GSTM1 and NAT2 polymorphisms in operable and non-operable lung cancer patients
Sai-Mei Hou4,
David Ryberg1,
Susann Fält,
An Deverill1,
Toril Tefre2,
Anne-Lise Børresen3,
Aage Haugen1 and
Bo Lambert
Environmental Medicine Unit, Department of Biosciences, Karolinska Institute, CNT/NOVUM, S-141 57 Huddinge, Sweden,
1 Department of Toxicology, National Institute of Occupational Health, PO Box 8149 Dep, 0033 Oslo,
2 Deparment of Health Care Education, Oslo College, Pilestredet 52, 0167 Oslo and
3 Department of Genetics, Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway
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Abstract
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We have genotyped 657 Norwegian men, including 282 lung cancer patients (147 non-operable and 135 operable) and 375 healthy referents (210 smokers and 165 non-smokers), to study the possibility that glutathione S-transferase M1 (GSTM1)-null and/or N-acetyl transferase 2 (NAT2)-slow genotypes confer susceptibility towards lung cancer in smokers. Compared with smoking referents, there was a significant over-representation of the GSTM1-null genotype among patients with squamous cell carcinoma (SQ) [odds ratio (OR) = 1.7, 95% confidence interval (95%CI) = 1.12.7], and the NAT2-slow genotype among patients with large cell carcinoma or mixed histological diagnosis (LM) (OR = 2.5, 95%CI = 1.06.1). In contrast to operable patients, non-operable patients showed a clear over-representation of slow genotypes if they were younger (
63 years; versus older: OR = 3.9, 95%CI = 1.78.8) or younger light smokers [
30 pack-years (PY); versus heavy smokers: OR = 5.7, 95%CI = 1.423.3]. Among younger light smokers, the slow genotype appeared to be associated with an increased risk of developing non-operable tumours only (OR = 6.3, 95%CI = 1.920.4), especially other types of tumours than SQ (OR = 10.8, 95%CI = 1.483.9). The null genotype (OR = 3.9, 95%CI = 1.113.5) and the null/slow combination (OR = 4.5, 95%CI = 1.513.8) seemed to increase the risk for non-operable SQ only. These results are supported by logistic regressions of patients allowing interactions between tumour type (or treatment) and PY (or age), and indicate that the GSTM1-null genotype could be an important susceptibility factor for SQ while the NAT2-slow genotype may have an impact on other types of lung cancer. Individuals with the GSTM1-null and/or NAT2-slow genotypes may constitute susceptible groups with increased risk to contract non-operable lung cancer at younger age and lower smoking dose.
Abbreviations: AD, adenocarcinoma; CI, confidence interval; GSTM1, glutathione S-transferase M1; LM, large cell carcinoma and mixed histological diagnosis; NAT2, N-acetyl transferase 2; OR, odds ratio; PAH, polycyclic aromatic hydrocarbon; PY, pack-year; SM, small cell carcinoma; SQ, squamous cell carcinoma.
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Introduction
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Genetically determined susceptibility to carcinogen exposure has been suggested to be one of the most important host factors in human cancer (reviewed in 1). Since lung cancer risk is clearly related to tobacco exposure, genetic susceptibility to lung cancer has been investigated in terms of variations in the ability to activate or detoxify potential carcinogens such as polycyclic aromatic hydrocarbons (PAHs) present in cigarette smoke. Most studies have focused on the polymorphism of the activating (phase I) cytochrome P450 enzymes such as CYP1A1 and CYP2D6, and the detoxifying (phase II) enzyme glutathione S-transferase M1 (GSTM1) which catalyses conjugation of electrophilic diol-epoxide derivatives of PAHs (reviewed in 1). Relatively few lung cancer studies have considered N-acetyl transferase 2 (NAT2), which primarily catalyses the N-acetylation of aromatic amine procarcinogens contained in tobacco smoke and functions as a phase II enzyme. Since half of the Caucasian population lack the GSTM1 activity or are slow acetylators, the implication of these polymorphisms in lung cancer need to be further elucidated, especially in terms of the combined genotypes.
