Background: Cruciferous vegetables, rich in isothiocyanates, may protect against lung cancer. Glutathione S-transferases are important in metabolizing isothiocyanates; hence, variants in GST genes may modify the association between cruciferous vegetable intake and lung cancer. We carried out a systematic review to characterize the association between cruciferous vegetable intake and lung cancer risk, with an emphasis on the potential interaction between cruciferous vegetables and GSTM1 and GSTT1 gene variants.

Methods: A search of the epidemiologic literature through December 2007 was conducted using 15 bibliographic databases without language restrictions. Thirty studies on the association between lung cancer and either total cruciferous vegetable consumption (6 cohort and 12 case-control studies) or specific cruciferous vegetables (1 cohort and 11 case-control studies) were included.

Results: The risk for lung cancer among those in the highest category of total cruciferous vegetable intake was 22% lower in case-control studies [random-effects pooled odds ratio, 0.78; 95% confidence interval (95% CI), 0.70-0.88] and 17% lower in cohort studies (pooled relative risk, 0.83; 95% CI, 0.62-1.08) compared with those in the lowest category of intake. The strongest inverse association of total cruciferous vegetable intake with lung cancer risk was seen among individuals with GSTM1 and GSTT1 double null genotypes (odds ratio, 0.41; 95% CI, 0.26-0.65; P for interaction = 0.01).

Conclusions: Epidemiologic evidence suggests that cruciferous vegetable intake may be weakly and inversely associated with lung cancer risk. Because of a gene-diet interaction, the strongest inverse association was among those with homozygous deletion for GSTM1 and GSTT1. (Cancer Epidemiol Biomarkers Prev 2009;18(1):184–95)

Lung cancer is the leading worldwide cause of cancer death (1). Cigarette smoking accounts for ∼85% of the population burden of lung cancer in developed countries such as the United States, but selected dietary factors may modulate lung cancer risk (2). A major report of the World Cancer Research Fund and the American Institute for Cancer Research concluded that the evidence was “limited suggestive” that vegetable intake is inversely associated with lung cancer (3). However, the associations with lung cancer may vary according to the specific class of vegetable considered.

In particular, cruciferous vegetables (broccoli, cabbage, cauliflower, Brussels sprouts, kale) have been hypothesized to have anticancer properties that may contribute to reduced risk for lung cancer. Cruciferous vegetables are a rich source of isothiocyanates. Isothiocyanates may inhibit the bioactivation of procarcinogens found in tobacco smoke such as polycyclic aromatic hydrocarbons and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (ref. 4). Isothiocyanates may also enhance excretion of carcinogenic metabolites before they can damage DNA (5, 6). Furthermore, sulforaphane, a major isothiocyanate found in broccoli, can induce cell cycle arrest and apoptosis (6, 7).

The mammalian glutathione S-transferase (GST) is a superfamily of phase II genes that are broadly categorized into four classes: Alpha, Mu, Theta, and Pi (7). Each class consists of genes that encode a variety of isoenzymes (e.g., GSTA1, GSTM1, GSTT1, and GSTP1), which play an important role in xenobiotic metabolism (7), as well as isothiocyanate metabolism (8). Variants of several GSTs have been studied in relation to dietary isothiocyanate intake and cancer risk, but GSTM1 and GSTT1 are the two variants most frequently studied that may modify the association between cruciferous vegetable intake and lung cancer risk (6, 9). A common polymorphism in the GSTM1 and GSTT1 genes results in gene deletion, and individuals with homozygous deletions are devoid of the respective enzyme activity (7). Individuals with homozygous deletion of GSTM1, GSTT1, or both may metabolize isothiocyanates less efficiently and may be more intensely exposed to them after consumption of cruciferous vegetables. For this reason, individuals with the null GSTM1 or GSTT1 genotypes may have a lower risk for lung cancer when exposed to isothiocyanates (10-12).

There has been a rapid accumulation of epidemiologic evidence on the association between cruciferous vegetable intake and lung cancer (6, 9, 13). No systematic reviews have previously been conducted to thoroughly unify this information and formally assess this evidence. To address this information gap, we did a meta-analysis of the evidence on this topic, including the potential gene-diet interaction between cruciferous vegetable intake and GSTM1 and GSTT1.

This systematic review stemmed from a project funded by the World Cancer Research Fund–American Institute for Cancer Research to develop a report entitled “Food, Nutrition, Physical Activity and the Prevention of Cancer: a Global Perspective” (3). All work adhered to a standardized protocol developed by World Cancer Research Fund (http://www.wcrf.org/research/second_wcrf_aicr_report.lasso; ref. 3).

Search Strategy

For the World Cancer Research Fund report, we sought all evidence on the associations between dietary intake, physical activity, or anthropometric measures and lung cancer that were reported in randomized clinical trials, cohort studies, and case-control studies. We used the search strategy for dietary factors as described previously in (14), adapted for the outcome of lung carcinoma as described in ref. 15. The following electronic databases were searched: PubMed, Embase, Pascal, ISI Web of Science, the Cochrane Library, Biological Abstracts, Cumulative Index to Nursing and Allied Health Literature, National Institute on Alcohol Abuse and Alcoholism–Alcohol and Alcohol Problems Science Database, Agricola, CINAHL-EBSCOhost, Index Medicus for WHO Eastern Mediterranean Region, Index Medicus for South East Asian Region, and Latin American and Caribbean Center on Health Sciences Information. The search included all studies published up to April 2006. We also hand-searched references in the relevant review articles from the bibliographic database search and those cited in the 1997 World Cancer Research Fund report (2) or chosen for data abstraction. After this original search, we extended the PubMed search through December 2007. There were no language restrictions. If a published article was in a language that was beyond the expertise of our research team, World Cancer Research Fund had the article (16) translated into English.

Study Selection

The following exclusion criteria were applied to the screening of articles for the World Cancer Research Fund report: (a) no original data (reviews, editorials, meta-analyses); (b) studies not addressing the association between dietary intake, physical activity, or anthropometric measures and lung cancer; (c) studies not in humans; and (d) case reports and case series. The eligibility of each abstract or full-text article was assessed independently by two reviewers.

For the present report, we further limited the studies to those that reported on the association between cruciferous vegetable intake and lung cancer. Cruciferous vegetables were measured in different ways, including (a) total cruciferous vegetable intake, (b) total isothiocyanate intake, and (c) intake of specific individual cruciferous vegetables (e.g., broccoli, cabbage, or cauliflower). When measures of association or variability were not reported or could not be calculated using the data provided, we excluded the articles from the formal meta-analysis but discussed the findings of the article qualitatively. We made no systematic effort to contact authors. If separate reports from the same study were published, the report with the most updated data was selected for inclusion.

Data Abstraction. For each eligible article, two reviewers abstracted the data into an electronic database created by World Cancer Research Fund. The data abstraction was done serially, with any disagreements between reviewers resolved by consensus. Each reviewer classified the vegetables studied in each article into classes (e.g., cruciferous vegetables, Allium vegetables) according to the World Cancer Research Fund protocol (3). If a specific vegetable was not listed in the protocol, a nutritionist (L.E. Caulfield) assigned the appropriate vegetable subgroup. In the World Cancer Research Fund protocol, broccoli, cabbage, turnip or mustard greens, kale, sauerkraut, and cauliflower were classified as cruciferous vegetables. One article (17) reported the results from two different cohort studies; we treated the studies as unique, and our reviewers abstracted the data for each study separately.

To assess study quality, we adapted the criteria used by Longnecker et al. (18) for observational studies.

