Abstract
The aim of this study is to summarize the available molecular epidemiologic studies of lung cancer and metabolic genes, such as NAD(P)H quinone reductase 1 (NQO1) and myeloperoxidase (MPO). NQO1 plays a dual role in the detoxification and activation of procarcinogens whereas MPO has Phase I activity by converting lipophilic carcinogens into hydrophilic forms. Variant genotypes of both NQO1 Pro187 Ser and MPO G-463A polymorphisms may be related to low enzyme activity. The Pro/Ser and Ser/Ser genotypes combined of NQO1 was significantly associated with decreased risk of lung cancer in Japanese [random effects odds ratio (OR) = 0.70, 95% confidence interval (CI) = 0.56—0.88] among whom the variant allele is common. The variant genotype of MPO was associated with decreased risk of lung cancer among Caucasians (random effects OR = 0.70, 95% CI = 0.47--1.04). Gene-environment interactions in both polymorphisms may be hampered by inaccurate categorization of tobacco exposure. Evidence on gene-gene interactions is extremely limited. As lung cancer is a multifactorial disease, an improved understanding of such interactions may help identify individuals at risk for developing lung cancer. Such a study should include larger sample size and other polymorphisms in the metabolism of tobacco-derived carcinogens and address interactions with smoking status. The effects of polymorphisms are best represented by their haplotypes. In future studies on lung cancer, the development of haplotype-based approaches will facilitate the evaluation of haplotypic effects, either for selected polymorphisms physically close to each other or for multiple genes within the same drug-metabolism pathway.
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GENES
NAD(P)H quinone reductase 1
NAD(P)H quinone oxidoreductase 1 (NQO1, EC 1.6.99.2), formerly referred to as DT-diaphorase, is an important flavoprotein that catalyzes the two-electron reduction of carcinogenic quinoid compounds into their reduced form, such as hydroquinones.1 Benzo(a)pyrene (BP) is one of the most important carcinogens, and the formation of BP quinone-DNA adduct is prevented by NQO1.2 In contrast, carcinogenic heterocyclic amines present in smoke are metabolically activated by NQO1.3 Therefore, this enzyme is thought to be involved in both metabolic activation and detoxification of carcinogens. Higher levels of tissue (cytoplasm) expression of the NQO1 have been detected in the lung, kidney, liver, and skeletal muscle, with lower levels in the heart, brain, and placenta.4
Myeloperoxidase
Myeloperoxidase (MPO, EC 1.11.1.7) is a lysosomal hemoprotein located in the azurophilic granules of polymorphonuclear leukocytes and monocytes. MPO is the most abundant protein in neutrophils, constituting approximately 5% of their dry weight.5 MPO has Phase I metabolizing activity by converting lipophilic carcinogens into hydrophilic forms.6 Exposure to a variety of pulmonary insults, including cigarette smoke, stimulates recruitment of neutrophils into lung tissue7 with local release of MPO.8,9 MPO has been shown to activate an intermediate metabolite of BP, the 7,8-diol BP, to the highly reactive and carcinogenic benzo(a)pyrene 7,8-diol-9,10 epoxide (BPDE)10 and to enhance the binding to BPDE to lung DNA in vitro.11 MPO also activates carcinogens in tobacco smoke including polycyclic aromatic hydrocarbons (PAHs),10–12 aromatic amines,13–15 and heterocyclic amines16 and catalyzed the endogenous formation of carcinogenic free radicals.17 MPO may also function as an antimicrobial agent in neutrophils by catalyzing the production of genotoxic hypochlorous acid and other reactive oxygen species.18 Upon activation of the neutrophils, MPO is released into phagocytic vacuoles and the extracellular milieu.19,20
VARIANTS
NQO1 variants
The NQO1 gene, which is also known as DTD, QR1, DHQU, DIA4, or NMORI, consists of 6 exons and 5 introns and is located on chromosome 16q22.1. It covers 35.35 kb, from 69536903 to 69501551, on the reverse strand. A common polymorphic variant is a C-to-T point mutation at position 609 of exon 6 of the NQO1 cDNA that encodes for a proline to serine substitution at position 187 in the amino acid sequence of the protein. The three genotypes of this gene are the Pro/Pro (normal activity), the Pro/Ser (mild activity), and the Ser/Ser (2–4% of normal activity).21–25 The genotype frequencies in different populations are shown in Table 1.26–65 The summary frequency of the Ser allele among Caucasians was 18.9% (95% CI = 15.6–22.1%), and the summary frequency of the Ser/Ser and Pro/Ser genotypes combined was 31.8% (95% CI = 30.0–33.7%).26–42 The Ser allele (summary frequency = 43.0%, 95% CI = 39.8–46.2%) was predominant among Asians; 68% (95% CI = 64–72%) of the individuals had the Ser/Ser and Pro/Ser genotypes combined.51–63 The frequency of Ser allele in Asians was approximately 2.3-times more than in Caucasians. The only other mutation in the exon 2 is a G-to-A transition (G8015A) leading to a synonymous mutation.66 Other single nucleotide polymorphisms of this gene are in the 5′-flanking region and intron 1.66
