]
22.  Cotterchio M, Boucher BA, Manno M, Gallinger S, Okey A, Harper P. Dietary phytoestrogen intake is associated with reduced colorectal cancer risk. J Nutr. 2006;136:3046-3053.  [PubMed]  [DOI]
23.  Rossi M, Negri E, Talamini R, Bosetti C, Parpinel M, Gnagnarella P, Franceschi S, Dal Maso L, Montella M, Giacosa A. Flavonoids and colorectal cancer in Italy. Cancer Epidemiol Biomarkers Prev. 2006;15:1555-1558.  [PubMed]  [DOI]
24.  Theodoratou E, Kyle J, Cetnarskyj R, Farrington SM, Tenesa A, Barnetson R, Porteous M, Dunlop M, Campbell H. Dietary flavonoids and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2007;16:684-693.  [PubMed]  [DOI]
25.  Akhter M, Iwasaki M, Yamaji T, Sasazuki S, Tsugane S. Dietary isoflavone and the risk of colorectal adenoma: a case-control study in Japan. Br J Cancer. 2009;100:1812-1816.  [PubMed]  [DOI]
26.  Kyle JA, Sharp L, Little J, Duthie GG, McNeill G. Dietary flavonoid intake and colorectal cancer: a case-control study. Br J Nutr. 2010;103:429-436.  [PubMed]  [DOI]
27.  Rossi M, Rosato V, Bosetti C, Lagiou P, Parpinel M, Bertuccio P, Negri E, La Vecchia C. Flavonoids, proanthocyanidins, and the risk of stomach cancer. Cancer Causes Control. 2010;21:1597-1604.  [PubMed]  [DOI]
28.  Rossi M, Negri E, Parpinel M, Lagiou P, Bosetti C, Talamini R, Montella M, Giacosa A, Franceschi S, La Vecchia C. Proanthocyanidins and the risk of colorectal cancer in Italy. Cancer Causes Control. 2010;21:243-250.  [PubMed]  [DOI]
29.  Budhathoki S, Joshi AM, Ohnaka K, Yin G, Toyomura K, Kono S, Mibu R, Tanaka M, Kakeji Y, Maehara Y. Soy food and isoflavone intake and colorectal cancer risk: the Fukuoka Colorectal Cancer Study. Scand J Gastroenterol. 2011;46:165-172.  [PubMed]  [DOI]
30.  Ekström AM, Serafini M, Nyrén O, Wolk A, Bosetti C, Bellocco R. Dietary quercetin intake and risk of gastric cancer: results from a population-based study in Sweden. Ann Oncol. 2011;22:438-443.  [PubMed]  [DOI]
31.  Zamora-Ros R, Not C, Guinó E, Luján-Barroso L, García RM, Biondo S, Salazar R, Moreno V. Association between habitual dietary flavonoid and lignan intake and colorectal cancer in a Spanish case-control study (the Bellvitge Colorectal Cancer Study). Cancer Causes Control. 2013;24:549-557.  [PubMed]  [DOI]
32.  Djuric Z, Severson RK, Kato I. Association of dietary quercetin with reduced risk of proximal colon cancer. Nutr Cancer. 2012;64:351-360.  [PubMed]  [DOI]
33.  Hirvonen T, Virtamo J, Korhonen P, Albanes D, Pietinen P. Flavonol and flavone intake and the risk of cancer in male smokers (Finland). Cancer Causes Control. 2001;12:789-796.  [PubMed]  [DOI]
34.  Knekt P, Kumpulainen J, Järvinen R, Rissanen H, Heliövaara M, Reunanen A, Hakulinen T, Aromaa A. Flavonoid intake and risk of chronic diseases. Am J Clin Nutr. 2002;76:560-568.  [PubMed]  [DOI]
35.  Lin J, Zhang SM, Wu K, Willett WC, Fuchs CS, Giovannucci E. Flavonoid intake and colorectal cancer risk in men and women. Am J Epidemiol. 2006;164:644-651.  [PubMed]  [DOI]
36.  Akhter M, Inoue M, Kurahashi N, Iwasaki M, Sasazuki S, Tsugane S. Dietary soy and isoflavone intake and risk of colorectal cancer in the Japan public health center-based prospective study. Cancer Epidemiol Biomarkers Prev. 2008;17:2128-2135.  [PubMed]  [DOI]
37.  Mursu J, Nurmi T, Tuomainen TP, Salonen JT, Pukkala E, Voutilainen S. Intake of flavonoids and risk of cancer in Finnish men: The Kuopio Ischaemic Heart Disease Risk Factor Study. Int J Cancer. 2008;123:660-663.  [PubMed]  [DOI]
38.  Simons CC, Hughes LA, Arts IC, Goldbohm RA, van den Brandt PA, Weijenberg MP. Dietary flavonol, flavone and catechin intake and risk of colorectal cancer in the Netherlands Cohort Study. Int J Cancer. 2009;125:2945-2952.  [PubMed]  [DOI]
39.  Wang L, Lee IM, Zhang SM, Blumberg JB, Buring JE, Sesso HD. Dietary intake of selected flavonols, flavones, and flavonoid-rich foods and risk of cancer in middle-aged and older women. Am J Clin Nutr. 2009;89:905-912.  [PubMed]  [DOI]
40.  Yang G, Shu XO, Li H, Chow WH, Cai H, Zhang X, Gao YT, Zheng W. Prospective cohort study of soy food intake and colorectal cancer risk in women. Am J Clin Nutr. 2009;89:577-583.  [PubMed]  [DOI]
41.  Ward HA, Kuhnle GG, Mulligan AA, Lentjes MA, Luben RN, Khaw KT. Breast, colorectal, and prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition-Norfolk in relation to phytoestrogen intake derived from an improved database. Am J Clin Nutr. 2010;91:440-448.  [PubMed]  [DOI]
