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Cancer Epidemiology Biomarkers & Prevention Vol. 13, 320-323, February 2004
© 2004 American Association for Cancer Research

Short Communications

Exon 5 Polymorphisms in the O6-Alkylguanine DNA Alkyltransferase Gene and Lung Cancer Risk in Non–Smokers Exposed to Second-Hand Smoke

Catherine Cohet1, Stephane Borel1, Fredrik Nyberg2, Anush Mukeria3, Irene Brüske-Hohlfeld4, Vali Constantinescu5, Simone Benhamou6, Paul Brennan1, Janet Hall1 and Paolo Boffetta1

1 International Agency of Research on Cancer, Lyon, France; 2 Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden; 3 Institute of Carcinogenesis, Moscow, Russia; 4 National Research Center for Environment and Health (GSF), Munich, Germany; 5 National Institute of Public Health, Bucharest, Romania; 6 National Institute of Health and Medical Research (Institut National de la Santé et de la Recherche Médicale) and Evry University, Evry, France


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Purpose: The objective of the study was to examine the association of three exon 5 variants in the O6-alkylguanine DNA alkyltransferase (AGT) gene involved in the repair of the mutagenic DNA lesion O6-alkylguanine formed by nitrosamines, with lung cancer risk in never-smokers.

Experimental Design: Exon 5 of the AGT gene was sequenced in genomic DNA from 136 cases and 133 hospital- or population-based controls for whom questionnaire information on second-hand smoke and diet was available to determine the frequencies of the Gly160Arg, Ile143Val, and Lys178Arg variant alleles.

Results: No codon 160Arg variant alleles were found in the study population. The codon 143Val and 178Arg variant alleles, present at allele frequencies of 0.07, showed 100% linkage. The odds ratio (OR) of lung cancer for these variant carriers was 2.05 [95% confidence interval (CI) 1.03–4.07]. The risk varied between the different lung cancer pathologies with an increased risk for adenocarcinoma (OR 2.67, 95% CI 1.21–5.87) or small cell carcinoma (OR 4.83, 95% CI 0.91–25.7) but not for squamous cell carcinoma (OR 1.07, 95% CI 0.27–4.18). Compared with individuals carrying the mutant alleles unexposed to second-hand smoke, the OR for exposed variant carriers was 1.95 (95% CI 0.53–1.15); a similar interaction, although not significative, was observed for low consumption of cruciferous vegetables and for green vegetables and tomatoes.

Conclusions: These results point toward a role of AGT polymorphisms in lung cancer susceptibility among never-smokers, in particular among subjects exposed to environmental carcinogens.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Second-hand smoke, a widely studied lung cancer risk factor among non-smokers, is a complex mixture containing several groups of carcinogens, including carcinogenic N-nitroso compounds (1) , the metabolites of which form the mutagenic DNA lesion O6-alkylguanine. This adduct is predominantly repaired via the activity of O6-alkylguanine DNA alkyltransferase (AGT), which irreversibly transfers the alkyl group to an internal cysteine acceptor site, leading to its inactivation and the restoration of the guanine moiety in the DNA. Animals lacking AGT are more sensitive to carcinogenesis and show increased cytotoxicity when exposed to alkylating agents (2) .

Several polymorphisms of the human AGT have been described. A Gly160Arg variant in exon 5, 15 amino acids away from the cysteine in the active site, was originally reported at an allele frequency of ~15% (3) ; however, lower frequencies, in the order of 0–1.5%, were found in subsequent studies (4, 5, 6, 7) . The exon 5 variants Ile143Val and Lys178Arg have been reported at allele frequencies of up to 21% with a strong linkage disequilibrium being noted between them (4 , 7 , 8) . In addition, five polymorphisms in the promoter, one in exon 1 and two in exon 3, have been reported (9) . In one study, presence of the codon 143 valine allele was shown to be associated with an increased lung cancer risk among smokers [odds ratio (OR) 2.1, 95% confidence interval (CI) 1.01–4.7; Ref. 7 ].

The goal of this present study was to examine the role of the three exon 5 variants as potential susceptibility factors for lung cancer in never-smokers. As alterations of the active site cysteine by oxidative stress may change the active site’s status, the potential interaction of the polymorphisms with other environmental factors such as dietary constituents containing antioxidants was also addressed.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects.
The DNA used was isolated from peripheral blood samples collected from participants in a multicenter case- control study of lung cancer in never-smokers conducted in eight countries between 1992 and 1994 (10) . All participants provided an informed consent and relevant review boards approved the study. Study subjects (136 incident cases and 133 controls, Table 1Citation ) were all Caucasian and had smoked <400 cigarettes or an equivalent amount of cigars, cigarillos, or pipe tobacco during their life; they had completed a questionnaire assessing exposure to second-hand tobacco smoke and frequency of consumption of selected foods and food groups (11) . Cases were recruited immediately after diagnosis among patients with histologically or cytologically confirmed primary lung cancer and were enrolled in the study before any therapy was started. Controls were selected either among patients from the same hospital as the cases or, in two countries, from healthy individuals identified from population registries. All hospital-based controls suffered from non tobacco-related diseases, i.e., injuries; diseases of the musculoskeletal system; diseases of the genitourinary system; diseases of the digestive system such as hernia, diverticula, and fistula; chronic sinusitis; and benign neoplasms and malignant melanoma of the skin.


