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Carcinogenesis Advance Access originally published online on August 27, 2007
Carcinogenesis 2007 28(10):2143-2148; doi:10.1093/carcin/bgm171
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Green tea and black tea consumption in relation to colorectal cancer risk: the Singapore Chinese Health Study

Can-Lan Sun*, Jian-Min Yuan1, Woon Puay Koh2, Hin-Peng Lee2 and Mimi C. Yu1

Division of Population Sciences, City of Hope National Medical Center and Beckman Research Institute, 1500 East Duarte Road, Duarte, CA 91010, USA
1 Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
2 Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore

* To whom correspondence should be addressed. Tel: +1 626 256 4673 ext. 64124; Fax: +1 626 930 5387; Email: casun{at}coh.org


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Funding
 References
 
The relationships between green tea and black tea consumption and colorectal cancer risk were examined within the Singapore Chinese Health Study, a prospective cohort study of diet and cancer involving >60 000 men and women. Intake of green tea and black tea was assessed through in-person interviews. Incident cancer cases and deaths among cohort members were identified through record linkage of the cohort database with respective databases from the nationwide Singapore Cancer Registry and the Singapore Registry of Births and Deaths. The proportional hazard regression method was used to examine the associations between intake of green and black tea separately and colorectal cancer risk with adjustment for potential confounders. After an average of 8.9 years of follow-up, 845 colorectal cancer cases were identified. Subjects who drank green tea exhibited a statistically non-significant increase in risk [relative risk (RR) = 1.12, 95% confidence interval (CI) = 0.97–1.29] relative to non-drinkers of green tea. This risk increase was mainly confined to men (RR = 1.31, 95% CI = 1.08–1.58); the comparable RR in women was 0.89 (95% CI = 0.71–1.12). In men, the green tea–colorectal cancer association was noted mainly in those with advanced disease (Duke C or D) (RR = 1.53, 95% CI = 1.19–1.97), and the association was dose dependent (P for trend = 0.0002). This latter association was especially strong within the colon subsite (RR = 1.75, 95% CI = 1.24–2.46; P for trend < 0.0001). Irrespective of gender, intake of black tea was not associated with risk of colorectal cancer (RR = 0.92, 95% CI = 0.79–1.07) in this Asian population.

Abbreviations: CI, confidence interval; ECG, epicatechin gallate; EGCG, epigallocatechin gallate; FFQ, food frequency questionnaire; RR, relative risk


   Introduction
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 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Funding
 References
 
Tea is a popular drink around the world, second only to water. Both green and black teas are derived from the leaves of the plant, Camellia sinensis. The fresh tea leaves contain large amounts of naturally occurring compounds called polyphenols which account for tea's pungency and unique flavor. The four primary polyphenols (also called catechins) in fresh tea leaves are epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin gallate (ECG) and epicatechin, with EGCG being most abundant. These four catechins account for up to 30% dry weight of the fresh tea leaves (1). Varying methods of processing the tea leaves after harvest lead to three major types of tea. To make green tea, fresh tea leaves are steamed or pan dried at high temperature right after plucking, resulting in minimal oxidation of the catechins in the tea leaves. Alternatively, fresh tea leaves are rolled or crushed to encourage oxidation and polymerization of the catechins in a process commonly known as fermentation to make black tea. This fermentation process results in the generation of other distinct polyphenols such as thearubigins and theaflavins that give black tea the characteristic aroma and red-orange color. An intermediate stage of enzymatic oxidation yields Oolong tea. About 78% of the tea production worldwide is black tea, which is the main tea beverage consumed in the USA and Europe. Green tea, which is the main tea beverage in Japan and parts of China, accounts for ~20% of worldwide production. The remaining 2% of tea production is Oolong tea which is consumed mainly in Southern China and Taiwan.

From mutagenicity to tumor development, using different carcinogens, different animal species and cell lines, most of the in vitro and non-human in vivo experiments support both green and black tea as chemopreventive agents for the development of colorectal cancer. On the other hand, the overall evidence from epidemiologic studies did not support an association between either green tea or black tea consumption and colorectal cancer risk reduction (2). Epidemiologic data on green tea are sparse, especially data from prospective studies with sufficient sample size and meaningful range of exposure. Although a greater number of epidemiologic studies have examined black tea intake and colorectal cancer, they were mainly conducted in Western populations (2).