Statistical Analysis

The primary quantitative analyses focused on total dietary intake of cruciferous vegetables. Total cruciferous vegetable consumption was typically defined as a combination of at least three cruciferous vegetables, which usually included broccoli and cabbage plus other cruciferous vegetables. We also analyzed the associations between specific cruciferous vegetables and lung cancer risk. Separate meta-analyses were conducted for case-control and prospective cohort studies, by smoking status (never smokers or ever smokers) and by ethnicity (Western or Asian).

Studies varied in how frequency of cruciferous vegetable intake was measured, either as “times eaten” or “servings.” Thus, the pooled estimates entailed combining results of studies based on either the number of times eaten or servings. This is a potential source of heterogeneity across studies. Furthermore, the time units ranged from amount consumed per week to per month.

For all studies, odds ratios or relative risks and their respective 95% confidence intervals (95% CI) were abstracted. When a study reported several relative risk estimates, we abstracted the one adjusted for the most covariates. Two studies investigated the interaction between isothiocyanates and genotypes of GSTM1 and GSTT1 but did not report estimates for the main effects association between dietary isothiocyanate intake and lung cancer risk (19, 20). For these studies, we used the raw data presented in the articles to calculate the unadjusted odds ratios and 95% CIs. Meta-analyses were done with and without these studies included. Pooled odds ratio and relative risk estimates were obtained using inverse-variance weights in random effects models. Statistical heterogeneity was assessed using the DerSimonian and Laird's Q statistic and the I2 statistic.

Sensitivity analyses to examine the influence of each individual study were conducted by excluding each study from the meta-analysis and comparing the point estimates including and excluding the study. Metaregression was used to explore for sources of heterogeneity. Publication bias was examined using funnel plots.

When sufficient data were presented in the original publication (≥3 exposure categories of intake frequency along with the numbers of cases and controls within each category), we assessed for the presence of a dose-response trend (21). For the dose-response analyses, we converted all results to amount consumed per day.

To assess for interaction between GST genotypes and cruciferous vegetable intake on the risk for lung cancer, we estimated the association between total cruciferous vegetable intake and lung cancer stratified by GSTM1 and GSTT1 status. With the exception of one cohort study (22) that used a genotyping assay that could differentiate between three GSTM1 and GSTT1 genotypes, two possible genotypes (present and null) were reported for GSTM1 and GSTT1 in all case-control studies. Data analyses were thus stratified as follows: GSTM1 present or null, GSTT1 present or null, and GSTM1/GSTT1 double present or double null. Only one study reported results for GSTM1/GSTT1 null/present or present/null genotypes, so this category was not included in the meta-analyses. We tested for within-study effect modification by GST genotype by calculating the difference in (log) odds ratios between GST subgroups within each study (23, 24). We then obtained a summary interaction P value by pooling these differences across studies.

Search Results

We identified 37 studies that quantified the association between cruciferous vegetable consumption and lung cancer risk (Fig. 1). Of these, we excluded three early reports from studies that subsequently published updated data (25, 26) or with larger sample size (27), two that reported on individual cruciferous vegetables but did not report the total number of cases (28, 29), one that reported on interaction between cruciferous vegetables and GST genes reported genotyping data that were not comparable and did not provide sufficient data to calculate SEs to be included in the meta-analysis (22), and one that reported only on a biomarker (rather than dietary intake) of isothiocyanates (10). Of the 30 studies included in the meta-analyses, 18 studies [6 cohort (17, 30-33) and 12 case-control (16, 19, 20, 34-42)] reported on total cruciferous vegetable intake. One cohort study (43) and 11 case-control studies (44-54) reported on intake of individual cruciferous vegetables. Quality assessment for the studies reported on total cruciferous consumption and lung cancer is summarized in Supplemental Fig. 1.

Figure 1.

Study selection process.

Figure 1.

Study selection process.

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Total Cruciferous Vegetables

Six prospective cohort studies (Table 1) and 12 case-control studies (Table 2), representing a total of 8,227 lung cancer cases, reported associations between total cruciferous vegetable intake and lung cancer risk. The studies were carried out in Europe (8 studies; refs. 16, 30, 31, 35, 37, 39-41), the United States (6 studies; refs. 17, 19, 20, 32, 33), Asia (2 studies; refs. 34, 38), Canada (1 study; ref. 42), and Australia (1 study; ref. 36). The duration of follow-up ranged from 4 to 12 years in the six prospective cohort studies (17, 30-33). All prospective studies adjusted for smoking status. Of the 12 case-control studies, 5 were confined to never smokers (34, 37, 39, 41, 42). Of the seven studies that included ever smokers, five reported odds ratios adjusted for smoking (16, 35, 36, 38, 40). The remaining two (19, 20) were studies that examined GST-diet interaction and thus estimates for the association between dietary isothiocyanates, and lung cancer risk were calculated unadjusted estimates based on published numbers of cases and controls.

Table 1.

Characteristics of cohort studies reporting relative risks and 95% CIs for the association between total cruciferous vegetable consumption (highest versus lowest category) and lung cancer incidence

Reference (study name, y)Country studyFollow-up (y)SexAge (at recruitment)No. of casesSize of cohortCase ascertainmentType of dietary questionnaireTotal CVs measured as cabbage, cauliflower, and Brussels sprouts plus
(33) Chow (LBIS, 1992) US 11.5 35+ 219 17,633 Death certificates FFQ Not specified 
(17) Feskanich (NHS, 2000) US 12 30-55 519 121,700 Pathology FFQ Broccoli, coleslaw/sauerkraut 
(17) Feskanich (HPFS, 2000) US 10 40-75 274 51,529 Medical records FFQ Broccoli, coleslaw/sauerkraut 
(31) Voornips (NCS, 2000)* Netherlands F/M N/A 1,010 3,500 Pathology and cancer registries FFQ Kale 
(32) Neuhouser (CARET, 2003) US (heavy smokers) F/M N/A 326 7,048 Pathology and clinical records FFQ Broccoli, coleslaw, sauerkraut, mustard greens, turnip greens, and collards 
(30) Miller (EPIC, 2004) Europe F/M 25-70 860 482,924 Histology, pathology, and cancer registries FFQ Broccoli 
Reference (study name, y)Country studyFollow-up (y)SexAge (at recruitment)No. of casesSize of cohortCase ascertainmentType of dietary questionnaireTotal CVs measured as cabbage, cauliflower, and Brussels sprouts plus
(33) Chow (LBIS, 1992) US 11.5 35+ 219 17,633 Death certificates FFQ Not specified 
(17) Feskanich (NHS, 2000) US 12 30-55 519 121,700 Pathology FFQ Broccoli, coleslaw/sauerkraut 
(17) Feskanich (HPFS, 2000) US 10 40-75 274 51,529 Medical records FFQ Broccoli, coleslaw/sauerkraut 
(31) Voornips (NCS, 2000)* Netherlands F/M N/A 1,010 3,500 Pathology and cancer registries FFQ Kale 
(32) Neuhouser (CARET, 2003) US (heavy smokers) F/M N/A 326 7,048 Pathology and clinical records FFQ Broccoli, coleslaw, sauerkraut, mustard greens, turnip greens, and collards 
(30) Miller (EPIC, 2004) Europe F/M 25-70 860 482,924 Histology, pathology, and cancer registries FFQ Broccoli 

Abbreviations: US, United States; FFQ, food frequency questionnaire; N/A, unknown; M, male; F, female; LBIS, Lutheran Brotherhood Insurance Society; NHS, Nurse's Health Study; HPFS, Health Professional Follow-up Study; NCS, Netherlands Cohort Study on Diet and Cancer; EPIC, European Prospective Investigation into Cancer and Nutrition; CARET, β-Carotene and Retinol Efficacy Trial; and CV, cruciferous vegetable.