42.  Hara A, Sasazuki S, Inoue M, Iwasaki M, Shimazu T, Sawada N, Yamaji T, Tsugane S. Isoflavone intake and risk of gastric cancer: a population-based prospective cohort study in Japan. Am J Clin Nutr. 2012;95:147-154.  [PubMed]  [DOI]
43.  Mutoh M, Takahashi M, Fukuda K, Komatsu H, Enya T, Matsushima-Hibiya Y, Mutoh H, Sugimura T, Wakabayashi K. Suppression by flavonoids of cyclooxygenase-2 promoter-dependent transcriptional activity in colon cancer cells: structure-activity relationship. Jpn J Cancer Res. 2000;91:686-691.  [PubMed]  [DOI]
44.  Suh Y, Afaq F, Johnson JJ, Mukhtar H. A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-kappaB-signaling pathways. Carcinogenesis. 2009;30:300-307.  [PubMed]  [DOI]
45.  So FV, Guthrie N, Chambers AF, Moussa M, Carroll KK. Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutr Cancer. 1996;26:167-181.  [PubMed]  [DOI]
46.  Dai J, Mumper RJ. Plant phenolics: extraction, analysis and their antioxidant and anticancer properties. Molecules. 2010;15:7313-7352.  [PubMed]  [DOI]
47.  Magnani L, Gaydou EM, Hubaud JC. Spectrophotometric measurement of antioxidant properties of flavones and flavonols against superoxide anion. Anal Chim Acta. 2000;411:209-216.  [PubMed]  [DOI]
48.  Heim KE, Tagliaferro AR, Bobilya DJ. Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J Nutr Biochem. 2002;13:572-584.  [PubMed]  [DOI]
49.  Riboli E, Norat T. Epidemiologic evidence of the protective effect of fruit and vegetables on cancer risk. Am J Clin Nutr. 2003;78:559S-569S.  [PubMed]  [DOI]
50.  Lunet N, Lacerda-Vieira A, Barros H. Fruit and vegetables consumption and gastric cancer: a systematic review and meta-analysis of cohort studies. Nutr Cancer. 2005;53:1-10.  [PubMed]  [DOI]
51.  Watkin BA question of attitudes. Nurs Mirror Midwives J. 1976;142:39.  [PubMed]  [DOI]
52.  González-Segovia R, Quintanar JL, Salinas E, Ceballos-Salazar R, Aviles-Jiménez F, Torres-López J. Effect of the flavonoid quercetin on inflammation and lipid peroxidation induced by Helicobacter pylori in gastric mucosa of guinea pig. J Gastroenterol. 2008;43:441-447.  [PubMed]  [DOI]
53.  Seelinger G, Merfort I, Wölfle U, Schempp CM. Anti-carcinogenic effects of the flavonoid luteolin. Molecules. 2008;13:2628-2651.  [PubMed]  [DOI]
54.  Ko CH, Shen SC, Lee TJ, Chen YC. Myricetin inhibits matrix metalloproteinase 2 protein expression and enzyme activity in colorectal carcinoma cells. Mol Cancer Ther. 2005;4:281-290.  [PubMed]  [DOI]
55.  Fini L, Hotchkiss E, Fogliano V, Graziani G, Romano M, De Vol EB, Qin H, Selgrad M, Boland CR, Ricciardiello L. Chemopreventive properties of pinoresinol-rich olive oil involve a selective activation of the ATM-p53 cascade in colon cancer cell lines. Carcinogenesis. 2008;29:139-146.  [PubMed]  [DOI]
56.  Fini L, Selgrad M, Fogliano V, Graziani G, Romano M, Hotchkiss E, Daoud YA, De Vol EB, Boland CR, Ricciardiello L. Annurca apple polyphenols have potent demethylating activity and can reactivate silenced tumor suppressor genes in colorectal cancer cells. J Nutr. 2007;137:2622-2628.  [PubMed]  [DOI]
57.  Fini L, Piazzi G, Daoud Y, Selgrad M, Maegawa S, Garcia M, Fogliano V, Romano M, Graziani G, Vitaglione P. Chemoprevention of intestinal polyps in ApcMin/+ mice fed with western or balanced diets by drinking annurca apple polyphenol extract. Cancer Prev Res (Phila). 2011;4:907-915.  [PubMed]  [DOI]
58.  D’Argenio G, Mazzone G, Tuccillo C, Grandone I, Gravina AG, Graziani G, Fogliano V, Romano M. Apple polyphenol extracts prevent aspirin-induced damage to the rat gastric mucosa. Br J Nutr. 2008;100:1228-1236.  [PubMed]  [DOI]
59.  Romano M, Vitaglione P, Sellitto S, D’Argenio G. Nutraceuticals for protection and healing of gastrointestinal mucosa. Curr Med Chem. 2012;19:109-117.  [PubMed]  [DOI]
60.  USDA database for the flavonoid contents of selected foods, Release 3 (2003). .  [PubMed]  [DOI]
61.  Chun OK, Chung SJ, Song WO. Estimated dietary flavonoid intake and major food sources of U.S. adults. J Nutr. 2007;137:1244-1252.  [PubMed]  [DOI]
62.  Kyle J, Duthie G. Flavonoids in foods. Flavonoids: Chemistry, biochemistry and applications. Boca Raton: CRC Press 2006; .  [PubMed]  [DOI]