The current study utilized the Singapore Chinese Health Study, a population-based prospective cohort study of 63 000 middle-age and older Chinese men and women, to examine green tea and black tea consumption in relation to colorectal cancer risk. The wide range in consumption of both green tea and black tea among Singapore Chinese provides the present study with a unique opportunity to carry out a comprehensive investigation on the independent and interactive effects of black tea and green tea as well as the overall effect of any tea intake in the development of colorectal cancer.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Funding
 References
 
Study population
The subjects were participants of the Singapore Chinese Health Study, a population-based, prospective investigation of diet and cancer risk (3). The cohort is drawn from permanent residents or citizens of Singapore who reside in government housing estates (86% of Singaporeans resided in such facilities during the enrollment period). We restricted study subjects to the two major dialect groups of Chinese in Singapore: the Hokkien, who originated from southern Fujian province, and the Cantonese, who came from central Guangdong province (these are contiguous provinces in Southeastern China). The eligible age range for cohort enrollment was 45–74 years. Between April 1993 and December 1998, 63 257 subjects (~85% of eligible subjects) were recruited. The mean age of cohort subjects at enrollment was 56.5 years. Among cohort participants, 1936 subjects were excluded because they had a baseline history of invasive cancer other than non-melanoma skin cancer. Another subject was excluded because of a history of in situ bladder cancer at baseline. Thus, the present study included 61 320 subjects.

Baseline interview
At recruitment, each subject was interviewed in person by a trained interviewer using a structured questionnaire. The questionnaire elicited demographic information, lifetime tobacco use, current physical activity profile, occupational exposure, medical history, family history of cancer and menstrual and reproductive history (women only). Dietary information (frequency and portion size) during the past 12 months also was obtained using a 165-item food frequency questionnaire (FFQ). The FFQ was subsequently validated against a series of 24-h dietary recalls (3). Daily intakes of ~100 nutritive/non-nutritive dietary components were computed via linkage of the FFQ response to the Singapore Food Composition Table that we developed in conjunction with the Singapore Cohort Study (3).

For green tea and black tea separately, study subjects were asked to choose their intake frequency during the past 12 months from nine predefined categories: never or hardly ever, one to three times a month, once a week, two to three times a week, four to six times a week, once a day, two to three times a day, four to five times a day and six or more times a day. Non-green tea drinkers were subjects who reported ‘never or hardly ever’ in response to the question regarding green tea intake frequency. The remaining ‘green tea drinkers' were grouped into three frequency levels (monthly, weekly, daily). Non-drinkers and drinkers of black tea were similarly defined. In terms of total tea intake (i.e. tea intake irrespective of type), subjects who never or hardly ever drank either type of tea were labeled as non-tea drinkers. Subjects who reported drinking either green tea or black tea daily were categorized as daily tea drinkers. For the remaining subjects, those reporting either green tea or black tea intake on a weekly basis were categorized as weekly tea drinkers. All remaining subjects were categorized as monthly tea drinkers.

Follow-up
Identification of incident colorectal cancer cases and deaths among cohort members were accomplished by record linkage of the cohort database with respective databases from the population-based Singapore Cancer Registry and the Singapore Registry of Births and Deaths. The nationwide cancer registry has been in place since 1968 and has been shown to be comprehensive in its recording of cancer cases (4,5). To date, only 17 subjects were lost to follow-up due to migration out of Singapore. As of 31 December 2004 [an average of 8.9 (median = 9.6) years of follow-up], 845 cohort participants who were cancer free at baseline had developed invasive colorectal cancer (516 colon cancers and 329 rectal/rectosigmoid cancers). Histological information on 821 (97.2%) colorectal cancer cases was confirmed via manual review of pathology reports. The cancer diagnoses of 14 cases (1.6%) were confirmed via review of medical records by a medically trained research staff. The remaining 10 cases (1.2%) were identified through death certificates.

Statistical analyses
For each study subject, person-years were counted from the date of baseline interview to the date of cancer diagnosis, date of death, date of last contact (for those 17 subjects who migrated out of Singapore) or 31 December 2004, whichever occurred first. Proportional hazards regression methods (6) were used to examine the tea and colorectal cancer association with adjustment for potential confounders. The strength of the association was measured by relative risks (RRs) and their corresponding 95% confidence intervals (CIs) and two-sided P values. The linear trend tests were based on the ordinal values of the tea intake frequency categories (0, 1, 2 and 3). A two-sided P value <0.05 would be considered statistically significant. Q statistics (7) were used to test for homogeneity of the RRs between the colon versus the rectum subsite. A two-sided P value <0.10 would be considered statistically significant.

