Affiliations of authors: W. P. Bennett, B. Blomeke, J. A. Welsh, E. D. Bowman, M. A. Khan, C. C. Harris (Laboratory of Human Carcinogenesis, Division of Basic Sciences), M. C. R. Alavanja (Radiation Epidemiology Branch, Division of Cancer Epidemiology), National Cancer Institute, Bethesda, MD; K. H. Vähäkangas, K. Castrén, Department of Pharmacology and Toxicology, University of Oulu, Finland; D. B. Flieder, Department of Pathology, Cornell University Medical Center, New York, NY.
Correspondence to: Curtis C. Harris, M.D., National Institutes of Health, Bldg. 37, Rm. 2C01, Bethesda, MD 20892-4255 (e-mail curtis_harris{at}nih.gov).
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ABSTRACT |
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INTRODUCTION |
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Several lung cancer susceptibility genes have been proposed, and enzymes activating or detoxifying chemical carcinogens have been investigated [reviewed in (10,11)]. To date, several cytochrome P450 pathway enzymes that activate chemical carcinogens and several glutathione S-transferase (GST) enzymes that detoxify chemical carcinogens have been associated with lung cancer susceptibility (12-16). The human GSTs are phase II detoxification enzymes encoded by four classes of polymorphic genes: alpha, mu, pi, and theta [reviewed in (17-19)]. All of these enzymes detoxify carcinogens and reactive oxygen species by conjugating them to glutathione, and alterations in the mu and theta class genes have been linked to tobacco-associated lung cancers. The mu class includes at least five genetic variants, and GSTM1 is notable for a "null" allele inactivated by a deletion of DNA coding sequences (20). Loss of GSTM1 enzymatic activity due to the homozygous null genotype occurs in about 50% of white populations of Europe and North America [reviewed in (21-23)], and it has been linked to increased risks of tobacco-associated cancers of the lung (12), head and neck (24,25), larynx (26), and bladder (27-30). Compared with men, women with the GSTM1 null genotype may have greater risks of tobacco-associated cancers (31). A meta-analysis of 1593 patients with lung cancer and 2135 control subjects concluded that GSTM1 deficiency confers an additional 40% risk of lung cancer to the individual cigarette smoker (odds ratio [OR] = 1.4; 95% confidence interval [CI] = 1.2-1.6) and accounts for 17% of all lung cancers because of its high prevalence (12).
The theta class of GSTs contains two isoenzymes including GSTTI (32), which has an inactivating homozygous deletion polymorphism that occurs in 11%-18% of whites (21). A functional deficiency of this enzyme activity (32) was associated with increased risks of smoking-associated laryngeal and bladder cancers (21), and combined deficiency of both GSTT1 and GSTM1 produced a substantial susceptibility to lung cancer in Finnish (16), American (33), and French (34) populations. The cytochrome P450 1A1 (CYP1A1) enzyme activates carcinogenic polycyclic aromatic hydrocarbons including the benzo[a]pyrene component of tobacco smoke (35), and a polymorphic valine allele in exon 7 increases both enzymatic activity and lung cancer risks in Japanese smokers [reviewed in (36)]. Furthermore, there is evidence for a gene-gene interaction between the variant (i.e., "mutant") CYP1A1 allele and homozygous deletion of GSTM1 to produce a more than additive risk of lung cancer in most Japanese and some white smokers [reviewed in (21)].
We extended the classical epidemiologic observations on ETS and lung cancer by conducting a molecular epidemiologic study of gene-environment interactions promoting lung cancer in never-smoking women. Our study was designed specifically to investigate ETS and lung cancer with the use of a population-based series of never-smoking case patients, and it employed telephone and in-person structured interviews to obtain information about multiple lung cancer risk factors, including ETS exposure, age, and intake of vegetables and animal fat (2,4,37). We examined dose-response relationships between ETS and lung cancer risk among women with functional genetic polymorphism for enzymes that activate (i.e., CYP1A1) and detoxify (i.e., GSTM1 and GSTT1) tobacco smoke carcinogens.
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METHODS |
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Exposure dosimetry for ETS. ETS exposure was quantified by telephone interviews determining the source (e.g., parent or spouse), intensity, and duration of exposure during childhood and adulthood (2). One ETS pack-year is the exposure, within a confined space such as a room, to ETS produced by an active smoker consuming one pack of 20 cigarettes each day for a year.
Sample collection. Tissue samples were requested for all 618 lung cancers from
never smokers and ex-smokers in the epidemiologic study (2,4,6,38-40);
request letters were sent to hospitals where resections or diagnostic biopsies were performed.