*

Case-cohort study (N of subcohort = 3500).

Table 2.

Characteristics of case-control studies reporting odd ratios and 95% CIs for the association between total cruciferous vegetable consumption (highest versus lowest category) and lung cancer risk, without stratification by GST status

Reference (y)Country studySource of controlsCases/controlsSexAge (mean)Case ascertainmentType of dietary questionnaireTotal CVs measured as broccoli, cabbage, and plus
(34) Koo (1988) Hong Kong Unknown (never smokers) 88/137 N/R (58) Histology FFQ Nonspecific 
(36) Pierce (1989) Australia: Melbourne Hospital 71/71 N/R (67) Histology and cytology Dietary questions Brussels sprouts 
(35) Agudo (1997) Spain Hospital 103/206 F/M 32-88 (63) Histology FFQ Cauliflower 
(37) Nyberg(1998) Sweden Hospital (never smokers) 124/235 F/M 30-80 (N/R) Histology and cytology FFQ Cauliflower 
(41) Brennan (2000) Europe: Sweden, Germany, France, Spain, UK, and Italy Hospital (never smokers) 506/1,045 F/M N/R Histology FFQ Kale, cauliflower 
(19) Spitz (2000) US Insurance registry (ever smokers) 503/465 F/M N/R (61) Histology FFQ Cauliflower, Brussels sprouts, kale, sauerkraut, mustard greens, turnip greens, collard greens 
(38) Zhao (2001) Asia: Singapore Hospital 233/187 N/R (64) Pathology FFQ Cauliflower, Chinese white/flowering cabbage, Chinese mustard, watercress, Chinese kale 
(39) Lewis (2002) Europe and South America N/R (never smokers) 122/123 F/M 18-85 (59) Histology FFQ Cauliflower 
(16) Caicoya (2002) Europe: Spain Hospital 197/196 F/M N/R Pathology and cytology FFQ Brussels sprouts 
(46) Hu (2002) Canada Population (never smokers) 161/483 20-70+ (N/R) Histology FFQ  
(20) Wang (2004) US Hospital; friends and non–blood related family members 716/939 F/M 18-85 (59) Histology FFQ Coleslaw/sauerkraut, cauliflower, Brussels sprouts, kale/mustard greens 
(40) Brennan (2005) Europe: Poland, Slovakia, Czech Republic, Romania, Russia, and Hungary Hospital and population 2,141/2,168 F/M N/R N/R FFQ Brussels sprouts 
Reference (y)Country studySource of controlsCases/controlsSexAge (mean)Case ascertainmentType of dietary questionnaireTotal CVs measured as broccoli, cabbage, and plus
(34) Koo (1988) Hong Kong Unknown (never smokers) 88/137 N/R (58) Histology FFQ Nonspecific 
(36) Pierce (1989) Australia: Melbourne Hospital 71/71 N/R (67) Histology and cytology Dietary questions Brussels sprouts 
(35) Agudo (1997) Spain Hospital 103/206 F/M 32-88 (63) Histology FFQ Cauliflower 
(37) Nyberg(1998) Sweden Hospital (never smokers) 124/235 F/M 30-80 (N/R) Histology and cytology FFQ Cauliflower 
(41) Brennan (2000) Europe: Sweden, Germany, France, Spain, UK, and Italy Hospital (never smokers) 506/1,045 F/M N/R Histology FFQ Kale, cauliflower 
(19) Spitz (2000) US Insurance registry (ever smokers) 503/465 F/M N/R (61) Histology FFQ Cauliflower, Brussels sprouts, kale, sauerkraut, mustard greens, turnip greens, collard greens 
(38) Zhao (2001) Asia: Singapore Hospital 233/187 N/R (64) Pathology FFQ Cauliflower, Chinese white/flowering cabbage, Chinese mustard, watercress, Chinese kale 
(39) Lewis (2002) Europe and South America N/R (never smokers) 122/123 F/M 18-85 (59) Histology FFQ Cauliflower 
(16) Caicoya (2002) Europe: Spain Hospital 197/196 F/M N/R Pathology and cytology FFQ Brussels sprouts 
(46) Hu (2002) Canada Population (never smokers) 161/483 20-70+ (N/R) Histology FFQ  
(20) Wang (2004) US Hospital; friends and non–blood related family members 716/939 F/M 18-85 (59) Histology FFQ Coleslaw/sauerkraut, cauliflower, Brussels sprouts, kale/mustard greens 
(40) Brennan (2005) Europe: Poland, Slovakia, Czech Republic, Romania, Russia, and Hungary Hospital and population 2,141/2,168 F/M N/R N/R FFQ Brussels sprouts 

NOTE: Bolded studies reported odd ratios and 95% CIs stratified by GST status.

Abbreviations: N/R, not reported; Ctrls, controls.

Compared with those in the lowest categories of total cruciferous vegetable intake, the risk for lung cancer among those in the highest consumption categories was 22% lower (random-effects pooled odds ratio, 0.78; 95% CI, 0.70-0.88; P heterogeneity = 0.53; I2 = 0%) in case-control studies and 17% lower in cohort studies (pooled relative risk, 0.83; 95% CI, 0.62-1.08; P heterogeneity = 0.02; I2 = 62.8%; Fig. 2). With the exclusion of the two case-control studies (19, 20) whose unadjusted odds ratios and confidence intervals were calculated from published data, the pooled odds ratio was attenuated only slightly at 0.81 (95% CI, 0.70-0.94; P heterogeneity = 0.48; I2 = 0%). Likewise, the results were the same when restricted to studies on never smokers (refs. 20, 34, 35, 37-42; pooled odds ratio, 0.78; 95% CI, 0.64-0.95; P heterogeneity = 0.54; I2 = 0%; Fig. 3).

Figure 2.

Forest plot of highest versus lowest category of total cruciferous vegetable or isothiocyanate content consumption and lung cancer risk in cohort and case-control studies.

Figure 2.

Forest plot of highest versus lowest category of total cruciferous vegetable or isothiocyanate content consumption and lung cancer risk in cohort and case-control studies.

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Figure 3.

Forest plot of highest versus lowest category of total cruciferous vegetable or isothiocyanate content consumption and lung cancer risk among never smokers.

Figure 3.

Forest plot of highest versus lowest category of total cruciferous vegetable or isothiocyanate content consumption and lung cancer risk among never smokers.

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All prospective cohort and 10 case-control studies reported at least three categories of total cruciferous vegetable intake (Table 3). Of the six prospective cohort studies, three studies were compatible with an inverse dose-response association between cruciferous vegetable intake and lung cancer risk (17, 31, 32), whereas three others showed no evidence of a dose-response trend (17, 30, 33). Eight case-control studies provided dose-response data in sufficient detail to be included in dose-response meta-analysis. The pooled odds ratio for lung cancer associated with an increase of one cruciferous vegetable serving per day was 0.74 (95% CI, 0.73-0.75). Two additional case-control studies (20, 35) reported frequency of intake (that is, low, medium, high) that could not be combined with the other studies. Of the two studies, one (35) was compatible with a decrease in lung cancer risk with increasing consumption of cruciferous vegetables whereas the other (20) showed no discernable pattern.

Table 3.