The GSTM1 deficiency is due to a homozygous deletion of the gene (null genotype) and was initially associated with an increased risk of lung cancer (2). Later, the deficiency was also found to predispose individuals to colorectal cancer and urothelial cancer (reviewed in 1), indicating that GSTM1 may be protective against aromatic amines as well as PAHs. Although the increased frequency of GSTM1 deficiency in lung cancer patients could not be confirmed in some studies, combined data from 12 case-control reports have suggested the GSTM1 deficiency to be a moderate risk factor for all major histological subtypes of lung cancer (3). GSTM1 is only weakly expressed in lung tissue, but the possession of the GSTM1 gene appears to determine the enzyme activity of both GSTM1 (4) and GSTM3 (5,6) in lung. This may be related to the finding that the GSTM3 gene is also polymorphic and the GSTM3*B allele is linked to the GSTM1*A allele (7).
Several studies (811) have, however, indicated that the putative GSTM1-associated lung cancer susceptibility may be influenced by age, gender and smoking dose, and differ with regard to tumour histology. The inconsistency in the results across studies may also partly be explained by difference in tumor stage, as suggested by recent findings. The GSTM1 polymorphism has been associated with performance status, the extent of regional lymph node and distant metastasis in patients with non-small-cell lung cancer, with a significantly higher frequency of the null genotype in non-operable patients compared with operable patients (12). Also in multiple cutaneous basal cell carcinomas (13) and primary breast cancers (14), the GSTM1 deficiency appeared to correlate with high tumour numbers or histological grading and low age at diagnosis.
At least 19 variant NAT2 alleles have been detected in the human population (15), but the NAT2*5, *6 and *7 alleles account for virtually all of the slow acetylator alleles in Caucasian populations, providing evidence for a high concordance between genotype and phenotype (16). The slow acetylator phenotype has been associated with lower risk for colorectal cancer but higher risk for occupational and smoking related bladder cancer (reviewed in 1). It has also been suggested that the NAT2-slow genotype is an important risk factor for breast cancer among post-menopausal women who are smokers (17). With regard to lung cancer risk, there was no association with NAT2-slow or rapid genotypes in a Spanish study (18). In contrast, the homozygous rapid genotype was associated with increased risk in a German study (19), and the slow acetylator status with increased risk in a Japanese study (20). Interestingly, Hirvonen et al. (21,22) reported a significantly increased risk of developing malignant and non-malignant pulmonary disorders among asbestos-exposed subjects with the combined GSTM1-null/NAT2-slow genotype.
To further study the possible influence of GSTM1 and NAT2 polymorphisms on lung cancer risk, we have used PCR-based techniques to identify the GSTM1-null individuals and the slow acetylators among operable and non-operable lung cancer patients. The results suggest that the genotype-related variation in lung cancer risk was modified by age and smoking, and differ with regard to tumour histology and stage.
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Materials and methods
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Study population
All subjects were males of Norwegian origin. Informed consent was obtained from each subject and all samples were coded after collection of blood and data (questionnaire on smoking habits, occupation and family history of cancer, etc.). The lung cancer patients have been included in previous studies (23,24). A total of 147 of the patients were consecutively admitted to the Norwegian Radium Hospital (Oslo) for non-surgical treatment (non-operable), and 135 to Haukeland Hospital (Bergen) or the National Hospital (Oslo) for surgical treatment (operable). Operable lung cancers account for ~15% of all diagnosed lung cancer cases in Norway. Non-small-cell lung cancer of stages I and II are generally surgically treated. Tumours of non-small-cell type with higher staging usually get radio-chemotherapy.
Histological data were available for all but four non-operable and 21 operable patients (Table I
). Squamous cell carcinoma (SQ) predominated in both groups (62/143 and 67/114, respectively). Small cell carcinomas (SM) were generally considered as non-operable, and represented the second largest group of non-operable tumors (41/143), but two cases of SM were included in the operable group. The non-operable group had fewer adenocarcinoma (AD, 22/143) than the operable group (32/114), but the fraction of large cell carcinoma or mixed histological diagnosis (LM) was comparable between the groups (18/143 and 13/114, respectively).
