This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hou, S.-M. Articles by Lambert, B. Search for Related Content PubMed PubMed Citation Articles by Hou, S.-M. Articles by Lambert, B.

Differential Interactions between GSTM1 and NAT2 Genotypes on Aromatic DNA Adduct Level and HPRT Mutant Frequency in Lung Cancer Patients and Population Controls¹

Environmental Medicine Unit (S-M. H., S. F., B. L.) and Molecular Epidemiology Unit (K. Y., K. H.), Department of Biosciences, The Karolinska Institute, S-141 57 Huddinge Sweden, and Division of Environmental Epidemiology (F. N., G. P.), Institute of Environmental Medicine at the Karolinska Institute, S-171 77 Stockholm, Sweden

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
We have studied the influence of GSTM1 and NAT2 genotypes on aromatic DNA adduct level (AL) and HPRT mutant frequency (MF) in smokers with newly diagnosed lung cancer and matched population controls. AL was analyzed in relation to genotypes in 170 cases and 144 controls (113 current/recent smokers and 201 former/never smokers), and MF in 157 cases and 152 controls (155 ever smokers and 154 never smokers). Both genotypes exhibited the a priori expected effects on AL and MF among controls only, especially among smoking controls [significantly lower pack-years (a pack-year is defined as 1 pack of cigarettes/day for 1 year) than among cases]. Among the 42 currently smoking controls, the NAT2 slow genotype [odds ratio (OR), 7.5; 95% confidence interval (CI), 1.5–38.4], in particular in combination with the GSTM1 null genotype (OR, 19.3, 95% CI, 1.1–338.6 for null/slow versus positive/rapid) was strongly associated with high AL. The null/slow combination was also significantly associated with high MF among ever smokers (cases and controls pooled) with lower pack-years (OR, 3.7; 95% CI, 1.3–10.7 versus all of the other genotypes; OR, 5.1; 95% CI, 1.2–22.4 versus positive/rapid). In contrast, an antagonistic gene-gene interaction was seen among smoking cases for both AL and MF. Only currently smoking cases with the combined GSTM1 null and NAT2 rapid genotype showed a positive correlation between lnAL and lnMF (r, 0.64; P = 0.1), and an increase of AL with both age and daily cigarette use. This genotype combination was also associated with high MF among ever-smoking cases (OR, 4.0; 95% CI, 0.9–17.7 versus positive/rapid). There was a significant interaction between NAT2 genotype and pack-years of smoking among cases, so that the rapid genotype was associated with high MF among ever-smoking cases diagnosed at higher pack-years, whereas the slow genotype was associated with high MF at lower pack-years. These findings suggest that the influence of NAT2 genotype on AL and MF and its interaction with GSTM1 genotype may be dose dependent. The NAT2 slow genotype, in particular when combined with the GSTM1 null genotype, may confer increased susceptibility to adduct formation, gene mutation, and lung cancer when the smoking dose is low.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
Most common cancers result from the interaction between genetic and environmental factors (1) . Because lung cancer risk is clearly related to tobacco exposure, genetic susceptibility to lung cancer has been investigated in terms of interindividual variations in the ability to activate or detoxify potential carcinogens such as PAHs³ and aromatic amines present in cigarette smoke. Among enzymes with common polymorphisms are GSTM1, which catalyzes conjugation of diol-epoxide derivatives of PAHs, and NAT2, which generally detoxifies aromatic amine procarcinogens by N-acetylation (2) . Approximately 50% of most Caucasian populations lack GSTM1 activity or are NAT2-slow acetylators.

The GSTM1 deficiency is attributable to a homozygous deletion of the GSTM1 gene (null genotype) and has been associated with increased risk of lung cancer, colorectal cancer, and urothelial cancer (2) . The NAT2-slow phenotype is attributable to homo- or heterozygosity of three major slow alleles (3) , and has been associated with higher risk for bladder cancer (2) . It may also be a risk factor for breast cancer among smoking postmenopausal women (4) . Regarding lung cancer risk, recent studies have shown contradictory results. An increased risk for lung cancer has been associated with the NAT2 rapid genotype in a German study (5) , but with the NAT2 slow genotype in a Japanese study (6) .