Results of studies examining the association between total cruciferous vegetable intake and lung cancer using more than two categories of vegetable intake (dose-response analyses)

Reference (y)Types of CV examinedIntake frequencyCases/controls*OR (95% CI)P for trendMatched/adjusted variables
ABCO
Cohort studies          
(33) Chow (LBIS, 1992) Not specified <2 Times/mo 43/58,455* 1.0 (ref) N/R √  √ √ 
  2-4 Times/mo 112/146,730* 0.9 (0.6-1.3)      
  5-8 Times/mo 46/56,035* 1.0 (0.7-1.5)      
  >8 Times/mo 18/25,861* 0.8 (0.5-1.4)      
          
(17) Feskanich (NHS, 2000) Cabbage, cauliflower, and Brussels sprouts, broccoli, coleslaw/sauerkraut 0-1.3 Servings/wk N/R 1.0 (ref) N/R √  √ √ 
  1.4-2.2 Servings/wk  0.80 (0.62-1.05)      
  2.3-3.2 Servings/wk  0.85 (0.65-1.12)      
  3.3-4.8 Servings/wk  0.76 (0.57-1.01)      
  >4.8 Servings/wk  0.74 (0.55-0.99)      
          
(17) Feskanich (HPFS, 2000) Cabbage, cauliflower, and Brussels sprouts, broccoli, coleslaw/sauerkraut 0-1.3 Servings/wk N/R 1.0 (ref) N/R √  √ √ 
  1.4-2.1 Servings/wk  1.12 (0.76-1.64)      
  2.2-3.3. servings/wk  1.05 (0.72-1.53)      
  3.4-5.0 Servings/wk  0.86 (0.57-1.30)      
  >5.0 Servings/wk  1.11 (0.76-1.64)      
          
(31) Voornips (NCS, 2000) Cabbage, cauliflower, and Brussels sprouts, kale ≤1 Time/mo 52/598* 1.0 (ref) 0.003 √ √ √ √ 
  2-3 Times/mo 150/2,713* 0.7 (0.4-1.1)      
  4 Times/mo 347/6,676* 0.6 (0.4-0.9)      
  8 Times/mo 308/6,085* 0.5 (0.4-0.8)      
  ≥12 Times/mo 53/988* 0.5 (0.3-0.9)      
          
(32) Neuhouser (CARET, 2003) Cabbage, cauliflower, and Brussels sprouts, broccoli, coleslaw, sauerkraut, mustard greens, turnip greens, and collards ≤0.5 Servings/wk N/R 1.0 (ref) 0.01 √ √ √ √ 
  0.6-1.2 Servings/wk  1.36 (0.98-1.88)      
  1.3-1.9 Servings/wk  0.89 (0.62-1.27)      
  2.0-3.4 Servings/wk  0.96 (0.67-1.39)      
  ≥3.5 Servings/wk  0.68 (0.45-1.04)      
          
(30) Miller (EPIC, 2004) Cabbage, cauliflower, and Brussels sprouts, and broccoli Q1 N/R 1.0 (ref) 0.25   √ √ 
  Q2  1.13 (0.89-1.43)      
  Q3  1.21 (0.94-1.55)      
  Q4  1.11 (0.87-1.43)      
  Q5  1.21 (0.92-1.60)      
          
Case-control studies          
(34) Koo (1988) Total CV: nonspecific Never to <1 time/mo 88/137 1.0 (ref) 0.36 √    
  1-3 Times/mo  1.3 (0.64-1.99)      
  ≥4 Times/mo  0.75 (0.28-2.00)      
          
(36) Pierce (1989) Total CV: Broccoli, cabbage, and Brussels sprouts Never to 1 time/mo 7/5 1.0 (ref) 0.23     
  1-5 Times/wk 21/43 0.35 (0.1-1.23)      
  ≥7 Times/wk 43/23 1.34 (0.38-4.68)      
          
(35) Agudo (1997) Total CV: Broccoli, cabbage, and cauliflower Low N/R 1.0 (ref) 0.13 √  √ √ 
  Medium N/R 0.93 (0.52-1.66)      
  High N/R 0.54 (0.26-1.13)      
          
(37) Nyberg (1998) Total CV: Broccoli, cabbage, and cauliflower <Weekly 49/81 1.0 (ref) 0.33 √ √  √ 
  1 Time weekly 28/66 0.79 (0.42-1.52)      
  >1 Time weekly 47/88 1.06 (0.58-1.92)      
          
(41) Brennan (2000) Total CV: Broccoli, cabbage/kale, and cauliflower Never to <weekly 200/382 1.0 (ref) 0.76 √ √  √ 
  <Weekly to weekly 111/234 1.0 (0.7-1.3)      
  >1 Time weekly to daily 113/254 1.1 (0.7-1.6)      
          
(39) Lewis (2002)§ Total CV: Broccoli, cabbage, and cauliflower <0.9 Portion/mo 54/51 1.0 (ref) 0.35 √ √  √ 
  1-4 Portions/mo 37/53 0.58 (0.26-1.32)      
  >4 Portion/mo 31/19 0.64 (0.25-1.67)      
          
(42) Hu (2002) Total CV: Broccoli and cabbage ≤0.9 Servings/wk 44/110 1.0 (ref) 0.43 √   √ 
  1-2 Servings/wk 50/155 0.7 (0.4-1.3)      
  2.1-6.0 Servings/wk 32/101 0.7 (0.4-1.4)      
  >6 Servings/wk 33/112 0.8 (0.4-1.4)      
          
(20) Wang (2004)§ Total CV: Broccoli, cabbage/coleslaw/sauerkraut, cauliflower, Brussels sprouts, kale/mustard greens Low 294/329 1.0 (ref) N/R  
  Medium 198/296 0.75 (0.59-0.95)      
  High 224/314 0.80 (0.63-1.01)      
          
(40) Brennan (2005)§ Total CV: Broccoli, cabbage, and Brussels sprouts <1 Time monthly 327/250 1 (ref) N/R √ √ √ √ 
  1 Time weekly 677/754 0.77 (0.62-0.95)      
  ≥1 Time weekly 1,137/1,164 0.78 (0.64-0.96)      
Reference (y)Types of CV examinedIntake frequencyCases/controls*OR (95% CI)P for trendMatched/adjusted variables
ABCO
Cohort studies          
(33) Chow (LBIS, 1992) Not specified <2 Times/mo 43/58,455* 1.0 (ref) N/R √  √ √ 
  2-4 Times/mo 112/146,730* 0.9 (0.6-1.3)      
  5-8 Times/mo 46/56,035* 1.0 (0.7-1.5)      
  >8 Times/mo 18/25,861* 0.8 (0.5-1.4)      
          
(17) Feskanich (NHS, 2000) Cabbage, cauliflower, and Brussels sprouts, broccoli, coleslaw/sauerkraut 0-1.3 Servings/wk N/R 1.0 (ref) N/R √  √ √ 
  1.4-2.2 Servings/wk  0.80 (0.62-1.05)      
  2.3-3.2 Servings/wk  0.85 (0.65-1.12)      
  3.3-4.8 Servings/wk  0.76 (0.57-1.01)      
  >4.8 Servings/wk  0.74 (0.55-0.99)      
          
(17) Feskanich (HPFS, 2000) Cabbage, cauliflower, and Brussels sprouts, broccoli, coleslaw/sauerkraut 0-1.3 Servings/wk N/R 1.0 (ref) N/R √  √ √ 
  1.4-2.1 Servings/wk  1.12 (0.76-1.64)      
  2.2-3.3. servings/wk  1.05 (0.72-1.53)      
  3.4-5.0 Servings/wk  0.86 (0.57-1.30)      
  >5.0 Servings/wk  1.11 (0.76-1.64)      
          