Archival, formalin-fixed, paraffin-embedded, tumor tissue samples were provided for 132
(21% of requested) patients, including 11 ex-smokers (who were excluded from further
analyses) and 121 never smokers. Composite histologies, average ages, and educational levels for
the 106 never smokers whose tissues yielded DNA and data on GSTM1 status are compared with
results for the entire series of 618 never smokers and ex-smokers to show that the subset analyzed
in this report is comparable to the full series (Table 1).
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Statistical analysis. ORs and 95% CIs were calculated by multiple logistic regression (41), and all comparisons were adjusted for age and other significant factors as defined in previous studies (2,4,6,38-40) (i.e., history of non-neoplastic lung disease, radon exposure, and intake of saturated fat and vegetables). All statistically significant associations were retested with the use of exact methods (46), but adjustments for confounding variables with the use of exact methods could not be performed by commercially available software in this dataset. All P values were calculated as two-sided statistics, which were considered to be significant for P<.05. The linearity of trends in risk according to levels of exposure to ETS was evaluated with a score test, which is equivalent to the Mantel extension test for linear trend (41). All comparisons were adjusted for age and other significant factors as defined in previous studies (2,4,6,38-40) (i.e., history of non-neoplastic lung disease, radon exposure, and intake of saturated fat and vegetables). One can estimate multiplicative gene-environment interactions in logistic models with data from case patients alone with even greater precision than from both case patients and control subjects, provided that the environmental factor and the genotype are statistically independent in the population and the disease is rare (42,47). It is unlikely that GSTM1 status is associated with adult ETS exposure, particularly among lifetime never smokers.
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RESULTS |
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The current series of 106 never-smoking, white women with lung
cancer is representative of the 618 cases in the original epidemiologic
study as shown in Table 1 (2,4,6,38-40).
Compared with the
complete population-based sample, the case patients reported here
were identical in race and sex and similar in mean age at diagnosis
(69.8 years versus 71.5 years) and education level. Similarly, the
tumors in this study were comparable in proportion of histologic
subtypes to those in the original study, with slight excesses of
adenocarcinomas (71% versus 62%) and bronchoalveolar carcinomas (8%
versus 4%) and slight deficits in squamous cell carcinomas (4%
versus 6%), small-cell lung cancers (2% versus 3%), and other/mixed
histologies (16% versus 25%) (Table 1
). The only
substantial
difference was in the proportion of ex-smokers, who accounted for
30% of the original population but who were specifically excluded
from the current study.
The GSTM1 genotypes were determined for the 106 never smokers as 60% absent
(i.e., homozygous for the null allele) and 40% present (i.e., with one or two functional
alleles present; Table 2). The slight excess of null alleles is typical for the
lung cancer series among the white population (12), and the average age
at diagnosis of the homozygous null group was slightly, but not statistically significantly, greater
than the heterozygous and homozygous wild-type genotypes, 70.0 years versus 69.4 years. Data
on the GSTT1 genotypes were available for 65 patients, with 18% absent (i.e.,
homozygous null) and 82% present (i.e., having one or two functional alleles; Table 3
); similar frequencies for white populations have been reported by multiple
investigators [reviewed in (21)]. There were 95 (91%)
case patients with two wild-type CYP1A1 alleles and nine (9%) with one or two mutant
alleles (Table 3
); similar frequencies have been reported for other white
populations (36).
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Association of the GSTMI homozygous null genotype with
substantial lung cancer risk at high levels of ETS exposure. Within
the group of 106 never smokers, there was a surplus of the GSTM1
homozygous null genotype (i.e., 60%); however, in the absence of ETS
exposure, the GSTM1 null genotype was a slight minority (27 versus 28
case patients; Table 2). Excess GSTM1 null alleles occurred in the
presence of ETS exposure and outnumbered the GSTM1-positive case
patients by 2 : 1 in the second and third quartiles of
ETS exposure and by 6 : 1 in the fourth quartile. The
first quartile was defined as absence of exposure to ETS, and the other
quartiles were approximately equal groups of the remaining patients;
the lower boundary for the fourth quartile was drawn at 55 pack-years
of exposure because it represented a natural clustering of 13 case
patients at the top of the exposure scale. Case patient-only analysis,
adjusted for confounding variables, determined that exposure to more
than 55 pack-years of ETS produced a 6.5-fold increased risk of lung
cancer for women with the GSTM1 homozygous null genotype (OR = 6.5;
95% CI = 1.2-35.0), and the trend test supported this judgment
(P = .02; see Table 2
). To exclude the possibility
that the dataset was too sparse or unbalanced to assure the validity of
asymptotic likelihood-based inference, we applied exact methods and
found a similar risk estimate (OR = 5.6; 95% CI = 1.1-56.3; trend
test P = .01), although adjustments for confounding variables
including age, radon exposure, saturated fat consumption, and vegetable
intake could not be performed with the use of the current software. The
categorical comparison of "no ETS" to "any ETS" demonstrated a
2.6-fold increased risk among GSTM1 null genotypes (OR = 2.6; 95% CI =
1.1-6.1) by use of logistic regression with adjustments and a 2.7-fold
elevation (OR = 2.7; 95% CI = 1.1-6.7) by use of exact inference
without adjustment for confounding variables.