The impact of genotypes on lung cancer risk has been supported by their influences on exposure biomarkers of tobacco smoke. A several-times higher urinary mutagenicity has been reported in GSTM1-null smokers as compared with GSTM1-positive smokers (7) . Individuals with the GSTM1-null genotype also have a greater likelihood of having detectable PAH-DNA ALs in lung (8) . Furthermore, benzo(a)pyrene diol-epoxide DNA adducts were detectable in currently smoking lung cancer patients only if they had the GSTM1 null genotype (9) .

Several studies have reported evidence that suggest GSTM1 and NAT2 as concurrent modifiers of genetic susceptibility to DNA damage. We have previously found that among Swedish garage workers with the NAT2 slow genotype, the aromatic DNA AL was significantly higher in those with the GSTM1 null genotype compared with those with GSTM1 present (10) . In a study of coke oven workers (11) , urine mutagenicity was found to occur at a higher frequency among smokers with the GSTM1-null/NAT2-slow combination than among smokers with other genotypes. Similarly, bus drivers with the null/slow combined genotype showed a significantly increased frequency of lymphocytes with chromosomal aberrations as compared with those with the positive/rapid genotype (12) . In addition, a significantly increased risk of developing malignant and nonmalignant pulmonary disorders was reported among asbestos-exposed subjects with the null/slow genotype (13 , 14) .

Recently, in a carefully designed study of Swedish nonsmoking and smoking lung cancer patients and matched population controls, we reported a possible gene-gene interaction (15) , with the NAT2 slow and GSTM1 positive genotype conferring particularly high risk among never smokers. Among smokers, rapid acetylators tended to show a steeper PY-related increase in risk compared with slow acetylators. We then studied the aromatic DNA AL and the MF in the HPRT reporter gene in peripheral lymphocytes of both cases and controls (16) . We found no difference between cases and controls and no effect of ETS among nonsmokers but a significant effect of smoking on the two biological end points in surrogate tissue. In addition, the increase of AL and MF with age and smoking dose was stronger in patients than in controls, which suggested an interaction between smoking and genetic host factors. In the present study, we have studied the influence of GSTM1 and NAT2 genotypes on the two biological end points in smokers, with special emphases on gene-gene and gene-environment interactions.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
Study Subjects.
The current study population originated from a larger epidemiological study designed to investigate the effect of passive smoking on lung cancer risk (17) . Cases were recruited during 1992–1995 at the three major county hospitals in Stockholm County responsible for diagnosis and treatment of lung cancer. Patients were asked to participate in the study when they had received a lung cancer diagnosis. Each never-smoking case was used as an index case for next diagnosed ever-smoking case of the same gender and age (30–49, 50–69, and 70 years) in the same hospital. Healthy population controls were extracted from the Stockholm residence files every 6 months and frequency matched to cases in regard to hospital catchment area, gender, and age group, as well as broad smoking categories: "smoker" (current or recent-quit within 2 years), former smoker and never smoker. Detailed exposure data on smoking, ETS (from spouse, work, or other places), and dietary habits, as well as residential and working histories, were collected mainly by personal interview according to a standard questionnaire.

A total of 185 cases and 164 controls supplied blood for genotyping (15) and measurement of aromatic DNA ALs and HPRT MFs (16) . More than 70% of the subjects were women. The age distribution was very similar in the groups of patients (median, 69; range, 30–92 years) and controls (median, 68; range, 30–89 years) because of matching. The patients had, however, a significantly higher dose, duration, or PYs of smoking and longer passive smoke exposures than the controls (16) . The majority of cases had adenocarcinoma (51%) or squamous cell carcinoma (22%). Ever smokers had a higher proportion of squamous cell carcinoma than never smokers (37% versus 7%), whereas adenocarcinomas were more frequent among never smokers (62%) than among ever smokers (40%).

All except 10 blood samples were taken before radio- or chemotherapy. All of the cases were, however, considered as eligible as the treatment was assumed not to affect the aromatic DNA AL nor the HPRT MF because the time between initiation of treatment and blood sampling was too short for expression of any induced mutants. Lymphocytes and granulocytes were isolated after density separation in Polymorphprep (Pharmacia, Sweden). The former were frozen (-135°C) in aliquots for subsequent mutant selection and adduct measurement, and the latter were freshly used for DNA isolation (using saturated NaCl) and genotyping.

