In our systematic review, which included 19 studies of the association between total cruciferous vegetable intake and lung cancer, we found a modest inverse association between cruciferous vegetable intake and lung cancer risk. Compared to those who consumed the least amount of cruciferous vegetables, the risk of lung cancer among those who consumed the most cruciferous vegetables was 23% lower in case-control studies (statistically significant) and 17% lower in prospective cohort studies (not statistically significant). Furthermore, case-control studies showed a significant inverse dose-response trend, although cohort studies provided only equivocal support for the presence of a dose-response trend. Intake of individual cruciferous vegetables (12 studies), such as broccoli and cabbage, was also inversely associated with lung cancer risk. These associations could not be explained by lack of adjustment for smoking in the original studies.
The summary estimates for case-control and cohort studies both provide evidence of an inverse association between cruciferous vegetable intake and lung cancer risk, but the association seen in cohort studies was slightly weaker and was not statistically significant. This may in part be due to the heterogeneity observed among the prospective cohort studies. A possible source of the heterogeneity in cohort studies may be the diverse populations studied. Of the six cohort studies, four were from the United States, and many of these were of unique study populations, such as white male life-insurance holders (15
), health professionals (30
), and asbestos-exposed, heavy smokers (29
). The levels of cruciferous vegetable intake, along with the prevalence of lung cancer risk factors, would be expected to range widely across these study populations. This could have introduced heterogeneity and attenuated the summary relative risk.
A unique characteristic of cruciferous vegetables is that they are a rich source of glucosinolates (53
). The anti-carcinogenic properties of cruciferous vegetables may be attributable to isothiocyanates derived specifically from glucosinolates (53
). Several experimental and mechanistic studies support a potential anti-cancer role of isothiocyanates (55
). Sulforaphane, an isothiocyanate found in broccoli, is involved in several pathways including induction of detoxifying genes, cell cycle control, and apoptosis; acting as an antioxidant (56
), and inhibiting histone deacetylase (57
). These experimental findings buttress the biologic plausibility of the association between cruciferous vegetable intake and lung cancer risk. However, the epidemiologic evidence considered in this systematic review does not allow inferences to pinpoint isothiocyanates as the key protective constituent of cruciferous vegetables as other nutrients and phytochemicals (e.g. folate, flavonols, and carotenoids) found in cruciferous vegetables may also be responsible for the protection against lung cancer.
Genetic factors related to isothiocyanate metabolism have been hypothesized to contribute to inter-individual differences in the degree of protection conferred by cruciferous vegetable consumption (58
). Specifically, individuals with GSTM1
null genotypes metabolize isothiocyanates less efficiently, permitting isothiocyanates to remain biologically active for a longer period (58
). In our meta-analysis, a gene-diet interaction was present; when stratified by GSTM1
variants, the inverse associations between cruciferous vegetable intake and lung cancer risk were more marked in those with the double null genotype. Corroborative findings were also reported in a nested case-control study carried out in China, in which the significant inverse association between urinary isothiocyanate levels and lung cancer risk was stronger among men with the GSTM1
double null genotype (8
). The only cohort study (20
) to report on the potential interaction between cruciferous vegetables and GSTM1
on lung cancer risk only presented partial results in the manuscript text, so could not be included in the formal meta-analyses, found no statistically significant interaction not for individuals with one functional allele or homozygous deletion (i.e. null). The presence of a potential gene-diet interaction adds internal consistency to the overall body of evidence on the association between cruciferous vegetables and lung cancer, and takes a step toward addressing the causal criteria of biologic plausibility and coherence. The genotype prevalences for GSTM1
homozygous deletion vary by race/ethnicity but range from 42-60% and 24-51%, respectively (60
), making this an important question to resolve due its public health relevance.
Any consideration of a dietary factor in relation to lung cancer needs to carefully evaluate the potential confounding role of cigarette smoking. Cigarette smoking is the principal cause of lung cancer and cigarette smokers tend to eat less healthful diets than nonsmokers (61
). Thus, even studies that statistically adjusted for cigarette smoking may show associations due to residual confounding (62
). The inverse association between cruciferous vegetable intake and lung cancer, however, was similar in studies limited to never smokers. Furthermore, residual confounding by smoking is unlikely to explain the interaction between cruciferous vegetable intake and GST
genotypes. A weakness of the evidence that comprises this systematic review is the measurement error inherent in the use of dietary questionnaires; in the retrospective case-control studies, the potential for recall bias due to cases and controls differential recall of dietary habits is a particular concern (63
). Furthermore, the association between cruciferous vegetables and lung cancer may differ depending on whether the vegetables are consumed raw or cooked, because this influences the bioavailability of isothiocyanates (64
). The lack of information about cooking methods is thus a potential source of heterogeneity in the results.
In this systematic review, higher intake of cruciferous vegetables was modestly inversely associated with lung cancer risk. The inverse association was stronger among individuals with the null genotype for both GSTM1 and GSTT1. Compared to case-control studies, the associations observed in cohort studies were weaker, were not statistically significant, and had more heterogeneity. Furthermore, the evidence for the gene-diet interaction is based only on case-control data. Consequently, additional cohort data are needed to help understand the lack of consistency in prospective studies and to provide a more precise estimate of the interaction between cruciferous vegetable intake and GST genotype.