MPO variants
The MPO gene is located on chromosome 17q23.1, consists of 11 introns and 12 exons. It covers 11.10 kb, from 56832934 to 56821840, on the reverse strand. A common G to A transition at position –463 in the promoter region of the MPO gene, which leads to the loss of a SP1 transcription binding site in an Alu hormone-responsive element,67,68 has been shown to reduce MPO mRNA expression.68,69 Because transcriptional activity is decreased in individuals with the variant A allele, less enzyme would ultimately be available for conversion of the BP intermediate to the highly carcinogenic BPDE. As shown in Table 2, the summary frequency of the A allele has been found to be 23.4% (95% CI = 21.8–25.0%) in Caucasians and 14.4% (95% CI = 11.3–17.6%) in Asians.36,46,50,62,70–101 The A allele was more frequently (1.6 times) observed in Caucasians than in Asians. Three missense mutations associated with MPO deficiency have been described, namely Tyr173Cys (exon 4),102 Met251Thr (exon 6, T4311C),103 and Arg569Trp (exon 10).104 Recently, another G-to-A transition at position –129 in the promoter region of the MPO gene was described.105 There are no reports of these polymorphisms in relation to lung cancer risk.
Disease
Although the incidence has peaked in the United States and most of Europe, lung cancer is showing increasing incidence and mortality in many countries around the world. An estimated 1,239,000 (902,000 males and 337,000 females) new cases of lung cancer were diagnosed worldwide in 2000, accounting for 12.3% of all new cases of cancer, and 1,103,000 (810,000 males and 293,000 females) died from the disease, accounting for 17.8% of all deaths from cancer.106 This disease ranks as the foremost cancer killer in men and the second largest in women. The case fatality (ratio of mortality to incidence), which is an indicator of prognosis, is 0.89 for lung cancer (the third-worst). Other cancers with bad prognosis are pancreas (0.99, the worst) and liver (0.97, the second-worst) cancers.107
Worldwide, the incidence rate in men exceeds that in women by a factor of 2.7. Lung cancer mortality among men is now abating in several countries, whereas the mortality in women continues to climb in most countries, as predicted by later onset tobacco abuse.108 Principal histological types of lung cancer are squamous cell carcinoma, large cell carcinoma, small cell carcinoma, and adenocarcinoma, and the former three are strongly associated with smoking. In recent decades, the frequency of adenocarcinoma has risen and that of squamous cell carcinoma has declined in a number of developed couries.109–115 The increase in incidence of adenocarcinoma could be partly explained by an increase in filtered cigarette smoking. Filter cigarettes with low-tar and low-nicotine have replaced nonfilter cigarettes. One key characteristic of such changes over time has been the increased nitrate content of the tobacco blend from about 0.5% to 1.3%.116 Tobacco-specific N-nitrosamines (TSNAs) are formed by N-nitrosation of nicotine and other minor alkaloids during tobacco processing and smoking.117 Because nitrate is the major precursor for nitrogen oxides, increased nitrate content leads to higher yields of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the smoke.118 To satisfy the craving for nicotine, a smoker of low-yield nicotine filtered cigarettes may tend to compensate by increasing the number and depth of puffs. Therefore, the peripheral lung, where adenocarcinoma generally arises, is exposed to a higher amount of smaller particles such as NNK. NNK is a systemic carcinogen that induced lung carcinoma in laboratory animals, whereas intratracheal instillation of PAHs preferentially induced squamous cell carcinoma.119 It is biologically plausible that TSNAs such as NNK cause adenocarcinoma in humans.