Genotyping.
The principles and details of the methods for GSTM1 and NAT2 genotyping have been described previously (10 , 15) . The presence or absence of the GSTM1 gene was detected by genomic PCR amplification of a short internal GSTM1 gene segment (177 bp) together with a NAT2 segment (284 bp) as an internal PCR control. Individuals with one or two copies of the GSTM1 allele were designated GSTM1 positive. Individuals with homozygous deletion of the GSTM1 allele were designated GSTM1 null.

Identification of the slow NAT2 alleles was performed by restriction analysis of a 578-bp genomic PCR product covering a large part of the intronless NAT2 coding region. The predominating NAT2*5A/B (341C, 481T) and NAT2*6A/B (590A) alleles (18) were identified by loss of a restriction site for KpnI and TaqI, respectively. Individuals in whom no, or only one, slow allele could be identified by these enzymes were further analyzed by BamHI and DdeI digestions for the identification of the NAT2*7A/B (857A) and NAT2*5C (341C, 803G) alleles, respectively. Individuals with at least one wild-type allele were classified as rapid, and those with two slow alleles as slow.

Aromatic DNA AL.
The ³²P TLC assay of aromatic DNA adducts was carried out as described previously (19) . In brief, DNA was extracted from the crude nuclei, using organic solvents after degrading RNAs and proteins, and was digested by micrococcal nuclease and spleen phosphodiesterase to 3' nucleotides. Adducts were then enriched by nuclease P1 treatment. A postlabeling reaction was carried out and applied on a TLC plate for adduct separation in three dimensions. After autoradiography, the adduct spots were excised from the TLC plate for the counting of radioactivity. Two to five assays were carried out for each sample.

HPRT MF.
Four matched lymphocyte samples (one from each of the four study groups) were analyzed concurrently to minimize the influence of possible methodological variation over time. The culture media used and the T-cell cloning procedure have been described in detail previously (20) . Briefly, all of the cells were stimulated for 44 h with 0.3% phytohemagglutinin (PHA, Difco) in RPMI 1640-based medium containing 5% FCS and 5% human serum, and then were subjected to cloning in a T-cell growth factor-enriched medium with or without 6-thioguanine.

The MF was obtained by dividing the cloning efficiency in the presence of 6-thioguanine by that in the absence of 6-thioguanine. A 95% CI was calculated for each MF from the variance of lnMF. Seven MF values with large CIs (>5 x MF, related to low cloning efficiency or too few positive or seeded wells in selection plates) were excluded from statistical analysis (16) .

Statistical Analysis.
The Wilcoxon rank-sum test was used to test differences in AL or MF between groups. The distribution of AL or MF was normalized by ln-transformations, and the influence of various factors on lnAL or lnMF was studied by multiple linear regression. Factors studied include age, gender, case status, smoking category, average or last daily cigarette dose and PYs of smoking. Strongly correlated variables, such as age and PY, were not used in the same model to assure the independence of explanatory variables. The relationship between lnAL and lnMF was quantified using Pearson’s correlation coefficient.

To allow calculation of ORs with 95% CIs, with adjustment for potential confounding factors, multiple logistic regression was carried out after assigning each AL (or MF) value high or low using the overall median level as cutoff point. Joint effects between two genotypes were studied by creating dummy variables, each representing the combination of two genotypes, with the putative low-risk combination as reference category. Departures from a multiplicative interaction model (as implicitly assumed by logistic regression) were evaluated by adding interaction terms to the main effect model. To plot interaction, a lnOR value was predicted for each individual using the ß-coefficients for the two main effects and the interaction term.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
AL.
Table 1 shows the ALs measured in a total of 171 cases and 146 controls. Smokers (current or recent) showed significantly higher ALs than nonsmokers (former or never). This difference was most clear among controls (median, 4.1 versus 3.4 per 10⁸ nucleotides; Wilcoxon P = 0.005) although the cigarette dose in smoking controls was significantly lower than in smoking cases (median, 11.6 versus 14.2 cigarettes/day; Wilcoxon P = 0.02). There was no apparent genotype effect in any of the subgroups, but controls with the NAT2 slow genotype showed consistently higher AL than controls with the rapid genotype.

View larger version (6K): [in this window] [in a new window]   Fig. 1. Correlation between lnMF and lnAL in currently smoking cases with the GSTM1 null genotype (n = 12; r, 0.54). lnMF = 2.13 (P = 0.002) + 0.70*lnAL (P = 0.07). , Null/rapid; , Null/slow.