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Table I. Distribution of GSTM1 and NAT2 genotypes among patients and referents stratified by the tumour histology or median age of patients
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The patients had a mean age (at the time of diagnosis) of 64 and 63 years, respectively (median 63 years, range 3085 years, four missing values in each group). The vast majority were known as smokers (current or former; 114/117 and 130/135, 30 and 0 missing data, for non-operable and operable patients, respectively). Detailed smoking data were available for 115 non-operable patients and 102 operable patients. The average tobacco consumption was 33 and 34 pack-years (PY) (1 PY = 20 cigarettes per day or 150 g of tobacco per week in 1 year), respectively (median 30 years, range 6122 years).
A total of 375 healthy Norwegian men (current or previous workers), 210 smokers and 165 non-smokers, were arbitrarily selected from several different companies in Norway, and genotyped as referents. They had a mean age of 50 years (median 47 years, range 2389 years). Information on cigarette consumption was available for 208 of the smokers and their PY ranged from 0.01 to 80 (mean 17 PY, median 14 PY).
GSTM1-genotyping
Genomic DNA were isolated either manually by phenolchloroform extraction or automatically on a nucleic acid extractor (23). The presence or absence of the GSTM1 gene in the non-operable patients and in 105 of the referents was detected by genomic PCR amplification of a short internal GSTM1 gene segment (177 bp, intron 4exon 5) together with a NAT2 segment (284 bp) as an internal PCR control. The primer sequences and the PCR conditions (annealing at 55°C) have been described elsewhere (25). The operable patients and the remaining 270 referents were genotyped using coamplification of the GSTM2 gene as internal control (26). A common sense primer was applied together with a gene-specific antisense primer to amplify a 270 bp GSTM1 and a 160 bp GSTM2 fragment. The PCR reaction was carried out with an annealing temperature of 53°C. Individuals with one or two copies of the GSTM1-allele showed both the GSTM1 and the control band, and were designated GSTM1-positive (+). Individuals with homozygous deletion of the GSTM1-allele had only the control gene amplified, and were designated GSTM1-null ().
NAT2 genotyping
Identification of the slow NAT2 alleles in the non-operable patients and in 105 of the referents was performed by restriction analysis of a 578 bp genomic PCR product covering a large part of the intronless NAT2 coding region, as described previously (25). The predominating NAT2*5A/B (341C, 481T) and NAT2*6A/B (590A) alleles (15) were identified by loss of a restriction site for KpnI and TaqI, respectively. Individuals in whom no or only one of the slow alleles could be identified by these enzymes were further analysed by BamHI and DdeI digestions for the identification of the NAT2*7A/B (857A) and NAT2*5C (341C, 803G) alleles, respectively. A genotyping strategy using the same four restriction digests but for all samples (27) was applied for the operable patients and the remaining referents. Individuals homo- or heterozygous for the wild-type allele were considered as NAT2-rapid (R), and those homozygous for the slow alleles as NAT2-slow (S). The NAT2 genotyping was successful for all but one non-operable patient.
Statistical methods
Differences in age and PY of smoking between groups were analysed by the MannWhitney U-test. The
2 test was used to study differences in the genotype distributions. Relative risk was estimated with odds ratio (OR) and the Cornfield 95% confidence interval (95%CI). In case of small sample size, the Woolf 95%CI was used. The MantelHaenszel heterogeneity test was used to compare age-related genotype distributions between different groups. P-values (two-sided) below 0.05, or OR with a 95%CI over or below 1.0 were considered statistically significant. Logistic regression was used to examine interactions between genotype and smoking (PY or age, second degree polynomial) with regard to lung cancer risk (case status as outcome variable), adjusting for other genotype and age (or PY, second degree polynomial). Since the patients had higher age and PY than the referents, an age stratification (below and over the median patient age of 63) was included in all models as an indicator variable.
A case-series design (28) was also used to assess the ratio of cancer risk associated with smoking (or age) for GSTM1() versus GSTM1(+) genotype, or slow versus rapid acetylators. PY (or age, including quadratic and interaction terms) was regressed on the genotype among cases only, adjusting for the other polymorphism, treatment, histology and age (or PY). Similar analyses were carried out to study the interactions between genotype and PY (or age) with regard to the relative risk of different tumours. Representative interaction models are shown with the fitted logits (lnOR) calculated from the ß-coefficients of interaction variables and terms, adjusted for other variables included in the model.