Lack of GSTTI and CYP1A1 effects on cancer risks from ETS exposure. Similar to
some, but not all, studies of smoking-associated lung cancer (21), this
case series provides no evidence that GSTT1 deficiency is associated with any lung cancer risk
due to ETS exposure (P = .29, trend test; Table 3), and
the GSTT1 homozygous
null group is too small to detect a genotypic interaction with GSTM1. Likewise, there is no
evidence that the CYP1A1 valine variant in exon 7 is associated with lung cancer risk from ETS
exposure (P = .50, trend test; Table 3
), either alone or in
concert with the
GSTM1 homozygous null genotype.
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DISCUSSION |
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This observation may have escaped prior notice because lung cancer series typically enroll active smokers, and it is possible that GSTM1 deficiency is most clinically significant at low carcinogen doses (49,50), such as with ETS exposure, because other detoxification pathways may be overloaded by active smoking (15,51,52). In addition, this study was designed specifically to measure the risks of ETS exposure (2), so never smokers were chosen as the primary study population (6), and the survey instruments were selected to optimize exposure assessment (53,54) and to minimize misclassification of never smokers (39,55-57). Recent results (31) also indicate that women with a GSTM1 homozygous null genotype may be at greater risk of developing lung cancer when compared with men who carry this "at risk" genotype. Additional studies are needed to confirm the risks of the ETS-GSTM1 homozygous null genotype interaction in white women and to expand the observation to other races and both sexes.
Tobacco smoke has many substrates for GSTM1, GSTT1, and CYP1A1, and individuals with multiple susceptibility alleles at these and other loci should have a greater risk of developing smoking-related lung cancer than those who carry only one such allele. One of the best known genetic interactions is the combination of GSTM1 homozygous null genotype and the valine allele in exon 7 of CYP1A1, which may produce 20-fold risks in Japanese smokers [reviewed in (21)]. However, similar to other series of white smokers (36), the CYP1A1 valine allele did not enhance the risk of ETS exposure among these never smokers, either alone or in combination with homozygous GSTM1 null genotype. This is possibly a statistical effect because the CYP1A1 valine allele is common among Japanese but relatively uncommon in whites; however, it is a good example of the ethnic and/or environmental variations that must be considered in investigations of causal factors. In addition, genetic interactions between null alleles of GSTM1 and GSTT1 have been suggested (33,34), but the low frequency of homozygous GSTT1 null alleles (i.e., 17%) does not permit such an assessment in our relatively small dataset. Although the absence of GSTT1 enzymatic activity has been sometimes associated with increased lung cancer risk in active smokers (21), these data do not support an interaction with ETS.
In short, we find that the GSTM1 homozygous null genotype is associated with a statistically significant lung cancer risk in never-smoking women exposed to high levels of ETS, which suggests that the observed excess lung cancer risk among never-smoking women results from cancers in two distinct groups: one that is genetically at high risk and one that is genetically at lower risk of lung cancer from exposure to ETS. Additional studies are needed to confirm these observations and to investigate the contributions of other detoxification pathways to lung cancer risk.
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NOTES |
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Present address: W. P. Bennett, Division of Molecular Medicine, City of Hope/Beckman Research Institute, Duarte, CA.
Present address: B. Blomeke, Department of Dermatology, Rheinisch Westfalische Technische Hochschule, Aachen, Germany.
We thank Dr. Ross C. Brownson for valuable assistance in accessing tissue samples, Dr. Jay H. Lubin for helpful discussions, Ms. Tuulikki Kärnä and Mr. Michael Bartel for laboratory assistance, and Ms. Dorothea Dudek for editorial assistance.
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Manuscript received February 11, 1999; revised September 7, 1999; accepted September 28, 1999.
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