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  		Table 1 Selected characteristics of cases and controlsa

 
Genotyping.
Exon 5 of the AGT gene was sequenced using PCR primers designed on the basis of the published human sequence (GenBank accession no. NT_008818). The amplification was carried out using 300 ng of sense (5'-TTGTCCAGATCCCTGACTGA-3') and 300 ng of antisense (5'-ATCCGATGCAGTGTTACACG-3') primers to generate a 310-bp fragment. Sequencing reactions were performed on the ABI 310 genetic Analyzer (Applied Biosystems, Foster City, CA) according to the manufacturer’s protocol (Big dye Terminator cycle sequencing kit; Applied Biosystems). Analysis of all samples was carried out blindly for case/control status. For quality control purposes, a 10% subset of samples were sequenced bi-directionally or reanalyzed with the results being 100% concordant (data not presented).

Statistical Methods.
Multivariate analysis was performed using unconditional logistic regression. The ORs and 95% CIs presented were adjusted for study center. Additional adjustment for age, gender, and education did not modify the results. Exposure to second-hand smoke was defined as ever exposure from the spouse or at the workplace; dietary exposure was defined as intake below the median level in the study population. Statistical analysis was conducted using STATA 7.0 software (12) , and all tests were two-sided.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The allele frequency of the codon 143Val and the codon 178Arg variants among controls was 0.07, although some variation was noted between different countries: from 0% in Poland and France to 13% in Sweden. All individuals carrying the codon 143Val variant were found to also carry the codon 178Arg variant. It was therefore assumed that complete linkage disequilibrium existed between these two variants. The genotype distributions were consistent with Hardy-Weinberg equilibrium in both cases and controls. No codon 160Arg variant alleles were found in the 269 samples sequenced. A statistically significant elevation in the risk of lung cancer was associated with the codon 143Val/178Arg variant alleles (OR 2.05, 95% CI 1.03–4.07): the OR was increased for adenocarcinoma and small cell carcinoma but not for squamous cell carcinoma (Table 2)Citation . Testing for heterogeneity showed that the histology-specific ORs were different (P = 0.001). As compared with wild-type individuals unexposed to second-hand smoke, the OR for exposed wild-type individuals was 1.25 (95% CI 0.65–2.38), whereas for exposed individuals carrying the mutant alleles, the OR was 1.95 (95%CI 0.53–1.15) compared with unexposed subjects (Table 3)Citation . Although not significant, an interaction similar to the one observed for second-hand smoke was suggested between low consumption of cruciferous vegetables (OR = 2.45, 95% CI 0.47–13.00) or green vegetables and tomatoes (OR = 1.92, 95% CI 0.27–13.58) and presence of these variants (Table 3)Citation .


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  		Table 2 Odds ratio of lung cancer for codon 143 and 178 polymorphismsa

 

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  		Table 3 Interaction between codon 143 and 178 polymorphisms and exposure to second-hand smoke and dietary factorsa

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study confirms previous results of an increased risk of lung cancer among carriers of AGT exon 5 variants and suggests that the risk might be strongest in the presence of low-level exposure to environmental pollutants, as in the case of non-smokers exposed to second-hand smoke. This study suffers from several potential limitations; firstly, the stratified analyses were underpowered, although the main analysis was not affected by limited power and resulted in statistically significant ORs. Secondly, controls were hospital or community based. However, the fact that the genotype distribution of cases and controls was in Hardy Weinberg equilibrium argues against bias in the selection of controls.