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Results
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The overall frequencies of the GSTM1-null (53.2%) and NAT2-slow genotypes (60.1%) in the patients were not significantly different from that in the referents (smokers or non-smokers) (Table I
). Referents older than the median age of 63 years had a relatively low fraction of GSTM1-null genotype (40%), but did not differ significantly from younger referents (OR = 1.5, 95%CI = 0.92.5) or older patients (OR = 1.5, 95%CI = 0.92.6). The age-related distribution of NAT2 genotype among the patients was, however, significantly different from that in the referents (P = 0.04). In contrast to the referents, younger patients had a significant over-representation of slow genotypes compared with older patients (OR = 1.8, 95%CI = 1.13.0). Interestingly, the rapid genotype was more common among the older patients than among the older referents (OR = 1.6, 95%CI = 1.02.9).
With regard to tumour histology (Table I
), the GSTM1-null genotype was least frequent among patients with non-operable LM (33.3%) or operable AD (43.8%), but most common among patients with operable SQ (62.7%) or LM (61.5%). The frequency of the null genotype in all SQ patients (58.9%) was significantly higher than that in smoking referents (45.7%; OR = 1.7, 95%CI = 1.12.7). The NAT2-slow genotype was most frequent among operable (76.9%) and non-operable patients with LM (83.3%). Together, they had a considerably higher frequency of slow genotypes (80.6%) compared with all other tumour types (57.4%; OR = 3.1, 95%CI = 1.37.6) or smoking referents (62.9%; OR = 2.5, 95%CI = 1.06.1). The numbers of LM patients were, however, limited.
The combined GSTM1 and NAT2 genotypes in smoking patients are shown in Table II
. An apparent heterogeneity in the age-related distribution of NAT2 genotypes between operable and non-operable patients (P = 0.06) was observed, with a clear over-representation of slow genotypes among younger non-operable patients (versus older, OR = 3.9, 95%CI = 1.78.8). In addition, the younger non-operable patients showed a clear over-representation of the null/slow combination (42.3%), with the null genotype slightly more common in slow (53.7%) than in rapid acetylators (45.5%). On the other hand, the combined null/rapid genotype was significantly under-represented among the younger non-operable patients compared with the older non-operable patients (OR = 0.2, 95%CI = 0.10.7). Among the younger non-operable patients, smokers with less than the median PY of 30 showed a higher frequency of the null, slow or null/slow genotype than those with higher PY. In particular, the frequency of slow genotypes among younger low-PY non-operable patients (90.3%) was significantly higher than that in younger high-PY non-operable patients (OR = 5.7, 95%CI = 1.423.3), or in younger low-PY operable patients (OR = 4.4, 95%CI = 1.117.4).
The comparison of genotype distributions among the younger low-PY patients with the corresponding referents (Table III
) indicated that the GSTM1-null genotype increased the risk for SQ only, while the NAT2-slow genotype elevated the risk for other types of tumours mainly. This was, however, mostly due to the non-operable patients. In contrast to operable patients, non-operable patients with SQ had more often the null genotype compared with other non-operable types (OR = 5.2, 95%CI = 1.124.2). Non-operable SQ patients were also the only group showing elevated frequency of the null genotype compared with the referents (OR = 3.9, 95%CI = 1.113.5). Non-operable patients with other types of tumours, however, had a considerably higher frequency of slow genotypes than the referents (OR = 10.8, 95%CI = 1.483.9). The null/slow combination (versus all others) was significantly associated with an elevated risk for non-operable tumours, especially for SQ (OR = 4.5, 95%CI = 1.513.8).
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Table III. Association between the GSTM1/NAT2 genotypes and risk for squamous cell carcinoma (SQ) or other lung tumours in younger ( 63 years) smokers with lower cigarette dose (PY 30)
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Using logistic regression, PY and age (second degree polynomial) were found to be the major and significant factors affecting the lung cancer risk in a model allowing interaction between GSTM1 genotype and age. The GSTM1() genotype was associated with an increase in the cancer risk compared with the GSTM1(+) genotype at younger age only. This could be confirmed by a case-only regression on the GSTM1 genotype allowing interaction between NAT2 genotype and age. The ratio of cancer risk for null versus positive genotype decreased with age, but increased with the SQ status (versus all other types, P = 0.08). When the analysis was confined to the SQ patients, PY, not age, was found to be the major factor affecting the GSTM1-dependent risk ratio (polynomial, P = 0.08). There was an initial decrease followed by an increase with increasing PY, which was due to a clear interaction (P = 0.06) between SQ status (versus others) and PY (polynomial) in addition to a positive contribution (P = 0.05) of the SQ diagnosis (Figure 1
). Similar interaction was obtained when the analysis was confined to non-operable patients (PY <60 among SQ).

