Groenten bieden bescherming tegen longkanker.*

Vooral groene kruisbloemige groente biedt bescherming tegen longkanker.
Tot die risicogevallen behoren mensen die een tekort hebben aan de twee genen, GSTM1 en GSTT1,  die een rol spelen bij de werking van isothiocyanaten, die de mens tegen deze vorm van kanker beschermen. En in alle soorten kool, in broccoli en in spruitjes zit een grote hoeveelheid van die isothiocyanaten, zo blijkt uit een onderzoek waarvan de resultaten worden gepubliceerd door het tijdschrift The Lancet.
Het onderzoek werd verricht door dr. Paul Brennan, van het in Lyon gevestigde Internationaal Bureau voor Kankeronderzoek en er namen 2141 longkankerpatiënten en 2168 gezonde personen aan deel. Het DNA van die proefpersonen werd onderzocht, net als hun eetgewoonten. En daaruit werd de conclusie getroffen dat het eten van groenten bij de mensen met één zo'n "niet-actief GSTM1 of GSTT1 gen" een derde meer bescherming biedt en dat mensen die beide genen misten zelfs 72 procent beter beschermt tegen deze gevreesde en vaak dodelijke vorm van kanker.

Cruciferous vegetables could protect against lung cancer
Eating vegetables from the cabbage family could help individuals with a certain genetic make-up reduce their risk of lung cancer. Weekly consumption of cruciferous vegetables had a 72% protective effect against lung cancer in people who had inactive forms of both the GSTM1 and GSTT1 genes.

The Lancet 2005; 366:1558-1560

DOI:10.1016/S0140-6736(05)67628-3

Effect of cruciferous vegetables on lung cancer in patients stratified by genetic status: a mendelian randomisation approach

Paul Brennan,   Charles C Hsu ,   Norman Moullan,   Neonilia Szeszenia-Dabrowska,   Jolanta Lissowska,   David Zaridze,   Peter Rudnai,   Eleonora Fabianova,   Dana Mates,   Vladimir Bencko,   Lenka Foretova,   Vladimir Janout,   Federica Gemignani,   Amelie Chabrier,   Janet Hall,   Rayjean J Hung,   Paolo Boffetta   and   Federico Canzian

Summary

Whether consumption of cruciferous vegetables protects against lung cancer is unclear, largely because of potential confounding factors. We therefore studied the role of cruciferous vegetables in lung cancer after stratifying by GSTM1 and GSTT1 status, two genes implicated in the elimination of isothiocyanates, the likely chemopreventative compound. In 2141 cases and 2168 controls, weekly consumption of cruciferous vegetables protected against lung cancer in those who were GSTM1 null (odds ratio=0·67, 95% CI 0·49–0·91), GSTT1 null (0·63, 0·37–1·07), or both (0·28, 0·11–0·67). No protective effect was seen in people who were both GSTM1 and GSTT1 positive (0·88, 0·65–1·21). Similar protective results were noted for consumption of cabbage and a combination of broccoli and brussels sprouts. These data provide strong evidence for a substantial protective effect of cruciferous vegetable consumption on lung cancer.

Observational studies have provided consistent evidence for a protective role of vegetable consumption against lung cancer, with the evidence being most apparent for green cruciferous vegetables such as broccoli and cabbage.1 Such vegetables are rich in isothiocyanates, which have been shown in animals to have strong chemopreventative properties against lung cancer.2 In a review of studies of the effect of cruciferous vegetables, a definite protective effect against any type of cancer could not be identified, in view of the small size of studies and potential for confounding from other dietary sources.3

Confounding could, however, be addressed by adoption of a mendelian randomisation approach.4 Isothiocyanates are thought to be eliminated by glutathione-S-transferase enzymes, most notably GSTM1 and GSTT1.5,6 Both GSTM1 and GSTT1 genes have null alleles with homozygous null genotypes, resulting in no enzyme being produced. Individuals who are homozygous for the inactive form of either or both genes probably have higher isothiocyanate concentrations because of their reduced elimination capacity. Furthermore, and implicit in the mendelian randomisation approach, the roles of GSTM1 and GSTT1 genes are likely to be independent of other dietary and lifestyle factors, reducing the possibility of confounding from these sources.

