In this case-control study nested in the Multiethnic Cohort Study, we found that an increased intake of cruciferous vegetables, as measured by urinary isothiocyanates, was associated with a decreased risk of colorectal cancer. When stratifying by GST
polymorphisms, there was the suggestion that the association was more pronounced among individuals with the GSTP1
GG or AG genotype, compared with individuals with the AA genotype. However, none of the findings in the stratified analyses were statistically significant. Our results are similar to those of two of the six previous studies that found no associations with the GSTM1
). Three of those six previous studies found suggestions of decreased risks of colorectal cancer or adenoma with increased intake of cruciferous vegetables or of isothiocyanates for individuals with a homozygous deletion of GSTM1
), or a combination of deletions of both GSTM1
), whereas the third found an increased risk of colorectal adenoma with higher cruciferous vegetable intake (22
Only two of these studies examined the possible interaction between cruciferous vegetable intake and GSTP1
polymorphisms in relation to colorectal cancer or adenomas. One found no association (20
) and the other found a positive association between colorectal adenoma risk and higher cruciferous vegetable intake among individuals with the low-activity GG genotype (22
The primary strength of this study is the assessment of the exposure, intake of cruciferous vegetables, with a biomarker that is more objective and less prone to systematic measurement error than self-report of diet. In a recent human cross-over feeding study in Denmark, it was shown that levels of isothiocyanates in the urine collected 48 hours after dietary intervention showed a strong dose response with amount of intake of cruciferous vegetables [r
) = 0.90, P
< 0.01; ref. 31
]. Moreover, although not many epidemiologic studies have been done using urinary isothiocyanates, a recent study in Shanghai found that increasing levels of urinary isothiocyanates were associated with a decreasing risk of breast cancer, but intake of cruciferous vegetables, as measured by a food frequency questionnaire, were not (25
). Similarly, another Shanghai study found an association between detectable urinary isothiocyanates and reduced risk of lung cancer, especially among those individuals with a homozygous deletion of both GSTM1
, whereas a similar analysis using estimated isothiocyanate intake was not possible due to the limited vegetable items on the dietary instrument (24
). In the present study, dietary intake of cruciferous vegetables is only mildly correlated with urinary isothiocyanates (Spearman correlation coefficient = 0.12, P
= 0.002), although one should note that diet was assessed on average 7 years before biospecimen collection. In a forthcoming report on vegetable intake and colorectal cancer risk in the entire Multiethnic Cohort Study, dietary intake of cruciferous vegetables was not significantly associated with colorectal cancer risk among men (RR of highest versus lowest quintile: 0.87; 95% CI, 0.71–1.08; P
for trend = 0.29) or women (RR of highest versus lowest quintile: 0.91; 95% CI, 0.73–1.14; P
for trend = 0.79; ref. 32
There are a number of limitations to the present study. It is possible that our population did not have a sufficiently high consumption of dietary isothiocyanates for us to detect a significant association with cancer risk, as the median urinary isothiocyanate level for all subjects in this study was 0.83 µmol/mg of creatinine (0.69 and 0.94 for cases and controls, respectively), compared with 1.71 for the Shanghai lung cancer study (24
); 1.71 and 2.31 for cases and controls, respectively, for the Shanghai breast cancer study (25
); and means of 2.32 and 2.75 for cases and controls, respectively, for a recent Shanghai colorectal cancer study (33
). Others have noted that Shanghai Chinese tend to consume 300% more cruciferous vegetables than Americans in Los Angeles (33
). The group with the largest intake in our population, Japanese Americans, had median isothiocyanate levels of about one third less than the Shanghai Chinese in the colorectal study.
Additionally, we were able to obtain only a one-time urinary sample, reflecting intake in the last 12 to 24 hours, and measurement during such a limited time period may not well reflect usual diet. However, a pilot study we conducted before the present study, wherein 3 overnight urine samples were collected more than 3 weeks from 20 volunteers, resulted in an intra-class correlation coefficient of 0.43 for urinary total isothiocyanates, suggesting its acceptability as a biomarker to study in association with colorectal cancer. The first-morning samples are potentially more problematic. However, when comparing the direct association of urinary isothiocyanate levels with risk of colorectal cancer in our population, the interaction between isothiocyanates and urinary collection method was not significantly different, although we found a slightly stronger reduction in risk for those with detectable isothiocyanates in their overnight samples than in the first-morning samples. Nonetheless, the issue of the representativeness of the biospecimen as a measure of long-term exposure would most likely result in an attenuation of the risk estimates rather than create a spurious association.
We also note that the median interval of time between collection of urine sample and diagnosis in the present study was short (1.4 years), whereas in the Shanghai colorectal cancer study, a significant association between urinary isothiocyanates and colorectal cancer risk was found only among those individuals from whom urine was collected 10 or more years before diagnosis (33
). Finally, the relatively small numbers of subjects in our study allowed us to detect only strong modifying effects of the GST
polymorphisms on the association between isothiocyanates and colorectal cancer risk and did not permit separate analyses for colon and rectal cancers.
In conclusion, these prospective findings add to the evidence for an inverse association between cruciferous vegetables and colorectal cancer risk by reporting that detectable urinary isothiocyanates are associated with a reduced risk of this malignancy. Significant interactions with the GSTM1, GSTT1, and GSTP1 polymorphisms were not found, but there was a weak suggestion of a further decrease in risk with increased urinary isothiocyanates for individuals with the GSTP1 AG or GG genotype.