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Fig. 1. Interaction between tumour histology (squamous versus non-squamous cell carcinoma) and PY in determining the ratio of lung cancer risk for GSTM1() versus GSTM1(+) genotype. Data from logistic regression of patients only, with fitted logits (lnOR) calculated from the ß-coefficients of interaction variables and terms, adjusted for NAT2 genotype, treatment status and age (strata of below/over 63 years and second degree polynomial).
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With regard to the relative risk associated with the NAT2-slow (versus rapid) genotype, a significant contribution of the GSTM1(+) genotype (P = 0.04) and a moderate interaction between LM status (versus SQ) and PY was observed, with a higher risk ratio for the LM type at lower PY (Figure 2
). When age was allowed to interact with NAT2 genotype and regressed on treatment status, the slow genotype was associated with a higher relative risk for non-operable tumours (versus operable) than the rapid genotype, but only at younger age (Figure 3
). Similarly, when age was allowed to interact with treatment status and regressed on NAT2 genotype, non-operable patients showed a higher NAT2-associated relative risk than operable patients, but again, only at younger age. The interaction was, however, less pronounced when adjusted for tumour histology, and an increased NAT2-dependent risk ratio was mainly associated with the LM diagnosis (versus SQ, P = 0.02), the GSTM1(+) genotype (P = 0.04) and younger age (P = 0.1).

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Fig. 2. Interaction between tumour histology (large and mixed versus squamous cell carcinoma) and PY in determining the relative risk associated with the NAT2-slow (versus rapid) genotype. lnOR were fitted according to the ß-coefficients of interaction variables and terms from logistic regression of patients, with adjustment for GSTM1 genotype, treatment status and age (younger/older than 63 years and second degree polynomial).
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Fig. 3. Interaction between NAT2-genotype and age in determining the risk for developing non-operable tumour relative to operable tumour. Fitted lnOR were calculated from the beta-coefficients of interaction variables and terms from logistic regression of patients, adjusting for GSTM1 genotype, age strata (below/over 63 years) and PY (second degree polynomial).
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Discussion
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In the present collection of Norwegian lung cancer patients, we have found the GSTM1-null genotype to be most frequent in SQ while the NAT2-slow genotype was most common in LM among both operable and non-operable patients (Table I
). However, clear differences in the age/PY- and histology-related distributions of GSTM1/NAT2 genotypes between operable and non-operable patients were observed (Tables II and III
). In particular, the slow genotype was significantly more frequent in the non-operable group compared with the operable group among younger light smokers. This may be partly related to their difference in the interaction between the genotype and age (or PY) (Figure 3
). Among younger light smokers, all the susceptible genotypes seemed to increase the risk for non-operable tumours only: the null and the null/slow genotype for SQ and the slow genotype for other types of tumours (Table III
). The higher null/slow-associated risk estimated for non-operable SQ was mainly due to an increased fraction of the null genotype among slow acetylators. In other words, the influence of null and null/slow, but not the slow genotype per se, was stronger in SQ than in other types of lung tumour.
Although the dichotomizations of patients with regard to age, PY, histology and treatment have reduced the group sizes considerably and the multiple comparisons between small subgroups may have lead to chance associations, the above findings are supported by the logistic regression analysis of patients. The relative risk associated with the two polymorphisms were differently affected by interactions between tumour histology and smoking dose (Figures 1 and 2
). The higher risk ratios estimated for SQ and LM at lower PY were mainly attributable to non-operable patients. The apparently higher GSTM1-associated relative risk for SQ at higher PY was, however, mostly due to operable patients. Indeed, 66% (21/32) of operable SQ, but only 45% (10/22) of non-operable SQ had the null genotype among heavy smokers (PY > 30). This is in agreement with the report of Nazar-Stewart et al. (4), who studied surgically treated patients with primary carcinoma of the lung or bronchus, and found a greater reduction of cancer risk among heavy smokers than among light smokers with high GSTM1 activity.