(31) Voornips (NCS, 2000) Cabbage, cauliflower, and Brussels sprouts, kale ≤1 Time/mo 52/598* 1.0 (ref) 0.003 √ √ √ √ 
  2-3 Times/mo 150/2,713* 0.7 (0.4-1.1)      
  4 Times/mo 347/6,676* 0.6 (0.4-0.9)      
  8 Times/mo 308/6,085* 0.5 (0.4-0.8)      
  ≥12 Times/mo 53/988* 0.5 (0.3-0.9)      
          
(32) Neuhouser (CARET, 2003) Cabbage, cauliflower, and Brussels sprouts, broccoli, coleslaw, sauerkraut, mustard greens, turnip greens, and collards ≤0.5 Servings/wk N/R 1.0 (ref) 0.01 √ √ √ √ 
  0.6-1.2 Servings/wk  1.36 (0.98-1.88)      
  1.3-1.9 Servings/wk  0.89 (0.62-1.27)      
  2.0-3.4 Servings/wk  0.96 (0.67-1.39)      
  ≥3.5 Servings/wk  0.68 (0.45-1.04)      
          
(30) Miller (EPIC, 2004) Cabbage, cauliflower, and Brussels sprouts, and broccoli Q1 N/R 1.0 (ref) 0.25   √ √ 
  Q2  1.13 (0.89-1.43)      
  Q3  1.21 (0.94-1.55)      
  Q4  1.11 (0.87-1.43)      
  Q5  1.21 (0.92-1.60)      
          
Case-control studies          
(34) Koo (1988) Total CV: nonspecific Never to <1 time/mo 88/137 1.0 (ref) 0.36 √    
  1-3 Times/mo  1.3 (0.64-1.99)      
  ≥4 Times/mo  0.75 (0.28-2.00)      
          
(36) Pierce (1989) Total CV: Broccoli, cabbage, and Brussels sprouts Never to 1 time/mo 7/5 1.0 (ref) 0.23     
  1-5 Times/wk 21/43 0.35 (0.1-1.23)      
  ≥7 Times/wk 43/23 1.34 (0.38-4.68)      
          
(35) Agudo (1997) Total CV: Broccoli, cabbage, and cauliflower Low N/R 1.0 (ref) 0.13 √  √ √ 
  Medium N/R 0.93 (0.52-1.66)      
  High N/R 0.54 (0.26-1.13)      
          
(37) Nyberg (1998) Total CV: Broccoli, cabbage, and cauliflower <Weekly 49/81 1.0 (ref) 0.33 √ √  √ 
  1 Time weekly 28/66 0.79 (0.42-1.52)      
  >1 Time weekly 47/88 1.06 (0.58-1.92)      
          
(41) Brennan (2000) Total CV: Broccoli, cabbage/kale, and cauliflower Never to <weekly 200/382 1.0 (ref) 0.76 √ √  √ 
  <Weekly to weekly 111/234 1.0 (0.7-1.3)      
  >1 Time weekly to daily 113/254 1.1 (0.7-1.6)      
          
(39) Lewis (2002)§ Total CV: Broccoli, cabbage, and cauliflower <0.9 Portion/mo 54/51 1.0 (ref) 0.35 √ √  √ 
  1-4 Portions/mo 37/53 0.58 (0.26-1.32)      
  >4 Portion/mo 31/19 0.64 (0.25-1.67)      
          
(42) Hu (2002) Total CV: Broccoli and cabbage ≤0.9 Servings/wk 44/110 1.0 (ref) 0.43 √   √ 
  1-2 Servings/wk 50/155 0.7 (0.4-1.3)      
  2.1-6.0 Servings/wk 32/101 0.7 (0.4-1.4)      
  >6 Servings/wk 33/112 0.8 (0.4-1.4)      
          
(20) Wang (2004)§ Total CV: Broccoli, cabbage/coleslaw/sauerkraut, cauliflower, Brussels sprouts, kale/mustard greens Low 294/329 1.0 (ref) N/R  
  Medium 198/296 0.75 (0.59-0.95)      
  High 224/314 0.80 (0.63-1.01)      
          
(40) Brennan (2005)§ Total CV: Broccoli, cabbage, and Brussels sprouts <1 Time monthly 327/250 1 (ref) N/R √ √ √ √ 
  1 Time weekly 677/754 0.77 (0.62-0.95)      
  ≥1 Time weekly 1,137/1,164 0.78 (0.64-0.96)      

NOTE: Matched or adjusted variables: A = age; B = sex; C = smoking status or exposure; and O = other.

Abbreviations: OR, odds ratio; ref, reference.

*

Person-years for cohort studies.

Never smokers only.

Odds ratio and 95% CI calculated from published data using EpiCalc 2000.

§

Bolded studies reported odds ratios and 95% CIs stratified by GST status.

Broccoli and cabbage as individual cruciferous vegetables were also inversely associated with lung cancer risk. In data generated from case-control studies, the pooled odds ratios for lung cancer risk comparing the highest versus lowest categories of intake were 0.53 (95% CI, 0.34-0.83; P heterogeneity = 0.14; I2 = 43.0%) for broccoli (42, 45, 47-49) and 0.70 (95% CI, 0.54-0.91; P heterogeneity = 0.02; I2 = 54.9%) for cabbage (40, 42-44, 46, 51-54).

Results Stratified by GST Genotypes

Five case-control studies (refs. 19, 20, 38-40; n = 3,715 lung cancer cases) reported on the association between cruciferous vegetable consumption and lung cancer risk stratified by GSTM1 and/or GSTT1 genotypes (Table 4). Of these, one reported only on GSTM1 (39), whereas four assessed GSTM1 and GSTT1 (19, 20, 38, 40). Cruciferous vegetable consumption was measured by food frequency questionnaire in all five studies, and exposure was quantified either as intake of isothiocyanates (n = 2 studies; refs. 19, 39) or of total cruciferous vegetables (n = 3 studies; refs. 20, 38, 40).

Table 4.

Evidence table of case-control studies reporting odds ratios and 95% confidence limits for the association between total cruciferous vegetable or isothiocyanate content consumption (highest versus lowest category) and lung cancer risk, stratified by GST status