View larger version (9K): [in this window] [in a new window]   Fig. 2. Interaction between NAT2 genotype and PYs of smoking on the risk (lnOR) for high MF (above the median of ever smokers, 18.6) among ever-smoking cases. ß = 2.51 (P = 0.017) for the slow genotype; ß = 0.040 (P = 0.085) for PY; ß = -0.085 (P = 0.006) for the interaction term slow*PY, adjusted for gender. , NAT2 rapid; , NAT2 slow.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

Also the antagonistic interaction between the GSTM1 null and NAT2 slow genotypes on MF among cases, as opposed to the synergistic interaction among controls, may be related to the high PY of smoking in the case group. This is supported by the similar difference in interaction pattern among smokers stratified by PY level instead of case status. Indeed, all but 1 of the 11 ever-smoking cases with the GSTM1 null/NAT2 rapid combination and high MF had PY above 23. Thus, the NAT2 rapid genotype may be associated with high MF among high-PY smokers with the GSTM1 null genotype. The NAT2 slow genotype may, however, be associated with high MF at lower PY in combination with the GSTM1 null genotype.

The impact of smoking dose on the influence of NAT2 genotype on MF was further demonstrated by the significant interaction of NAT2 genotype with PY of smoking on the odds for high MF among ever-smoking cases. Whereas the NAT2 rapid genotype appeared to be associated with high MF at higher PY, the slow genotype was associated with high MF at lower PY. A similar interaction was observed between the slow genotype and age on lnMF in currently smoking cases (data not shown). Among cases diagnosed at younger age, slow acetylators tended to show higher MF than rapid acetylators, whereas the known positive association with age (16) was evident only for rapid acetylators. The rapid genotype appears, thus, to be associated with an accumulation of mutants as age and cumulative dose reaches higher levels. The rapid genotype was also previously shown to confer greater lung cancer risk at these higher PY levels than did the slow genotype (15) . Homozygous rapid NAT2 genotype has been associated with an increased lung cancer risk in a German study (5) . Notable is that the 17 cases (of 155) with the homozygous rapid genotype were relatively old but did not have a exceedingly high cigarette consumption. In a recent study of Norwegian nonoperable lung cancer patients (21) , a clear overrepresentation of NAT2 slow genotypes was seen among those who were younger (63 years), as well as among younger light smokers (PY 30). Consistent with above findings, the NAT2 slow genotype was more markedly associated with an increased risk for adenocarcinoma in a Japanese study (6) , when the analysis was confined to patients under the age of 65. The incidence of p53 mutations among the younger adenocarcinoma patients who had the slow genotype was also higher than that among patients with the rapid genotype. These results suggest that individuals with the NAT2 slow genotype may represent a group that is more prone to acquire gene mutations and lung cancer at younger age or lower PY of smoking. Conversely, with the rapid genotype, high MF and lung cancer risk results only with high age or cumulative smoking dose because most somatic mutations are known to be persistent over time (16) .

Considering the detoxification reactions catalyzed by NAT2 and the method used for adduct measurement, the observed association between the NAT2-slow genotype and high AL in controls is perhaps surprisingly strong. The enrichment of DNA adducts in the present study was carried out by digestion with nuclease P1, which may have caused arylamines bound to the C8 position of guanine to be lost more extensively than if the butanol extraction method has been used (22) . However, extensive or complete recovery should be obtained from aromatic amines and PAHs bound to the exocyclic positions of guanine or adenine in the present work. The bottom line is that the identity of adducts detected by the present postlabeling method is unknown, as is the proportion of PAH-DNA adducts (19 , 22) .

Further supporting our AL data are the low-dose dependency of the NAT2 effect and its interaction with the GSTM1 null genotype, which is in agreement with what we found on MF. The NAT2 effect is also consistent with the study of Vineis et al. (23) , who found a higher level of 4-aminobiphenyl-hemoglobin adducts in slow acetylators compared with rapid acetylators, but only at low or zero nicotine-cotinine levels. Our data on genotype-related AL and MF in nonsmokers do not support the previous finding of an increased lung cancer risk among never smokers with the GSTM1 positive and NAT2 slow genotype (15) . Rather, a positive interaction between the GSTM1 null and the NAT2 slow genotype on MF was seen among never-smoking controls, similar to that seen among ever-smoking controls. This is consistent with the fact that the vast majority of never smokers (if not all) were ever exposed to ETS, and controls had an overall much lower cumulative smoking and ETS dose compared with cases. These results suggest that the NAT2 slow genotype, in particular when combined with the GSTM1 null genotype, may confer increased susceptibility to tobacco mutagens when exposure is low. It is plausible that at higher exposures, the effect of NAT2 genotype regulating carcinogen detoxification may be overwhelmed, and other metabolic pathways or mechanisms such as DNA repair activity or efficiency may play a more important role for individual susceptibility.