To clarify the role of cruciferous vegetable consumption in the prevention of lung cancer, and their interaction with GST genotypes, large-scale studies are needed. We therefore investigated this relation in a case-control study of 2141 cases and 2168 controls in six countries of central and eastern Europe, a region that has traditionally high rates of cruciferous vegetable consumption. Incident cases and age-sex matched hospital or population controls were recruited from 15 centres in Poland, Slovakia, Czech Republic, Romania, Russia, and Hungary by use of an identical protocol and questionnaire. All participants completed a detailed standardised lifestyle and food frequency questionnaire that had been piloted in all centres before use. The dietary component of the questionnaire listed 23 foods, of which three were cruciferous vegetables (cabbage and a combination of brussels sprouts with broccoli). The questionnaire was repeated for two different periods: the year before interview; and before political and market changes in 1989 (1991 in Russia); a weighted average of the two was calculated on the basis of the age of the individual. A blood sample was also obtained for all individuals, and DNA was extracted. Genotyping for GSTM1 and GSTT1 was done with PCR-based techniques (protocol available from the authors, on request).

Neither GSTM1 nor GSTT1 were related to potential confounding factors in the controls, such as country, age, smoking status, education, and dietary variables including cruciferous vegetable consumption. As expected, cruciferous vegetable consumption was related to other dietary variables, such as fruit and other vegetables, and smoking status, although these associations do not detract from the validity of the mendelian randomisation comparison. All interviewees provided written informed consent before their participation in the study. Ethical approval for recruitment of participants and subsequent genotyping was obtained from institutional review boards in all the study centres, and from the International Agency for Research on Cancer (IARC) ethics committee.7

An overall protective effect was seen for consumption of cruciferous vegetables at least once a week compared with less than monthly (adjusted odds ratio=0·78, 95% CI 0·64–0·96), which was much the same for both cabbage consumption and for broccoli and brussels sprout consumption. When stratified by GST status, any protective effect of high consumption was restricted to those who were null for GSTM1 (0·67, 0·49–0·91), GSTT1 (0·63, 0·37–1·07), or both GSTM1 and GSTT1, (0·28, 0·11–0·67). No protective effect was seen in those who were GSTM1 and T1 positive, with a moderate non-significant protective effect for those who had only one null genotype (0·80, 0·60–1·08). The interaction between GSTM1 null/GSTT1 null versus other GSTM1/GSTT1 groups and cruciferous vegetable consumption was significant (p=0·03). Similar results were observed separately for cabbage and broccoli/brussels sprout consumption, after adjustment for the other, suggesting an independent protective effect of both sources of cruciferous vegetables.

When the population was stratified by smoking history (never vs ever), the protective effect in never smokers was largely independent of GSTM1 and GSTT1 status, being recorded in those who were positive for both M1 and T1 (0·31, 0·14–0·70) and negative for M1 and T1 (0·12, 0·01–1·54). No interaction was noted for GSTM1/GSTT1 null versus other GSTM1/GSTT1 combinations in never smokers (p=0·70), although there was evidence of interaction in those who had smoked (p=0·05). Since one might expect GST enzyme concentrations to be higher in smokers than in non-smokers because of the presence of tobacco-specific substrates, GSTM1 and GSTT1 might not modify the protective effect of cruciferous vegetables in non-smokers.

These results provide strong evidence for our a-priori hypothesis that the protective effect of cruciferous vegetables is most apparent in those who have low values of circulating GST enzymes, because they have null alleles for GSTM1 and GSTT1 genes. The results also accord with those of several smaller studies of lung cancer, breast cancer, and colorectal adenomas, which showed a protective effect in GSTM1 and GSTT1 null carriers.2 However, we cannot draw definitive conclusions from these individual studies because of their small sample size (the three previous studies of lung cancer, based in Shanghai, Singapore, and Texas, consisted of a total of 968 cases and 1362 controls).5,8,9 Taking into consideration the size of the protective effects that have been reported in this and other studies, which are likely to have been substantially diluted by measurement error, these findings raise the prospect of an important chemopreventive effect against lung cancer for cruciferous vegetables in general, and isothiocyanates in particular.

