1 Molecular and Genetic Epidemiology Unit, Ospedale Maggiore IRCCS, Italy;
2 INSERM, Villejuif, France, and Geneva Cancer Registry;
3 IARC, Lyon, France;
4 Institute of Clinical Pharmacology, Georg August University, Goettingen, Germany;
5 Institute of Clinical Pharmacology, Gliwice, Poland;
6 Ernst Moritz Arndt University, Greifswald, Germany;
7 Fox Chase Cancer Center, Philadelphia, PA USA;
8 University of Ljubljana, Slovenia;
9 National Institute of Occupational Health, Oslo, Norway;
10 Finnish Institute of Occupational Health Helsinki, Finland;
11 PJ afárik University, Ko
ice, Slovakia;
12 Institut de Pathologie, Liège-Belgium;
13 University of Hawaii-Honolulu, HA, USA;
14 National Institute for Environmental Health Sciences Research Triangle Park, NC USA;
15 Karolinska Institutet Stockholm, Sweden;
16 University of Pittsburgh, Pittsburgh, PA USA;
17 National Institute of Environmental Health, Budapest, Hungary;
18 Lund University, Lund, Sweden;
19 Keele University, Staffordshire UK;
20 INSERM, Villejuif, France;
21 Hospital Clinic Provincial, Barcelona, Spain;
22 EOHSI, UMDNJ, Picataway, NJ USA and Genetics Research Institute Milano, Italy.
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Abstract |
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Methods The effect of metabolic gene polymorphisms on lung cancer at young ages was studied by pooling data from the Genetic Susceptibility to Environmental Carcinogens (GSEC) database. All primary lung cancer cases of both sexes who were Caucasian and 45 years of age at diagnosis, and the corresponding controls were selected. We obtained 261 cases and 1452 controls.
Results There was a marginally significant association between lung cancer and GSTT1 null genotype (OR=1.2; 95% CI:1.01.6), and a significant association between lung cancer and the homozygous CYP1A1 Msp1 variant allele (CYP1A1*2A and *2B) genotype (OR=4.7 95% CI:1.219.0). When data were stratified by smoking status, the association between CYP1A1 genotype and lung cancer was confined to never smokers.
Conclusions These results suggest that metabolic genetic factors play a role in lung cancer developing at young ages.
Lung cancer (LC) among smokers of middle and old ages is a major cause of death in western countries. However, LC at younger ages and among non-smokers is a rare disease: approximately 5% of LC are diagnosed under age 45 years, and 46% of total cases are never smokers. Although smoking is still a known risk factor at younger ages, it might be hypothesized that early-onset LC among both smokers and non-smokers may have a stronger genetic component in its pathology than that seen at older ages. Polymorphisms in genes involved in both Phase 1 and Phase 2 of xenobiotic metabolism have been associated with a modest increase in LC risk. These genes modulate the effect of tobacco by metabolism of carcinogens in tobacco smoke.1 The association of metabolic genes and LC, and their effect on the association between LC and smoking at younger ages, has never been studied because the rarity of these cases has not allowed gathering of sufficient subjects. Epidemiological data show that early-onset LC is associated with familial aggregation of other cancers,2 and suggest that a genetic component in early-onset LC may be present in non-smokers.3 We wanted to address the hypothesis that polymorphisms in Phase 1 and Phase 2 xenobiotic metabolizing genes are associated with lung cancer at young ages. We used data from the Genetic Susceptibility to Environmental Carcinogens (GSEC) database,4 a pooled analysis containing genotype data and epidemiological information on over 15 000 cancer cases and 15 000 controls.
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Material and Methods |
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Statistical analysis |
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Results |
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Discussion |
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Additional information derived from the present analysis is that the association between LC and CYP1A1 genotype appears to be potentially relevant for never smokers. This interpretation is possible because some metabolic gene variants (such as CYP1A1 variants) seem to exert their effect at low doses of exposure to carcinogens.8,10 Similar data have been reported in the meta-analysis, when the data are stratified by dose of exposure to environmental carcinogens.9 Never smokers included in our study could be exposed to low doses of environmental carcinogens from other sources, such as passive smoking, dietary polyaromatic hydrocarbons or occupation. Another explanation for our results could be that LC at young age in never smokers is a disease with a strong genetic component, and therefore the effect of metabolic gene polymorphisms becomes more evident in this subpopulation. There is evidence that familiarity for LC is associated with increased risk of early-onset, but not late-onset, LC.11 A recent publication on risk factors for LC in young women12 shows a smaller association of LC with smoking, especially at very young ages (below age 35). No other known risk factors for LC at young ages are reported in the literature. Our data should be viewed with caution due to the relatively small number of subjects in the never smoking group, and the very few subjects homozygous variant for CYP1A1 among never smokers.
Our analysis does not suggest a major role for Phase 2 genetic polymorphisms GSTM1 and GSTT1 in this age group. Moreover, no combined effect was observed for Phase 1 and Phase 2 genes, in contrast with some published data suggesting an effect of both GSTM1 deletion and CYP1A1 polymorphism on LC risk in women.14
One of the limitations of the present analysis is the difference in laboratory methods for detection of the Exon7 CYP1A1 polymorphisms. Most of the data sets included in the GSEC database contain information on this polymorphism obtained with a method15 that may not accurately distinguish between the Exon 7 variant alleles having a C2455 base change (CYP1A1*2A and *2B) and the more recently described CYP1A1*4 allele having a C2453 base change. Newer studies using more precise methods16 may give different results compared with the previous studies that used the old method. In the current analysis, only one study used the alternative, more precise method, and this study was excluded when analysing the CYP1A1 polymorphisms, for purposes of consistency and homogeneity among studies. Once a sufficient number of subjects have been typed using the new method, a new pooled analysis using these data will be necessary in order to give a more precise estimate of the role of the CYP1A1 Exon 7 polymorphism in the individual LC risk.
There are other limitations in this study, such as uncertainty about standardization of some epidemiological information such as smoking history, and the impossibility of conducting more detailed analysis on environmental exposure. For example, we were unable to study in detail the effect of metabolic polymorphisms at different smoking doses, or other sophisticated analysis of interaction. Population stratification among Caucasians should not be an issue, as we and others have previously shown7,17 that inter-ethnic differences in allele frequencies for these genes in Caucasians are not large. Heterogeneities among studies, such as patient recruitment, distribution of histological types, proportion of subjects successfully genotyped out of the total population, cannot be addressed in this pooled analysis.
However, this is the largest study conducted so far on young LC cases including the measure of metabolic gene polymorphisms, and was possible because of the ongoing collaborative project on genetic susceptibility to environmental carcinogens. Pooled analyses allow investigation of relatively large numbers of cases of rare cancers, and also of the role of genetic factors in particular subgroups of the population at risk. Our study suggests that, in addition to smoking, the main risk factor for LC, metabolic gene polymorphisms may play a role in LC at young ages.
KEY MESSAGES
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Acknowledgments |
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References |
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