Our present study confirms the important role of gene-gene and gene-environment interaction in the etiology of common cancer such as lung cancer (1) . Additional studies in regard to the effect of dietary factors and other genetic polymorphisms, especially those involved in DNA repair, will be necessary to further improve understanding of individual susceptibility to DNA damage, gene mutation, and the development of lung cancer.

	Footnotes

 
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 Supported by the Swedish Cancer Society.

² To whom requests for reprints should be addressed, at Environmental Medicine Unit, The Karolinska Institute, CNT/NOVUM, S-141 57 Huddinge Sweden.

³ The abbreviations used are: PAH, polycyclic aromatic hydrocarbon; ETS, environmental tobacco smoke; GSTM1, glutathione S-transferase M1; NAT2, N-acetyl transferase 2; HPRT, hypoxanthine-guanine phosphoribosyl transferase; MF, mutant frequency; AL, adduct level, OR, odds ratio; CI, confidence interval; PY, pack-year (1 pack of cigarettes/day for 1 year).

Received 6/ 6/00; revised 10/24/00; accepted 11/29/00.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Perera F. P. Environment and cancer: who are susceptible?. Science (Washington DC), 278: 1068-1073, 1997.[Abstract/Free Full Text]
2. D’Errico A., Taioli E., Chen X., Vineis P. Genetic metabolic polymorphisms and the risk of cancer: a review of the literature.. Biomarkers, 1: 149-173, 1996.
3. Cascorbi I., Drakoulis N., Brockmoller J., Maurer A., Sperling K., Roots I. Arylamine N-acetyltransferase (NAT2) mutations and their allelic linkage in unrelated Caucasian individuals: correlation with phenotypic activity.. Am. J. Hum. Genet., 57: 581-592, 1995.[Medline]
4. Ambrosone C. B., Freudenheim J. L., Graham S., Marshall J. R., Vena J. E., Brasure J. R., Michalek A. M., Laughlin R., Nemoto T., Gillenwater K. A., Shields P. G. Cigarette smoking, N-acetyltransferase 2 genetic polymorphisms, and breast cancer risk.. J. Am. Med. Assoc., 276: 1494-1501, 1996.[Abstract]
5. Cascorbi I., Brockmoller J., Mrozikiewicz P. M., Bauer S., Loddenkemper R., Roots I. Homozygous rapid arylamine N-acetyltransferase (NAT2) genotype as a susceptibility factor for lung cancer.. Cancer Res., 56: 3961-3966, 1996.[Abstract/Free Full Text]
6. Oyama T., Kawamoto T., Mizoue T., Yasumoto K., Kodama Y., Mitsudomi T. N-acetylation polymorphism in patients with lung cancer and its association with p53 gene mutation.. Anticancer Res, 17: 577-581, 1997.[Medline]
7. Hirvonen, A., Nylund, L., Kociba, P., Husgafvel-Pursiainen, K., and Vainio, H. Modulation of urinary mutagenicity by genetically determined carcinogen metabolism in smokers [published erratum appears in Carcinogenesis, 15: 1767, 1994].Lond.), 15: 813–815, 1994.
8. Shields P. G., Bowman E. D., Harrington A. M., Doan V. T., Weston A. Polycyclic aromatic hydrocarbon-DNA adducts in human lung and cancer susceptibility genes.. Cancer Res., 53: 3486-3492, 1993.[Abstract/Free Full Text]
9. Rojas M., Alexandrov K., Cascorbi I., Brockmoller J., Likhachev A., Pozharisski K., Bouvier G., Auburtin G., Mayer L., Kopp-Schneider A., Roots I., Bartsch H. High benzo[a]pyrene diol-epoxide DNA adduct levels in lung and blood cells from individuals with combined CYP1A1 MspI/Msp-GSTM1*0/*0 genotypes.. Pharmacogenetics, 8: 109-118, 1998.[Medline]