In all analyses, we considered the following factors as potential confounders: gender (in analyses involving both genders), age at baseline interview (years), year of interview (1994–1998), dialect group (Cantonese, Hokkien), level of education (no formal education, primary school, secondary school or higher), cigarette smoking (never, light, heavy; see definition below) (8), alcohol consumption (non-drinker, less than seven drinks per week, seven or more drinks per week) (8), coffee drinking (never/occasionally, one cup per day, two or more cups per day), body mass index (<20, 20 to <24, 24 to <28, 28+ kg/m2), familial history of colorectal cancer (no, yes), history of diabetes (no, yes) (9), weekly moderate physical activity (no, yes; see definition below), intakes of total calories (Kcal), total fat (% of total calories), dietary fiber (mg/1000 Kcal), calcium (mg/1000 Kcal) and vitamin C (mg/1000 Kcal). For cigarette smoking, heavy smokers were defined as those who started to smoke before 15 years of age and smoked 13 or more cigarettes per day. The remaining smokers were categorized as light smokers. Moderate physical activities included brisk walking, bowling, bicycling on level ground, tai chi or chi kung. Subjects who engaged in such activities at least 30 min/week were classified into the ‘weekly moderate physical activity’ category.

Rate of replacement hormone use in women in our cohort was low (6%), as were use of vitamin supplements (6%) and use of non-steroidal anti-inflammatory drugs (1%) irrespective of gender. Additional inclusion of these covariates did not materially change any of the study results. Similarly, results with or without the inclusion of intakes of fruit, vegetables and red meats as covariates were comparable. The presented results are derived from regression models that did not include these covariates.

Statistical computing was conducted using SAS version 9.1 (SAS Institute, Cary, NC) and STATA statistical software (College Station, TX). The study protocol was approved by the Institutional Review Boards of the University of Minnesota and the National University of Singapore.


   Results
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 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Funding
 References
 
The distributions of selected demographic and lifestyle factors by green tea and black tea consumption levels in men and women are presented in Tables I and II. Men were more likely to drink either green tea or black tea compared with women. In both men and women, Cantonese were more likely to be green tea drinkers whereas Hokkien were more likely to be black tea drinkers. Tea drinkers (regardless of type) had higher levels of education, were less likely to smoke but more likely to drink alcoholic beverages, less likely to drink coffee and were more likely to engage in moderate physical activities. Among men, more green tea drinkers than non-tea drinkers reported a history of diabetes.


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  		Table I. Distribution of selected characteristics among non-tea drinkers, green tea and black tea drinkers in women, the Singapore Chinese Health Study, 1993–2004

 


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  		Table II. Distribution of selected characteristics among non-tea drinkers, green tea and black tea drinkers in men, the Singapore Chinese Health Study, 1993–2004

 
As of 31 December 2004, 845 incident cases of invasive colorectal cancer cases (470 males and 375 females) were identified after an average of 8.9 years of follow-up (SD = 2.3). There were 516 colon cancer cases and 329 rectal cancer cases. Majority of the cancers were adenocarcinoma (n = 747, 88%). The mean age at cancer diagnosis was 67 years (SD = 8.0). The mean interval between entry into the study and cancer diagnosis was 5.5 years (range: 1 month to 11.6 years). Three hundred and twenty-two cases (38.1%) were classified as localized (Duke A or B) and 472 (55.9%) as advanced disease (Duke C or D). Fifty-one cases (6%) could not be staged due to insufficient clinical and histopathological information.

Total tea consumption was not associated with colorectal cancer risk (RR = 1.04, 95% CI = 0.90–1.20) (Table III). The null association did not differ by subsites; the RR (95% CI) for colon cancer was 1.04 (0.86–1.25) and for rectal cancer, 1.04 (0.83–1.32) (P for heterogeneity between two sites = 1.00). We then examined tea intake by type (green versus black tea). Neither green tea consumption (RR = 1.12, 95% CI = 0.97–1.29) nor black tea consumption (RR = 0.92, 95% CI = 0.80–1.07) was associated with colorectal cancer risk, and these null effects were seen in both the colon and rectum subsites (data not shown). However, when tea intake in relation to colorectal cancer risk was examined separately in men and women, men who reported drinking green tea monthly or more frequently showed a statistically significant 30% increase in colorectal cancer risk (RR = 1.31, 95% CI = 1.08–1.58). No such association was noted in women (RR = 0.89, 95% CI = 0.71–1.12). Black tea consumption was not associated with colorectal cancer risk in either men (RR = 0.88, 95% CI = 0.73–1.07) or women (RR = 1.00, 95% CI = 0.78–1.27) (Table III).