Contributors

P Brennan, N Szeszenia Dabrowska, L Lissowska, D Zaridze, P Rudnai, E Fabianova, D Mates, V Bencko, L Foretova, V Janout, and P Boffetta jointly designed the study and organised the interviewee recruitment. N Moullan, A Chabrier, R Hung, F Gemignani, J Hall and F Canzian organised biological sample storage, DNA extraction, and genotyping. C C Hsu, R Hung, and P Brennan did the statistical analysis. P Brennan prepared the first draft, and all co-authors contributed to the final draft.

Conflict of interest statement

We declare that we have no conflict of interest

Acknowledgments

Interviewee recruitment was supported by a grant from the European Commission's INCO-COPERNICUS Programme (contract # IC15-CT96-0313). Genotyping and analysis was funded by a National Cancer Institute R01 grant (contract # CA 092039-01A2). Neither funding agency had any involvement in the study design, collection, analysis, and interpretation of the data or in the writing of the report and decision to submit the paper. C C Hsu was supported by a Postdoctoral Fellowship from the International Agency for Research on Cancer. F Gemignani is a recipient of a fellowship of the International Association for the Study of Lung Cancer (IASLC), part of the Cancer Research Foundation of America (CRFA).

References

1. World Cancer Research Fund. Food, nutrition and the prevention of cancer: a global perspective. Washington: American Institute for Cancer Research, 1997:.

2. Hecht SS. Chemoprevention of lung cancer by isothiocyanates. Adv Exp Med Biol 1996; 401: 1-11.

3. IARC Handbook of cancer prevention. Cruciferous vegetables, isothiocyanates and indoles. Lyon, France: IARC Press, 2004:.

4. Davey Smith G, Ebrahim S. ‘Mendelian Randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease?. Int J Epidemiol 2003; 32: 1-22.

5. London SJ, Yuan JM, Chung FL, et al. Isothiocyanates, glutathione S-transferase M1 and T1 polyphormims, and lung-cancer risk: a prospective study of men in Shanghai, China. Lancet 2000; 356: 724-729.

6. Fowke JH, Shu XO, Dai Q, et al. Urinary isothiocyanate excretion, brassica consumption, and gene polymorphisms among women living in Shanghai, China. Cancer Epidemiol Biomarkers Prev 2003; 12: 1536-1539.

7. Hung RJ, Brennan P, Canzian F, et al. Large-scale investigation of base excision repair genetic polymorphisms and lung cancer risk in a multicenter study. J Natl Cancer Inst 2005; 97: 567-576.

8. 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: 1063-1067.

9. 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: 1017-1020.

Affiliations
a International Agency for Research on Cancer, Lyon, France
b Department of Epidemiology, Institute of Occupational Medicine, Lodz, Poland
c Department of Cancer Epidemiology and Prevention, Cancer Center and M Sklodowska-Curie Institute of Oncology, Warsaw, Poland
d Institute of Carcinogenesis, Cancer Research Centre, Moscow, Russia
e Foder Jozsef National Centre for Public Health, Budapest, Hungary
f Regional Authority of Public Health, Banska Bystrika, Slovakia
g Institute of Public Health, Bucharest, Romania
h Charles University of Prague Institute of Hygiene and Epidemiology, First Faculty of Medicine, Czech Republic
i Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic
j Department of Preventive Medicine, Palacky University of Medicine, Olomouc, Czech Republic

Correspondence to: Dr Paul Brennan International Agency for Research on Cancer, Lyon 69008, France  (Okt. 2005) (opm. Weer een onderzoek dat de belangrijkheid van voldoende glutathion tegen kanker aantoont.)