10. Hou S.-M., Lambert B., Hemminki K. Relationship between hprt mutant frequency, aromatic DNA adducts and genotypes for GSTM1 and NAT2 in bus maintenance workers.. Carcinogenesis (Lond.), 16: 1913-1917, 1995.[Abstract/Free Full Text]
11. Gabbani G., Hou S. M., Nardini B., Marchioro M., Lambert B., Clonfero E. GSTM1 and NAT2 genotypes and urinary mutagens in coke oven workers.. Carcinogenesis (Lond.), 17: 1677-1681, 1996.[Abstract/Free Full Text]
12. Knudsen L. E., Norppa H., Gamborg M. O., Nielsen P. S., Okkels H., Soll-Johanning H., Raffn E., Jarventaus H., Autrup H. Chromosomal aberrations in humans induced by urban air pollution: influence of DNA repair and polymorphisms of glutathione S-transferase M1 and N-acetyltransferase 2.. Cancer Epidemiol. Biomark. Prev., 8: 303-310, 1999.[Abstract/Free Full Text]
13. Hirvonen A., Pelin K., Tammilehto L., Karjalainen A., Mattson K., Linnainmaa K. Inherited GSTM1 and NAT2 defects as concurrent risk modifiers in asbestos-related human malignant mesothelioma.. Cancer Res., 55: 2981-2983, 1995.[Abstract/Free Full Text]
14. Hirvonen A., Saarikoski S. T., Linnainmaa K., Koskinen K., Husgafvel-Pursiainen K., Mattson K., Vainio H. Glutathione S-transferase and N-acetyltransferase genotypes and asbestos-associated pulmonary disorders.. J. Natl. Cancer Inst., 88: 1853-1856, 1996.[Abstract/Free Full Text]
15. Nyberg F., Hou S. M., Hemminki K., Lambert B., Pershagen G. Glutathione S-transferase µ1 and N-acetyltransferase 2 genetic polymorphisms and exposure to tobacco smoke in nonsmoking and smoking lung cancer patients and population controls.. Cancer Epidemiol. Biomark. Prev., 7: 875-883, 1998.[Abstract]
16. Hou S. M., Yang K., Nyberg F., Hemminki K., Pershagen G., Lambert B. Hprt mutant frequency and aromatic DNA adduct level in non-smoking and smoking lung cancer patients and population controls.. Carcinogenesis (Lond.), 20: 437-444, 1999.[Abstract/Free Full Text]
17. Nyberg F., Agrenius V., Svartengren K., Svensson C., Pershagen G. Environmental tobacco smoke and lung cancer in nonsmokers: does time since exposure play a role?.. Epidemiology, 9: 301-308, 1998.[Medline]
18. Vatsis K. P., Weber W. W., Bell D. A., Dupret J. M., Evans D. A., Grant D. M., Hein D. W., Lin H. J., Meyer U. A., Relling M. V., Sim E., Suzuki T., Yamazoe Y. Nomenclature for N-acetyltransferases.. Pharmacogenetics, 5: 1-17, 1995.[Medline]
19. Yang K., Airoldi L., Pastorelli R., Restano J., Guanci M., Hemminki K. Aromatic DNA adducts in lymphocytes of humans working at high and low traffic density areas.. Chem. Biol. Interact., 101: 127-136, 1996.[Medline]
20. Hou S. M., Fält S., Steen A. M. Hprt mutant frequency and GSTM1 genotype in non-smoking healthy individuals.. Environ. Mol. Mutagen., 25: 97-105, 1995.[Medline]
21. Hou S. M., Ryberg D., Fält S., Deverill A., Tefre T., Borresen A. L., Haugen A., Lambert B. GSTM1 and NAT2 polymorphisms in operable and non-operable lung cancer patients.. Carcinogenesis (Lond.), 21: 49-54, 2000.[Abstract/Free Full Text]
22. Gupta R. C., Earley K. ³²P-adduct assay: comparative recoveries of structurally diverse DNA adducts in the various enhancement procedures.. Carcinogenesis (Lond.), 9: 1687-1693, 1988.[Abstract/Free Full Text]
23. Vineis P., Bartsch H., Caporaso N., Harrington A. M., Kadlubar F. F., Landi M. T., Malaveille C., Shields P. G., Skipper P., Talaska G., Tannenbaum S. R. Genetically based N-acetyltransferase metabolic polymorphism and low-level environmental exposure to carcinogens.. Nature (Lond.), 369: 154-156, 1994.[Medline]