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  		Table III. Green tea and black tea consumption in relation to colorectal cancer risk, the Singapore Chinese Health Study, 1993–2004

 
We further examined the tea–colorectal cancer association in men according to subsite (colon versus rectum) and stage of disease (localized versus advanced) (Table IV). There was no evidence that risk of localized disease was associated with green tea intake (RR = 1.19, 95% CI = 0.88–1.62). On the other hand, there was a highly statistically significant, dose-dependent positive association between green tea intake and risk of advanced colorectal cancer (RR for monthly, weekly and daily drinkers were 1.38, 1.35 and 1.85, respectively, P trend = 0.0002). This latter association was primarily present in the colon subsite (RR for monthly, weekly and daily drinkers were 1.11, 1.69 and 2.26, respectively, P trend < 0.0001). There were no associations between black tea consumption and colorectal cancer in men by subsite or stage of disease.


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  		Table IV. Green tea and black tea consumption in relation to colorectal cancer risk in men, by subsite and stage of disease, the Singapore Chinese Health Study, 1993–2004

 
We also examined the effect of duration of follow-up on the green tea–colorectal cancer association in men. Among men with 5 or fewer years of follow-up, the RR for green tea drinkers compared with non-green tea drinkers was 1.39 (95% CI = 1.05–1.86), similar to those with 6–10 years of follow-up (RR = 1.40, 95% CI = 1.07–1.83). Among these men with relatively short duration (under 10 years) of follow-up, the associations with green tea intake was primarily confined to those with advanced stage disease (RR = 1.85, 95% CI = 1.24–2.76 for those with ≤5 years of follow-up and RR = 1.59, 95% CI = 1.12–2.27 for those with 6–10 years of follow-up). In contrast, men with >10 years of follow-up exhibited a reduced risk of colorectal cancer (RR = 0.51, 95% CI = 0.23–1.13) (Table V).


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  		Table V. Green tea in relation to colorectal cancer risk in men by length of follow-up, the Singapore Chinese Health Study, 1993–2004

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Funding
 References
 
Using data from the Singapore Chinese Health Study, we demonstrated that green tea but not black tea consumption was associated with an increased risk of colorectal cancer in men. This positive green tea/colorectal cancer risk association was mainly confined to patients with advanced colorectal cancer (Duke C or D) and was more evident for the colon subsite. No association between colorectal cancer and either green or black tea was observed in women.

Although experimental studies have supported the notion of a protective effect of green tea or tea catechins on colorectal carcinogenesis (10–17), epidemiologic data on this association in humans are still limited. Only eight studies have examined green tea and colorectal cancer; six were conducted in Japan where few people were non-daily drinkers of green tea (2). All four cohort studies were conducted in Japan. In our recent meta-analysis (2), the summary RR for colorectal cancer in green tea drinkers, based on the four cohort studies, was 0.97 (95% CI = 0.82–1.16). Our finding of a RR of 1.12 (95% CI = 0.97–1.29) in total subjects is compatible with the meta-analysis results (P for heterogeneity = 0.21). Two of the four previously published cohort studies provided gender-specific estimates (pooled summary RR = 0.95, 95% CI = 0.65–1.40 for men). Again, our finding in men was compatible with the published literature (P for heterogeneity = 0.14).

Recently, we examined and reported on the relationship between levels of EGC and 4'-O-methyl-EGC in urine samples collected at baseline and subsequent risk of colorectal cancer within the Shanghai Cohort Study, a prospective investigation of 18 000 men aged 45–64 years followed since 1986 (18). Due to the repeated thawing of urine specimens in early cases, only colorectal cancer patients with ≥5 years of follow-up were included in this study. We observed a statistically significant, dose-dependent inverse association between colorectal cancer risk and baseline urinary EGC and 4'-O-methyl-EGC. Consistent with our earlier observation in Shanghai, the present study noted a 50% reduction in risk among men with >10 years of follow-up. Due to the small number of subjects in this subgroup, the reduced risk estimate was not statistically different from the null hypothesis.