Although a mechanistic interpretation of these results is not straightforward, codons 143 and 178 are both close to the active site of the repair protein and AGT activity might be influenced by amino acid substitutions in this region. The AGT activity has been previously measured using an in vitro assay with DNA containing O6-methylguanine as the substrate in lymphocyte protein extracts prepared from 145 of the individuals studied here (13) . The presence of the codon 143 and 178 variant alleles did not correlate with a significant change in the mean enzyme activity in either the cases or controls (Ps of difference, Mann-Whitney test, 0.31 and 0.27, respectively). In that analysis, a weak, nonsignificant difference in AGT activity was detected between cases and controls. The AGT genotype shows a stronger association with lung cancer risk than measurement of its enzymatic activity in peripheral blood lymphocytes at the time of disease. However, the functional consequences of these polymorphisms remain to be established. Because the reaction of AGT leads to its inactivation, any substrate for the protein acts as an irreversible inhibitor. The presence of the codon 160Arg variant, although having only a small effect on the activity of AGT toward methylated DNA in vitro (3) , reduces the inactivation of the AGT protein by the inhibitor O6-benzylguanine with at least a 20-fold increase in the ED50 (14) , suggesting that the ability to inactivate is also a critical factor in the response of AGT to environmental carcinogens. Although comparable data on the effect of codon 143 and codon 178 variants on inactivation of AGT are not available, it has been shown that several amino acid substitutions within the active site pocket of AGT can influence its inactivation, and it remains to be determined whether these natural variants can also impart resistance (15) . In conclusion, individual susceptibility from polymorphisms in genes involved in critical steps of carcinogenesis may play a particularly important role in circumstances of low-level exposure to environmental carcinogens (16) : our results support this notion in the case of lung cancer development among non-smokers exposed to second-hand smoke.


   Acknowledgments
 
We thank L. Simonato, C. Fortes, A. Menezes, and H. Batura-Gabryel who provided access to study subjects.


   Footnotes
 
Grant support: European Commission, DG Research Contract No. EV5V-CT94-0555. C. C. and S. B. worked on the study under the tenure of Special Training Awards from the International Agency for Research on Cancer.

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.

Note: V. Gaborieau participated in the management of the project.

Requests for reprints: Dr. Paolo Boffetta, Chief, Unit of Environmental Cancer Epidemiology, International Agency for Research on Cancer, 150 cours Albert Thomas, 69008 Lyon, France. Phone: 33-4-72738441; Fax: 33-4-72738320; E-mail: boffetta{at}iarc.fr.

Received 5/29/03; revised 9/17/03; accepted 9/29/03.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. IARC. Tobacco smoke and involuntary smoking. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 83. IARC: Lyon, France, in press, 2004.
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  3. Imai Y., Oda H., Nakatsuru Y., Ishikawa T. A. polymorphism at codon 160 of human O6-methylguanine-DNA methyltransferase gene in young patients with adult type cancers and functional assay. Carcinogenesis (Lond.), 16: 2441-2445, 1995.[Abstract/Free Full Text]
  4. Deng C., Xie D., Capasso H., Zhao Y., Wang L. D., Hong J. Y. Genetic polymorphism of human O6-alkylguanine-DNA alkyltransferase: identification of a missense variation in the active site region. Pharmacogenetics, 9: 81-87, 1999.[Medline]
  5. Gerson S. L., Schupp J., Liu L., Pegg A. E., Srinivasen S. Leukocyte O6-alkylguanine-DNA alkyltransferase from human donors is uniformly sensitive to O6-benzylguanine. Clin. Cancer Res., 5: 521-524, 1999.[Abstract/Free Full Text]
  6. Wu M. H., Lohrbach K. E., Olopade O. I., Kokkinakis D. M., Friedman H. S., Dolan M. E. Lack of evidence for a polymorphism at codon 160 of human O6-alkylguanine-DNA alkyltransferase gene in normal tissue and cancer. Clin. Cancer Res., 5: 209-213, 1999.[Abstract/Free Full Text]
  7. Kaur T. B., Travaline J. M., Gaughan J. P., Richie J. P., Jr., Stellman S. D., Lazarus P. Role of polymorphisms in codons 143 and 160 of the O6-alkylguanine DNA alkyltransferase gene in lung cancer risk. Cancer Epidemiol. Biomark. Prev., 9: 339-342, 2000.[Abstract/Free Full Text]
  8. Ford B. N., Ruttan C. C., Kyle V. L., Brackley M. E., Glickman B. W. Identification of single nucleotide polymorphisms in human DNA repair genes. Carcinogenesis (Lond.), 21: 1977-1981, 2000.[Abstract/Free Full Text]
  9. Egyhazi S., Ma S., Smoczynski K., Hansson J., Platz A., Ringborg U. Novel O6-methylguanine-DNA methyltransferase SNPs: a frequency comparison of patients with familial melanoma and healthy individuals in Sweden. Hum. Mutat., 20: 408-409, 2002.
  10. Malats N., Camus-Radon A. M., Nyberg F., Ahrens W., Constantinescu V., Mukeria A., Benhamou S., Batura-Gabryel H., Bruske-Hohlfeld I., Simonato L., Menezes A., Lea S., Lang M., Boffetta P. Lung cancer risk in nonsmokers and GSTM1 and GSTT1 genetic polymorphism. Cancer Epidemiol. Biomark. Prev., 9: 827-833, 2000.[Abstract/Free Full Text]
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