StudyCases/controlsExposureIntake frequencyGSTM1 null
GSTT1 null
GST statusOR (95% CI)
CasesControlsCasesControlsPresentNull
(19) Spitz, 2000           
 503/465 Dietary ITC* intake ≤Median 246 (49.4) 226 (48.8) 132 (27.3) 104 (22.7) GSTM1 0.56 (0.38-0.82) 0.81 (0.55-1.19) 
   >Median     GSTT1 0.69 (0.50-0.94) 0.53 (0.31-0.91) 
        GSTM1&T1 0.67 (0.50-0.89) 0.46 (0.20-1.04) 
(38) Zhao, 2001           
 233/187 Dietary ITC* intake ≤Median 146 (62.7) 119 (63.6) 132 (56.7) 102 (54.5) GSTM1 0.78 (0.39-1.59) 0.55 (0.33-0.93) 
   >Median     GSTT1 0.75 (0.40-1.40) 0.54 (0.310.95) 
        GSTM1/T1 0.69 (0.41-1.17) 0.47 (0.23-0.95) 
(39) Lewis, 2002           
 122/123 Dietary CV intake <1/mo 65 (53.3) 53 (43.1) N/A N/A GSTM1 0.65 (0.16-2.66) 0.27 (0.06-1.33) 
   >4/mo        
(20) Wang, 2004           
 716/939 Dietary CVs intake Low 404 (56.4) 516 (55.0) 138 (19.4) 185 (19.8) GSTM1 0.61 (0.39-0.95)§ 1.15 (0.78-1.68)§ 
   High     GSTT1 0.87 (0.63-1.21)§ 0.81 (0.42-1.51)§ 
        GSTM1&T1 0.67 (0.54-0.82)§ 0.70 (0.391.26)§ 
(40) Brennan, 2005           
 2,141/2,168 Dietary CV intake <1 Time/mo 1,022 (47.7) 986 (45.4) 340 (15.8) 344 (15.8) GSTM1 0.89 (0.67-1.18) 0.67 (0.49-0.91) 
   ≥4 Times/mo     GSTT1 0.83 (0.66-1.03) 0.63 (0.37-1.07) 
        GSTM1&T1 0.88 (0.65-1.21) 0.28 (0.11-0.67) 
StudyCases/controlsExposureIntake frequencyGSTM1 null
GSTT1 null
GST statusOR (95% CI)
CasesControlsCasesControlsPresentNull
(19) Spitz, 2000           
 503/465 Dietary ITC* intake ≤Median 246 (49.4) 226 (48.8) 132 (27.3) 104 (22.7) GSTM1 0.56 (0.38-0.82) 0.81 (0.55-1.19) 
   >Median     GSTT1 0.69 (0.50-0.94) 0.53 (0.31-0.91) 
        GSTM1&T1 0.67 (0.50-0.89) 0.46 (0.20-1.04) 
(38) Zhao, 2001           
 233/187 Dietary ITC* intake ≤Median 146 (62.7) 119 (63.6) 132 (56.7) 102 (54.5) GSTM1 0.78 (0.39-1.59) 0.55 (0.33-0.93) 
   >Median     GSTT1 0.75 (0.40-1.40) 0.54 (0.310.95) 
        GSTM1/T1 0.69 (0.41-1.17) 0.47 (0.23-0.95) 
(39) Lewis, 2002           
 122/123 Dietary CV intake <1/mo 65 (53.3) 53 (43.1) N/A N/A GSTM1 0.65 (0.16-2.66) 0.27 (0.06-1.33) 
   >4/mo        
(20) Wang, 2004           
 716/939 Dietary CVs intake Low 404 (56.4) 516 (55.0) 138 (19.4) 185 (19.8) GSTM1 0.61 (0.39-0.95)§ 1.15 (0.78-1.68)§ 
   High     GSTT1 0.87 (0.63-1.21)§ 0.81 (0.42-1.51)§ 
        GSTM1&T1 0.67 (0.54-0.82)§ 0.70 (0.391.26)§ 
(40) Brennan, 2005           
 2,141/2,168 Dietary CV intake <1 Time/mo 1,022 (47.7) 986 (45.4) 340 (15.8) 344 (15.8) GSTM1 0.89 (0.67-1.18) 0.67 (0.49-0.91) 
   ≥4 Times/mo     GSTT1 0.83 (0.66-1.03) 0.63 (0.37-1.07) 
        GSTM1&T1 0.88 (0.65-1.21) 0.28 (0.11-0.67) 

NOTE: Highest versus lowest (reference group).

Abbreviation: ITC, isothiocyanate content, cv; cruciferous vegetables; N/A, not applicable.

*

Isothiocyanate contents estimated from dietary intake of cruciferous vegetables.

GSTM1&T1 is GSTM1 and GSTT1.

GSTM1/T1 is GSTM1 or GSTT1.

§

Odds ratio and 95% CI calculated from published data using EpiCalc 2000.

In these five studies, the pooled odds ratio of lung cancer for the highest versus lowest category of cruciferous vegetable intake was 0.74 (95% CI, 0.66-0.84; Fig. 4). When stratified by genotype, the inverse association between cruciferous vegetable intake and lung cancer was stronger in those who were null for GSTM1 and GSTT1 (pooled odds ratio, 0.41; 95% CI, 0.26-0.65; P heterogeneity = 0.64; I2 = 0) than in those with the GSTM1 and GSTT1 present genotype (odds ratio, 0.75; 95% CI, 0.62-0.91; P heterogeneity = 0.43; I2 = 0). This gene-diet interaction was statistically significant (P for interaction = 0.01). In the lone study to characterize the association between cruciferous vegetables and lung cancer among those with GSTM1 present/GSTT1 null or GSTM1 null/ GSTT1 present genotypes, the highest versus lowest intake of cruciferous vegetables was associated with a nonsignificant 20% reduction (odds ratio, 0.80; 95% CI, 0.60-1.08) in lung cancer risk (40), an association more similar to that among those with the double present genotypes (odds ratio, 0.88; 95% CI, 0.65-1.21) than among those with the double null genotypes (odds ratio, 0.28; 95% CI, 0.11-0.67).

Figure 4.

Forest plot of highest versus lowest category of total cruciferous vegetable or isothiocyanate content consumption and lung cancer risk in case-control studies, stratified by GSTM1 and GSTT1 genotypes.

Figure 4.

Forest plot of highest versus lowest category of total cruciferous vegetable or isothiocyanate content consumption and lung cancer risk in case-control studies, stratified by GSTM1 and GSTT1 genotypes.

Close modal

Heterogeneity and Publication Bias

Metaregression results showed that study size, geographic location, or gender could not explain the observed heterogeneity for cohort studies. Sensitivity analysis results showed that the exclusion of individual studies did not substantially alter the pooled relative risks, which ranged from 0.75 to 0.91. All funnel plots to assess for possible indication of publication bias for meta-analyses of cohort and case-control studies, in addition to subgroup analyses by GST status, seemed symmetrical (data not shown).

There is growing interest in the potential association between cruciferous vegetables and lung cancer. For example, 72% of the studies ascertained in this review were published in 2000 onward. By objectively synthesizing the complete body of epidemiologic evidence on this topic, the enhanced signal-to-noise ratio allows the overall associations to be seen more clearly across a range of different study approaches. An additional contribution of the present report is that pooling the evidence across studies allows the results within important subgroups to have much greater statistical precision than any individual study. For this specific topic, there is particular value in investigating the association across subgroups defined by cigarette smoking status and GSTM1/GSTT1 genotypes.

The results of this systematic review, which included 18 studies, indicate that cruciferous vegetable intake is inversely associated with lung cancer risk. Compared with those who consumed the least amount of cruciferous vegetables, the lung cancer risk among those who consumed the most cruciferous vegetables was 22% 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. Cohort studies provided only equivocal support for the presence of a dose-response trend. Intake of individual cruciferous vegetables (e.g., broccoli, cabbage) was strongly inversely associated with lung cancer risk.

A unique characteristic of cruciferous vegetables is that they are a rich source of glucosinolates (13). The anticarcinogenic properties of cruciferous vegetables may be attributable to isothiocyanates derived specifically from glucosinolates (13, 57). Several experimental and mechanistic studies support a potential anticancer role of isothiocyanates (58, 59). 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 (59) and inhibiting histone deacetylase (60). These experimental findings buttress the biological 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 because other nutrients and phytochemicals (e.g., folate, flavonols, and carotenoids) found in cruciferous vegetables may also contribute to the inverse association with lung cancer.