Smoking
Most of the lung cancer debate has been focused on tobacco smoking. Given the many risk factors that have been identified for lung cancer, a practical question is the relative contribution of these factors to the summary burden of lung cancer. The population attributable fraction (PAF) takes into account the magnitude of relative risk that is associated with an exposure along with the likelihood of exposure in the general population. The WHO Global Burden of Disease 2000 study reported that the PAF of lung cancer mortality due to smoking was 79% in men and 48% in women.120 The risk among smokers relative to the risk among never-smokers is 8 to 15 times in men and 2 to 10 times in women.121 Smoking cessation significantly reduces lung cancer risk, and after many years the risk of ex-smokers approaches that of never-smokers. It took more than 20 years for the risk in ex-smokers to approach the level in never-smokers.122 A recent meta-analysis showed that environmental tobacco smoke exposure from husbands conferred a 1.20 times increase in lung cancer risk among nonsmoking women.123
Other risk factors
The PAF for lung cancer deaths due to environmental tobacco exposure accounts for 0.7%, 0.2% in men and 2.5% in women.124 Doll and Peto estimated that approximately 20% of lung cancer deaths in the United States were potentially avoidable by the modification of diet.125 Willett also estimated that 20% (range, 10–30%) was avoidable by dietary factors.126 The PAF for lung cancer deaths due to outdoor air pollution accounts for 1% to 3.6%.127 Radon may be responsible for only 1% of lung cancers.128 In the USA, occupational exposure to carcinogens accounts for approximately 9% to 15% of lung cancer cases.129
Genetic epidemiology
Cigarette smoke contains several thousand chemicals. Most of these compounds are procarcinogens that must be activated by Phase I enzymes, such as cytochrome P450s (CYPs). All reactive carcinogens can bind to DNA and form DNA adducts that are capable of inducing mutations and initiating carcinogenesis. CYP1-CYP4 are primarily involved in the drug metabolism.130 Other Phase I enzymes are MPO, NQO1, microsomal epoxide hydrolase 1 (EPHX1), and alcohol dehydrogenase. A significant increased risk (2.4 to 3 times) of lung cancer for the CYP1A1 T3801C or A2455G (Ile462Val) polymorphisms was observed among Japanese131 and Caucasians.132 Although a molecular epidemiological association is possible between the prevalence of the high activity genotype of CYP2D6 and lung cancer, such an association, if it exists, could be weak.131 As for CYP2E1, no clear evidence has been found that the reported polymorphisms are related to lung cancer risk.131 Studies on other CYP2 subfamily have indicated a relation between lung cancer and the occurrence of a rare allele, although future research is needed to establish a significant association.131
After the Phase I reaction, Phase II enzymes like glutathione S-transferases (GSTs) are responsible for detoxifying the activated forms of PAH epoxides. The GSTs also form a superfamily.133,134 The major isoforms, which involve the metabolic activation of carcinogens derived from tobacco smoke or the detoxification of the respective activated carcinogens, are GSTM1, GSTM3, GSTT1, and GSTP1. Other Phase II enzymes are EPHX1, NQO1, N-acetyltransferases (NATs), UDP-glucuronosyltransferase, aldehyde dehydrogenase, sulfotransferase, and superoxide dismutase. The GSTM1 null genotype and the concurrent lack of GSTM1 and GSTT1 may be modestly associated (approximately 2 times) with susceptibility to lung cancer.135 It may be of great importance to study both NAT1 and NAT2 together as putative contributing factors for lung cancer susceptibility.136 Among metabolic polymorphisms, MPO, NQO1, and EPHX1 have been less reviewed than CYPs, GSTs, and NATs. The rest of the candidate genes remain little investigated.
The capacity to repair DNA damage induced by chemical carcinogens appears to be another host factor that may influence lung cancer risk. Potentially important DNA repair genes are 8-oxoguanine-DNA glycosylase 1, x-ray cross-complementing Group 1 (XRCC1), xeroderma pigmentosum C (XPC), excision repair cross-complementing Group 1 (ERCC1), ERCC2 (XPD), ERCC3 (XPB), ERCC4 (XPF), ERCC5 (XPG), xeroderma pigmentosum C (XPC), and XRCC3. Although each DNA repair gene may not be a major determinant of lung cancer susceptibility, ERCC2 seems to be the most promising among DNA repair genes.137 Furthermore, cell-cycle control genes (p53, cyclins, etc.), genes that influence smoking behavior [dopamine receptor (DR) D2, DRD4, DRD5, neuronal nicotine acetylcholine receptor, dopamine transporter and serotonin transporter] and genes involved in development of the immune system (interleukins and tumor necrosis factor) may have the potential to substantially affect lung cancer risk.