Interestingly, the present study suggests that green tea may contain substances that exert a late-stage effect on colorectal cancer in men, primarily impacting on tumor progression and metastasis. We noted a dose-dependent, statistically significant association between green tea intake and advanced colorectal cancer (Duke C or D) that is only evident among subjects with <10 years of follow-up. There is limited experimental support for a promotional effect of green tea on colorectal cancer progression/invasion. In one study in which green tea was administered after carcinogen exposure, green tea-treated rats experienced increased colon carcinoma formation (19). In another study, EGCG increased the intra- and extracellular production of pro-matrix-metalloproteinase (MMP)-7 protein in a dose- and time-dependent manner (20). MMP-7 messenger RNA expression has been shown to correlate with colorectal cancer progression (21). Finally, two recent studies show that ECG and EGCG inhibit hypoxia-inducible factor-1{alpha} degradation in breast (22) and prostate cancer cell lines (23). It is known that hypoxia develops during tumor progression, including colorectal cancer (24), due to the inability of existing vascular system to supply the growing tumor with adequate amounts of oxygen (25). Over-expression of hypoxia-inducible factor-1{alpha} has been observed in primary and metastatic tumors of common human cancers, including colon cancer (26).

Recent findings from the Women’s Health Initiative Trial (27,28) corroborated reports of observational studies (29,30) in support of progestin, and possibly other female sex hormones, having a direct, beneficial effect on colorectal carcinogenesis. Recently, we noted that among post-menopausal female participants of this Singapore Chinese cohort, green tea drinkers exhibited statistically significant, reduced levels of plasma estrogens relative to non-tea drinkers (31). Thus, a sex hormone-mediated pathway may be involved in the observed positive association between green tea intake and late-stage colorectal cancer, which seems to be restricted to the male gender.

This is the first prospective study of black tea and colorectal cancer risk in an Asian population. Consistent with the literature, we failed to note any relationship between black tea intake and colorectal cancer. Although the overall levels of polyphenols are similar between green tea and black tea (32), the contents of catechins are vastly different between the two types of tea. The main polyphenols in black tea are thearubigins and theaflavins; the catechins in black tea are only one-third to one-tenth the comparable levels in green tea (33). Therefore, it is not surprising that black tea fails to exhibit a similar, positive association with colorectal cancer risk as green tea.

While we cannot totally rule out the possibility of chance finding, we have, however, adjusted for all possible confounders in our statistical analysis. The positive green tea–colorectal cancer association in men persisted after adjustment for cigarette smoking, alcohol consumption and history of diabetes. There is some suggestion that coffee intake might be negatively associated with colorectal cancer risk (34,35). Further adjustment for coffee consumption did not materially change the association.

This study has several strengths. To our knowledge, there is no widespread, organized colorectal cancer screening in Singapore, in contrast to several government-subsidized, high-profiled, nationwide mammography and pap smear screening programs among age-eligible citizens in the past 5 and 3 years, respectively. Therefore, the potential of screening-identified cases affecting the validity of the observed associations is quite unlikely. Dietary assessment was conducted using a validated, semi-quantitative FFQ. The study population is genetically homogeneous since they are full-blooded descendents of natives from two contiguous prefectures in southern China. Finally, all exposure assessments took place prior to cancer diagnosis, and therefore, could be presumed to be free of recall bias.

In conclusion, we observed a novel, positive association between green tea consumption and risk of advanced colorectal cancer in men. On the other hand, for the subgroup of subjects with long duration of follow-up (>10 years), the results are compatible with our earlier findings of a beneficial effect of green tea intake on colorectal cancer risk. Thus, this study suggests a dual (i.e. deleterious versus beneficial) role of green tea on colorectal carcinogenesis that is dependent on the time of exposure (early versus late). Our findings require confirmation in other population-based cohorts and experimental studies are needed to elucidate the mechanisms behind this apparent late-stage, progression-/invasion-related effect of green tea on colorectal carcinogenesis. At present, there should be caution in recommending green tea as a health-promoting compound for men.


   Funding
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
References
 
National Cancer Institute, Bethesda, MD (R01 CA55069, R35 CA53890, R01 CA80205 and R01 CA98497).


   Acknowledgments
 
We thank Ms Siew-Hong Low of the National University of Singapore for supervising the fieldwork of the Singapore Chinese Health Study and Ms Kazuko Arakawa of the University of Southern California for the development and management of the cohort study database. We also thank the Singapore Cancer Registry for assistance with the identification of cancer outcomes.

Conflict of Interest Statement: None declared.


   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
 References
 

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Received March 16, 2007; revised July 9, 2007; accepted July 19, 2007.


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