Genetic factors related to isothiocyanate metabolism have been hypothesized to contribute to interindividual differences in the degree of protection conferred by cruciferous vegetable consumption (9). Specifically, individuals with GSTM1 and GSTT1 null genotypes metabolize isothiocyanates less efficiently, permitting isothiocyanates to remain biologically active for a longer period (9, 61). In our meta-analysis, a gene-diet interaction was present; when stratified by GSTM1 and GSTT1 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 and GSTT1 double null genotype (10). The lone cohort study (22) to report on the potential interaction between cruciferous vegetables and GSTM1 on lung cancer risk only reported results in the text that were not detailed enough to be included in the formal meta-analyses. The reported P value for interaction was not statistically significant (P = 0.38). 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 biological plausibility and coherence. The prevalence of the GSTM1 and GSTT1 homozygous deletion genotypes ranges from 42% to 60% and 24% to 51%, respectively. The high prevalence of these putative low-risk (in this setting) genotypes, coupled with the possibility that those with the null genotypes may derive greater benefit from an isothiocyanate-rich diet, underscores the potential public health importance of this gene-diet interaction.

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 (62). Thus, even studies that statistically adjusted for cigarette smoking may show associations because of residual confounding (63). In the present report, several lines of evidence suggest that the inverse association between cruciferous vegetable intake and lung cancer may be independent of cigarette smoking. First, the inverse association between cruciferous vegetable intake and lung cancer remained robust even in analyses limited to never smokers. Second, the summary association was barely affected by the inclusion or exclusion of estimates from studies that were not adjusted for cigarette smoking. Third, 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. The measurement error is of less concern if it is nondifferential, but the evidence from case-control studies may be prone to differential reporting because of recall bias, whereby the dietary recall of lung cancer cases may differ from controls (64). That the observed summary estimate for case-control studies was so similar to that for cohort studies suggests that in this instance recall bias does not play a prominent role. Another weakness in the evidence is that the biological potency of cruciferous vegetables may differ, depending on whether the vegetables are consumed raw or cooked, because this influences the bioavailability of isothiocyanates (65). The lack of information about cooking methods thus introduces 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 data accumulated to date are consistent across study designs and the different populations studied. The evidence is robust that this association is independent of cigarette smoking. The association is biologically plausible, and the case for plausibility is strengthened by the stronger inverse association observed among individuals with the null genotype for GSTM1 and GSTT1. This line of inquiry seems to hold promise for lung cancer prevention.

No potential conflicts of interest were disclosed.