META-ANALYSIS METHODS
Identification and eligibility of relevant studies
We conducted a MEDLINE search using “NAD(P)H quinone reductase 1,” “myeloperoxidase,” “lung cancer,” and “polymorphism” for articles published before August 2004. Additional articles were identified through the references cited in the first series of articles selected. Articles included in meta-analysis were English and non-English, human, published in the primary literature and had no obvious overlap of subjects with other studies. Case-control studies were eligible, if they had determined the distribution of the relevant genotypes in lung cancer cases and in concurrent controls using a molecular method for genotyping. We excluded studies with the same data or overlapping data by the same authors.
Data extraction and assessment of study quality
Two investigators (C.K. and K.Y.) independently extracted data and reached consensus on all items except for the Hardy-Weinberg equilibrium. The following items were sought from each report: authors, year of publication, place of study, ethnic group of the study population, characteristics of lung cancer cases (age distribution, sex ratio, histological type, smoking and occupational exposure), characteristics of controls (age distribution, sex ratio, source of population, smoking and occupational exposure), number of genotyped cases and controls, frequency of the genotypes, ORs, adjusted factors for OR, and the method for quality control of genotyping. For studies including subjects of different ethnic groups, data were extracted separately for each ethnic group, whenever possible.
Methods for defining study quality in genetic studies are more clearly defined than those for observational studies. We assessed the Hardy-Weinberg equilibrium via a goodness-of-fit χ2 test (Pearson) to compare the observed and expected genotype frequencies among controls. We also assessed the homogeneity of the study population (Caucasian only or mostly Caucasian).
Meta-analysis
Data were combined using both fixed effects (Mantel-Haenszel) and random effects (DerSimonian and Laird method) models.139 Fixed effects and random effects analyses address fundamentally different research questions. The former asks what the best estimate of the true effect size is in the population studied, whereas the latter asks what the range and distribution of effect sizes in the sample of populations studied. Therefore, the calculation of the mean of the distribution of population effect sizes (random effects model) provides different information from the calculation of the mean of the distribution of sample effect sizes (fixed effects model). Random effects incorporate an estimate of the between-study variance and tend to provide wider confidence intervals, when the results of the constituent studies differ among themselves. The random effects model, compared to the fixed effects model, reduces the weight for each individual study proportion to the difference in effect size of an individual study from the pooled estimate of the effect for all other studies. Random effects model are more appropriate when heterogeneity is present.138 Thus, estimates values were basically based on random effects model. Heterogeneity, evaluated by the Cochrane Q test139,140 among the studies, was considered significant for P < 0.10. Both Begg's141 and Egger's142 tests were used to test for publication bias, which was considered significant for P < 0.10. Both the tests could also assess whether larger studies give different results from small studies. In a sensitivity analysis (subgroup analysis), we combined only studies with allelic frequencies being in Hardy-Weinberg equilibrium (Pearson χ2 test, P ≫ 0.05) because departure from Hardy-Weinberg equilibrium can imply the presence of genotyping error, possible ethnic admixture in the population or selection bias (short of representativeness of the general population). As the ethnic differences were observed in Tables 1 and 2, subgroup analyses by ethnic were also performed. Subgroup analyses by histologic type were performed if available. All the calculations were performed with computer program STATA Version 8.2 (Stata Corporation, College Station, TX).
ASSOCIATIONS
NQO1 Pro187Ser polymorphism and lung cancer risk
As the variant allele is related to low enzyme activity, subjects with at least one variant allele may be associated with decreased risk of lung cancer if NQO1 enzyme acts as a mechanism for metabolic activation of several carcinogens present in tobacco smoke. The Pro/Ser and Ser/Ser genotypes combined was significantly associated with decreased risk of lung cancer in Mexican-Americans.64 All three Japanese40,53,54 studies have also shown that the combined genotype was associated with decreased risk of lung cancer. In Chinese,60 Hawaiians,40 Caucasians,40 and African-Americans,64 the combined genotype was weakly associated with decreased risk of lung cancer. No evidence for an influence of genetic polymorphism in NQO1 on lung cancer risk was found in two Caucasian populations29,46 and one Taiwanese population.63 In contrast, the combined genotype26,43 was nonsignificantly associated with increased risk of lung cancer in Caucasians.
