The present study showed a statistically significant, inverse association between urinary total ITC level and colorectal cancer for cases diagnosed at least 5 years post-enrollment. This inverse ITC-colorectal cancer association became stronger with longer time intervals between exposure assessment (baseline urine collection) and diagnosis of colorectal cancer. Interestingly, high level of ITC was associated with a statistically non-significant increase in risk of colorectal cancer diagnosed within 5 years of enrollment and this positive ITC-cancer risk association was statistically significantly different from the negative ITC-cancer risk association noted among cases with a longer time period of follow-up. One might argue that baseline measurements in cancer cases diagnosed within one year of enrollment were non-informative, due to possible dietary changes as a result of clinical symptoms. Thus, we repeated the analysis with exclusion of subjects with less than one year of follow-up time, the positive ITC-cancer association in cases diagnosed within 5 years of enrollment actually became stronger (from OR=1.93, p=0.12 to OR=2.40, p=0.07). These results suggest that in a given individual, timing of the ITC exposure may be an important co-determinant of the ITC-colorectal cancer risk association.
The present study confirms our earlier observation in Singapore (10
), and supports the hypothesis that ITC protects against colorectal cancer in humans. Experimental studies have shown that dietary intake of Chinese cabbage significantly reduced adduct formation in the colon of rats treated with a known colon carcinogen (8
). Dietary ITCs significantly reduced the formation of chemical-induced colonic aberrant crypt foci in rats (9
). In humans, high consumption of cruciferous vegetables, the primary source of ITC exposure, has been linked to reduced risk of colorectal cancer (10
) and colon adenoma, a recognized precancerous lesion of colorectal cancer (21
Humans are exposed to ITCs through the consumption of cruciferous vegetables, which are rich in glucosinolates, precursors of ITCs. Different cruciferous vegetables contain different types and levels of glucosinolates (23
). Therefore, exposure levels to specific types of ITCs for a given population depend on both the quantities and types of cruciferous vegetables being consumed. Subjects of the present study, on average, consumed 50% more cruciferous vegetables than Singapore Chinese (43 g/1000 kcal versus 29 g/1000 kcal per day) and their frequency of consumption is three times that of Americans in Los Angeles (8 servings versus 2.6 servings per week) (24
). The most commonly consumed cruciferous vegetables in Shanghai and Singapore Chinese are bok choi, choi sum, cabbage/wong nga pak and kai lan (16
) whereas for whites in the United States, broccoli is by far the most commonly consumed cruciferous vegetable (20
). Thus, results on consumption of total cruciferous vegetables in relation to risk of colorectal cancer across different study populations should be interpreted cautiously.
This is the first prospective study to examine the association between a validated biomarker of ITC exposure and colorectal cancer risk. Strengths of this study include the prospective study design. The biospecimens for ITC measurements were collected before the occurrence of colorectal cancer, avoiding the direct impact of disease on assessment of exposure. The long duration of follow-up (up to 16 years) allowed the present study to examine the long-term protective effect of ITC against the development of colorectal cancer. The almost complete follow-up for incident cancer and death minimized the potential bias on results due to the loss to follow-up. The present study also has several potential limitations. It cannot be assumed that ITC levels in a randomly-timed, single void urine sample correlates with usual intake of dietary ITC. However, we had earlier demonstrated among Chinese in Singapore, who share a similar cultural and dietary heritage as our study population in Shanghai, a close and statistically significant correlation between dietary ITC ascertained from a validated food frequency questionnaire and total ITC levels in a randomly-timed spot urine (16
). The absence of multiple time-point samples does not allow for the correction of regression dilution resulting from the within-person variation in ITC exposure across a wide spectrum of time, which was up to 16 years in the present study. Therefore, the reported inverse ITC-colorectal cancer association could well be underestimated. We did not collect information on intake of specific cruciferous vegetables at baseline, thus prohibiting the examination of dietary ITC in relation to colorectal cancer risk in this report. Although the inverse association between urinary ITC levels and colorectal cancer risk remained statistically significant after adjustment for multiple covariates, the possibility of residual confounding cannot be ruled out completely. Further studies are required to confirm the findings of the present study.
In summary, the present study demonstrates a statistically significant inverse association between levels of total ITCs in urine, collected 10 years before cancer diagnosis, and the risk of developing colorectal cancer. The present study confirms our earlier observation in Singapore Chinese and implicates ITCs as potential chemopreventive agents against the development of colorectal cancer in humans.