Consistent with earlier reports (3), our present results from the overall study population are indicative of a modest influence of the GSTM1 genotype on lung cancer risk. However, the stratified analysis revealed a significant association of the GSTM1-null genotype with an increased risk of contracting SQ, especially non-operable tumours in light smokers at younger age. Elevated frequency of the GSTM() genotype has previously been reported in Finnish SQ patients (8), in Swedish female SQ and younger SM patients (9), and in Japanese younger female SQ or SM patients (10). Among the younger smokers (all males) in the present study, non-operable SQ patients (70%) and especially light smokers (79%) showed an over-representation of the null genotype (54% in the heavy smokers and 48% in the referents). This is in contrast to the result of Kihara et al. (10), who found an increasing proportion of the null genotype with increasing tobacco consumption in younger male SQ or SM patients, but in agreement with London et al. (11), who observed an elevated GSTM1-null associated lung cancer risk in lighter smokers only, especially for SQ. However, no information on tumour stage or treatment was available in these reports.
The impact of age and smoking dose was further demonstrated by the finding of a clear association of the NAT2-slow genotype with non-operable tumours in younger individuals who smoked less. The non-operable patients with slow genotypes were indeed significantly younger than those with rapid genotypes (P = 0.01), especially among the GSTM1() patients (P = 0.0008; no such differences existed among the referents). This is consistent with a recent study of 124 Japanese non-small-cell lung cancer patients (20), in which slow acetylators tended to be younger and more common among the patients with AD than among the patients with SQ. A 3-fold relative risk for AD among younger individuals was observed among slow acetylators compared with rapid acetylators. In our present study, the slow/rapid risk ratio appeared to be higher for AD than for SQ at younger age (data not shown), but a more clear interaction was seen between LM and PY (Figure 2
).
In contrast, the relatively rare NAT2-rapid homozygote genotype was associated with an increased risk in a study of 155 German lung cancer patients (19). Notable is that the 17 NAT2*4/4 cases were relatively old but did not have an exceedingly high cigarette consumption. In our present study, only eight patients (2.9%) but 19 referents (5.1%) were rapid homozygotes. However, we did observe an over-representation of rapid acetylators, including both homo- and heterozygotes, among the older patients compared with the older referents (Table I
). In our study of Swedish lung cancer patients and population controls (25), a steeper increase in risk with increasing PY was observed for rapid than for slow acetylators, which could partly be explained by a significant interaction between age and the NAT2 genotype (data not shown). These findings suggest that individuals with the NAT2(R) genotype may have an increased risk of contracting lung cancer at higher age. The reason for this association remains unknown. Lung tissue is deficient in the N-oxidation capability (29) which is normally provided by CYP1A2 and necessary for the activating role of the NAT2- (or NAT1-) associated O-acetyl transferase activity. A significant association was recently observed between the rare NAT1-slow heterozygotes (versus the rare NAT1-rapid homozygotes) and lung cancer risk, without any interaction with NAT2 genotypes (30).
Our results suggest that both GSTM1 and NAT2 polymorphisms affect the risk of developing lung cancer, but the influences are highly dependent on age, smoking dose, tumour histology and stage. While the GSTM1 deficiency could be a major susceptibility factor for SQ, the NAT2-slow status may have an impact on other types of lung cancer. The increased lung cancer risk associated with GSTM1 deficiency and/or slow acetylation seems to be more pronounced for high-stage tumours developing at younger age and after a lower dose of tobacco consumption. Further studies with larger cohorts of male and female patients at different tumour stages and with controls matched to the patients regarding age, gender and smoking may be necessary in order to confirm these observations. Of particular interest would be to compare with non-smoking lung cancer patients. The possible contribution of NAT2 as well as GSTM1 polymorphism to the smoking-related risk of lung cancer is of particular significance due to their high prevalence in the human population.
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Acknowledgments
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We thank Ketil Heimdal (Department of Oncology, Norwegian Radium Hospital) for help in data collection. This study was supported by the Swedish and the Norwegian Cancer Societies and the Swedish Match Research Fund.
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Notes
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4 To whom correspondence should be addressed Email: saimei.hou{at}csb.ki.se 
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Received May 24, 1999;
revised September 23, 1999;
accepted September 30, 1999.