This article has been cited by other articles:

				C. Carlsten, G. S. Sagoo, A. J. Frodsham, W. Burke, and J. P. T. Higgins Glutathione S-Transferase M1 (GSTM1) Polymorphisms and Lung Cancer: A Literature-based Systematic HuGE Review and Meta-Analysis Am. J. Epidemiol., April 1, 2008; 167(7): 759 - 774. [Abstract] [Full Text] [PDF]

				H. E. Liu, P.-Y. Hsiao, C.-C. Lee, J.-A. Lee, and H.-Y. Chen NAT2*7 Allele Is a Potential Risk Factor for Adult Brain Tumors in Taiwanese Population Cancer Epidemiol. Biomarkers Prev., March 1, 2008; 17(3): 661 - 665. [Abstract] [Full Text] [PDF]

				A. G. Schwartz, G. M. Prysak, C. H. Bock, and M. L. Cote The molecular epidemiology of lung cancer Carcinogenesis, March 1, 2007; 28(3): 507 - 518. [Abstract] [Full Text] [PDF]

				T. Kohno, T. Sakiyama, H. Kunitoh, K. Goto, Y. Nishiwaki, D. Saito, H. Hirose, T. Eguchi, N. Yanagitani, R. Saito, et al. Association of polymorphisms in the MTH1 gene with small cell lung carcinoma risk Carcinogenesis, December 1, 2006; 27(12): 2448 - 2454. [Abstract] [Full Text] [PDF]

				P. Wallstrom, K. Frenkel, E. Wirfalt, B. Gullberg, J. Karkoszka, J. Seidegard, L. Janzon, and G. Berglund Antibodies against 5-Hydroxymethyl-2'-deoxyuridine Are Associated with Lifestyle Factors and GSTM1 Genotype: A Report from the Malmo Diet and Cancer Cohort Cancer Epidemiol. Biomarkers Prev., May 1, 2003; 12(5): 444 - 451. [Abstract] [Full Text] [PDF]

				F. Nyberg, S.-M. Hou, G. Pershagen, and B. Lambert Dietary fruit and vegetables protect against somatic mutation in vivo, but low or high intake of carotenoids does not Carcinogenesis, April 1, 2003; 24(4): 689 - 696. [Abstract] [Full Text] [PDF]

				K. Alexandrov, I. Cascorbi, M. Rojas, G. Bouvier, E. Kriek, and H. Bartsch CYP1A1 and GSTM1 genotypes affect benzo[a]pyrene DNA adducts in smokers' lung: comparison with aromatic/hydrophobic adduct formation Carcinogenesis, December 1, 2002; 23(12): 1969 - 1977. [Abstract] [Full Text] [PDF]

				D. H. Phillips Smoking-related DNA and protein adducts in human tissues Carcinogenesis, December 1, 2002; 23(12): 1979 - 2004. [Abstract] [Full Text] [PDF]

				J. D. Hunt, A. Strimas, J. E. Martin, M. Eyer, M. Haddican, B. G. Luckett, B. Ruiz, T. W. Axelrad, W. L. Backes, and E. T. H. Fontham Differences in KRAS Mutation Spectrum in Lung Cancer Cases between African Americans and Caucasians after Occupational or Environmental Exposure to Known Carcinogens Cancer Epidemiol. Biomarkers Prev., November 1, 2002; 11(11): 1405 - 1412. [Abstract] [Full Text] [PDF]

				G E Goodman Lung cancer * 1: Prevention of lung cancer Thorax, November 1, 2002; 57(11): 994 - 999. [Abstract] [Full Text] [PDF]

				S.-M. Hou, S. Falt, S. Angelini, K. Yang, F. Nyberg, B. Lambert, and K. Hemminki The XPD variant alleles are associated with increased aromatic DNA adduct level and lung cancer risk Carcinogenesis, April 1, 2002; 23(4): 599 - 603. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hou, S.-M. Articles by Lambert, B. Search for Related Content PubMed PubMed Citation Articles by Hou, S.-M. Articles by Lambert, B.