Grant support: World Cancer Research Fund.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1
Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002: Cancer incidence, mortality and prevalence worldwide. Lyon: IARC Press; 2004.
2
Food, nutrition, and the prevention of cancer: a global perspective. Washington D.C: World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR); 1997.
3
World Cancer Research Fund/American Institute for Cancer Research. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Washington DC: AICR; 2007.
4
Hecht SS. Inhibition of carcinogenesis by isothiocyanates.
Drug Metab Rev
2000
;
32
:
395
–411.
5
Gasper A, Al-janobi A, Smith J, et al. Glutathione S-transferase M1 polymorphism and metabolism of sulforaphane from standard and high-glucosinolate broccoli.
Am J Clin Nutr
2005
;
82
:
1283
–91.
6
Seow A, Vainio H, Yu MC. Effect of glutathione-S-transferase polymorphisms on the cancer preventive potential of isothiocyanates: An epidemiological perspective.
Mutat Res
2005
;
592
:
58
–67.
7
Ketterer B. A bird's eye view of the glutathione transferase field.
Chem Biol Interact
2001
;
138
:
27
–42.
8
Bianchini F, Vainio H. Isothiocyanates in cancer prevention.
Drug Metab Rev
2004
;
36
:
655
–67.
9
Lampe JW, Peterson S. Brassica, biotransformation and cancer risk: genetic polymorphisms alter the preventive effects of cruciferous vegetables.
J Nutr
2002
;
132
:
2991
–4.
10
London SJ, Yuan JM, Chung FL, et al. Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms, and lung-cancer risk: a prospective study of men in Shanghai, China.
Lancet
2000
;
356
:
724
–9.
11
Hirvonen A. Polymorphisms of xenobiotic-metabolizing enzymes and susceptibility to cancer.
Environ Health Perspect
1999
;
107
Suppl 1:
37
–47.
12
Keum YS, Jeong WS, Kong AN. Chemoprevention by isothiocyanates and their underlying molecular signaling mechanisms.
Mutat Res
2004
;
555
:
191
–202.
13
Higdon JV, Delage B, Williams DE, Dashwood RH. Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis.
Pharmacol Res
2007
;
55
:
224
–36.
14
Gallicchio L, Matanoski G, Tao XG, et al. Adulthood consumption of preserved and nonpreserved vegetables and the risk of nasopharyngeal carcinoma: a systematic review.
Int J Cancer
2006
;
119
:
1125
–35.
15
Celik I, Gallicchio L, Boyd K, et al. Arsenic in drinking water and lung cancer: a systematic review.
Environ Res
2008
;
108
:
48
–55.
16
Caicoya M. [Lung cancer and vegetable consumption in Asturias, Spain. A case control study].
Med Clin (Barc)
2002
;
119
:
206
–10.
17
Feskanich D, Ziegler RG, Michaud DS, et al. Prospective study of fruit and vegetable consumption and risk of lung cancer among men and women.
J Natl Cancer Inst
2000
;
92
:
1812
–23.
18
Longnecker M, Berlin J, Orza M, Chalmers T. A meta-analysis of alcohol consumption in relation to risk of breast cancer.
JAMA
1988
;
260
:
652
–6.
19
Spitz MR, Duphorne CM, Detry MA, et al. Dietary intake of isothiocyanates: evidence of a joint effect with glutathione S-transferase polymorphisms in lung cancer risk.
Cancer Epidemiol Biomarkers Prev
2000
;
9
:
1017
–20.
20
Wang LI, Giovannucci EL, Hunter D, et al. Dietary intake of cruciferous vegetables, glutathione S-transferase (GST) polymorphisms and lung cancer risk in a Caucasian population.
Cancer Causes Control
2004
;
15
:
977
–85.
21
Greenland S, Longnecker MP. Methods for trend estimation from summarized dose-response data, with applications to meta-analysis.
Am J Epidemiol
1992
;
135
:
1301
–9.
22
Sorensen M, Raaschou-Nielsen O, Brasch-Andersen C, et al. Interactions between GSTM1, GSTT1 and GSTP1 polymorphisms and smoking and intake of fruit and vegetables in relation to lung cancer.
Lung Cancer
2007
;
55
:
137
–44.
23
Altman DG, Bland JM. Interaction revisited: the difference between two estimates.
BMJ
2003
;
326
:
219
.
24
Thompson SG, Higgins JP. Treating individuals 4: can meta-analysis help target interventions at individuals most likely to benefit?
Lancet
2005
;
365
:
341
–6.
25
Miller AB. Vegetables and fruits and lung cancer.
IARC Sci Publ
2002
;
156
:
85
–7.
26
Agudo A, Slimani N, Ocke MC, et al. Consumption of vegetables, fruit and other plant foods in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohorts from 10 European countries.
Public Health Nutr
2002
;
5
:
1179
–96.
27
Seow A, Zhao B, Lee EJ, et al. Cytochrome P4501A2 (CYP1A2) activity and lung cancer risk: a preliminary study among Chinese women in Singapore.
Carcinogenesis
2001
;
22
:
673
–7.
28
Steinmetz KA, Potter JD, Folsom AR. Vegetables, fruit, and lung cancer in the Iowa Women's Health Study.
Cancer Res
1993
;
53
:
536
–43.
29
Speizer FE, Colditz GA, Hunter DJ, Rosner B, Hennekens C. Prospective study of smoking, antioxidant intake, and lung cancer in middle-aged women (USA).
Cancer Causes Control
1999
;
10
:
475
–82.
30
Miller AB, Altenburg HP, Bueno-de-Mesquita B, et al. Fruits and vegetables and lung cancer: findings from the European Prospective Investigation into Cancer and Nutrition.
Int J Cancer
2004
;
108
:
269
–76.
31
Voorrips LE, Goldbohm RA, Verhoeven DT, et al. Vegetable and fruit consumption and lung cancer risk in the Netherlands Cohort Study on diet and cancer.
Cancer Causes Control
2000
;
11
:
101
–15.
32
Neuhouser ML, Patterson RE, Thornquist MD, et al. Fruits and vegetables are associated with lower lung cancer risk only in the placebo arm of the β-carotene and retinol efficacy trial (CARET).
Cancer Epidemiol Biomarkers Prev
2003
;
12
:
350
–8.
33
Chow WH, Schuman LM, McLaughlin JK, et al. A cohort study of tobacco use, diet, occupation, and lung cancer mortality.
Cancer Causes Control
1992
;
3
:
247
–54.
34
Koo LC. Dietary habits and lung cancer risk among Chinese females in Hong Kong who never smoked.
Nutr Cancer
1988
;
11
:
155
–72.
35
Agudo A, Esteve MG, Pallares C, et al. Vegetable and fruit intake and the risk of lung cancer in women in Barcelona, Spain.
Eur J Cancer
1997
;
33
:
1256
–61.
36
Pierce RJ, Kune GA, Kune S, et al. Dietary and alcohol intake, smoking pattern, occupational risk, and family history in lung cancer patients: results of a case-control study in males.
Nutr Cancer
1989
;
12
:
237
–48.
37
Nyberg F, Agrenius V, Svartengren K, Svensson C, Pershagen G. Dietary factors and risk of lung cancer in never-smokers.
Int J Cancer
1998
;
78
:
430
–6.
38
Zhao B, Seow A, Lee EJ, et al. Dietary isothiocyanates, glutathione S-transferase -M1, -T1 polymorphisms and lung cancer risk among Chinese women in Singapore.
Cancer Epidemiol Biomarkers Prev
2001
;
10
:
1063
–7.
39
Lewis S, Brennan P, Nyberg F, et al. Cruciferous vegetable intake, GSTM1 genotype and lung cancer risk in a non-smoking population.
IARC Sci Publ
2002
;
156
:
507
–8.
40
Brennan P, Hsu CC, Moullan N, et al. Effect of cruciferous vegetables on lung cancer in patients stratified by genetic status: a mendelian randomisation approach.
Lancet
2005
;
366
:
1558
–60.
41
Brennan P, Fortes C, Butler J, et al. A multicenter case-control study of diet and lung cancer among non-smokers.
Cancer Causes Control
2000
;
11
:
49
–58.
42
Hu J, Mao Y, Dryer D, White K. Risk factors for lung cancer among Canadian women who have never smoked.
Cancer Detect Prev
2002
;
26
:
129
–38.
43
Linseisen J, Rohrmann S, Miller AB, et al. Fruit and vegetable consumption and lung cancer risk: updated information from the European Prospective Investigation into Cancer and Nutrition (EPIC).
Int J Cancer
2007
;
121
:
1103
–14.
44
Axelsson G, Rylander R. Diet as risk for lung cancer: a Swedish case-control study.
Nutr Cancer
2002
;
44
:
145
–51.
45
Bond GG, Thompson FE, Cook RR. Dietary vitamin A and lung cancer: results of a case-control study among chemical workers.
Nutr Cancer
1987
;
9
:
109
–21.
46
Hu J, Johnson K, Mao Yea. A case-control study of diet and lung cancer in northeast China.
Int J Cancer
1997
;
71
:
924
–31.
47
Le Marchand L, Murphy SP, Hankin JH, Wilkens LR, Kolonel LN. Intake of flavonoids and lung cancer.
J Natl Cancer Inst
2000
;
92
:
154
–60.
48
Mettlin C. Milk drinking, other beverage habits, and lung cancer risk.
Int J Cancer
1989
;
43
:
608
–12.
49
Mohr DL, Blot WJ, Tousey PM, Van Doren ML, Wolfe KW. Southern cooking and lung cancer.
Nutr Cancer
1999
;
35
:
34
–43.
50
Kvale G, Bjelke E, Gart JJ. Dietary habits and lung cancer risk.
Int J Cancer
1983
;
31
:
397
–405.
51
Sankaranarayanan R, Varghese C, Duffy SW, et al. A case-control study of diet and lung cancer in Kerala, south India.
Int J Cancer
1994
;
58
:
644
–9.
52
Ruano-Ravina A, Figueiras A, Dosil-Diaz O, Barreiro-Carracedo A, Barros-Dios JM. A population-based case-control study on fruit and vegetable intake and lung cancer: a paradox effect?
Nutr Cancer
2002
;
43
:
47
–51.
53
Gao CM, Tajima K, Kuroishi T, Hirose K, Inoue M. Protective effects of raw vegetables and fruit against lung cancer among smokers and ex-smokers: a case-control study in the Tokai area of Japan.
Jpn J Cancer Res
1993
;
84
:
594
–600.
54
Galeone C, Negri E, Pelucchi C, et al. Dietary intake of fruit and vegetable and lung cancer risk: a case-control study in Harbin, northeast China.
Ann Oncol
2007
;
18
:
388
–92.
55
Wang J, Deng Y, Cheng J, Ding J, Tokudome S. GST genetic polymorphisms and lung adenocarcinoma susceptibility in a Chinese population.
Cancer Lett
2003
;
201
:
185
–93.
56
Wang Y, Spitz MR, Schabath MB, et al. Association between glutathione S-transferase p1 polymorphisms and lung cancer risk in Caucasians: a case-control study.
Lung Cancer
2003
;
40
:
25
–32.
57
Fahey JW, Zalcmann P, Talalay P. The chemistry diversity and distribution of glucosinolates and isothiocyanates among plants.
Phytochemistry
2001
;
56
:
5
–51.
58
Myzak MC, Dashwood RH. Chemoprotection by sulforaphane: keep one eye beyond Keap1.
Cancer Lett
2006
;
233
:
208
–18.
59
Juge N, Mithen RF, Traka M. Molecular basis for chemoprevention by sulforaphane: a comprehensive review.
Cell Mol Life Sci
2007
;
64
:
1105
–27.
60
Myzak MC, Tong P, Dashwood WM, Dashwood RH, Ho E. Sulforaphane retards the growth of human PC-3 xenografts and inhibits HDAC activity in human subjects.
Exp Biol Med (Maywood)
2007
;
232
:
227
–34.
61
Kolm RH, Danielson UH, Zhang Y, Talalay P, Mannervik B. Isothiocyanates as substrates for human glutathione transferases: structure-activity studies.
Biochem J
1995
;
311
:
453
–9.
62
Alberg AJ. The influence of cigarette smoking on circulating concentrations of antioxidant micronutrients.
Toxicology
2002
;
180
:
121
–37.
63
Stram DO, Huberman M, Wu AH. Is residual confounding a reasonable explanation for the apparent protective effects of β-carotene found in epidemiologic studies of lung cancer in smokers?
Am J Epidemiol
2002
;
155
:
622
–8.
64
Natarajan L, Flatt SW, Sun X, et al. Validity and systematic error in measuring carotenoid consumption with dietary self-report instruments.
Am J Epidemiol
2006
;
163
:
770
–8.
65
Vermeulen M, van den Berg R, Freidig AP, van Bladeren PJ, Vaes WH. Association between consumption of cruciferous vegetables and condiments and excretion in urine of isothiocyanate mercapturic acids.
J Agric Food Chem
2006
;
54
:
5350
–8.