The 10 case-control studies in 13 different ethnic populations of lung cancer and the combined genotype included 2746 lung cancer cases and 3902 controls. As a clear gene-dose effect was suggested by the genotype-phenotype association studies,21–25 a genetic model (codominant or decreasing model), in which lung cancer risks of the genotypes Pro/Pro, Pro/Ser, and Ser/Ser decrease in that order, was applied. As the Ser/Ser genotype has not been separated due to a low prevalence of the rare Ser allele in several studies, we combined the Pro/Ser genotype with Ser/Ser genotype. In our meta-analysis, summary frequencies of the combined genotype among Caucasians and Japanese based on random effects model were 30.8% (95% CI = 23.6–38.0%) and 62.9% (95% CI = 59.8–66.0%), respectively (Table 3). The summary ORs for the combined genotype in Caucasians and Japanese were 1.12 (95% CI = 0.96–1.47) and 0.70 (95% CI = 0.56–0.88), respectively. Statistically significant heterogeneity (P = 0.032) was seen in case of all studies combined. This result was not reproduced in any sensitivity analysis. Possible sources of heterogeneity are ethnicity (the prevalence of the "at risk" allele, ethnic differences in roles of the polymorphism), study design, and so on. The Begg's test was statistically significant (P = 0.09) for publication bias but not the Egger's test (P = 0.11) in a sensitivity analysis among mostly Caucasian and Caucasian only populations, because the largest study of Xu et al. showed null association.46 The presence of heterogeneity and/or publication bias may compromise the interpretation of meta-analyses and result in an erroneous and potentially misleading conclusion.143,144 The presence of publication bias indicates that nonsignificant or negative findings remain unpublished. Although publication bias is always a possible limitation of combining data from various sources as in a meta-analysis, Sutton et al. concluded that publication or related biases did not affect the conclusions in most meta-analyses.145 The results of our meta-analysis indicate that the Ser allele, which is linked to low enzyme activity, was significantly associated with decreased risk of lung cancer in Asians among whom the variant allele is common. But such an association was not observed in Caucasians. The impact of NQO1 was different among different populations. Reasons for this apparent difference in risk with different ethnic populations are as yet unknown but, if real, may be related to other genetic or environmental factors.
Histologic data were available for six studies and four studies have indicated a significant association between NQO1 polymorphism and risk of certain histologic types of lung cancer. Small cell carcinomas were more likely to occur with a significant difference among those who had the Pro/Ser and Ser/Ser genotypes combined, compared to those who had two copies of the Pro allele (OR = 0.26, 95% CI = 0.08–0.84).26 In Chinese, the combined genotype relative to the Pro/Pro genotype increased the OR for squamous cell carcinoma (3.23, 95% CI = 1.00–10.38).60 In Caucasians, the Pro/Ser and Ser/Ser genotypes combined was significantly associated with increased risk of squamous cell carcinoma (OR = 2.21, 95% CI = 1.03–4.84).29 The Ser/Ser genotype was significantly associated with decreased risk for adenocarcinoma among Japanese (OR = 0.47, 95% CI = 0.22–0.97).54 There was no association between NQO1 genotype and lung cancer risk, regardless of histologic type.46,63 In subgroup analyses by histologic type among Caucasians and Asians, the Pro/Ser and Ser/Ser genotypes combined was marginally associated with increased risk of squamous cell carcinoma (OR = 1.29, 95% CI = 0.97–1.72), whereas the combined genotype was not associated with increased risk of adenocarcinoma (OR = 0.89, 95% CI = 0.71–1.13) (data not shown). The decreased risk (OR = 0.79, 95% CI = 0.59–1.07) was observed for adenocarcinoma patients with the combined genotype among Asians, however (data not shown). There was no clear evidence of the different role of NQO1 among different histologic types, however.
MPO G-463A polymorphism and lung cancer risk
As the variant allele is related to low metabolic activation activity, subjects with at least one variant allele may be associated with decreased risk of lung cancer. London et al.79 first reported that subjects with the A/A genotype were significantly associated with decreased risk of lung cancer in Caucasians and a nonsignificant reduction in African Americans compared with those with the G/G genotype. A second study82 of populations with Caucasian, Japanese, or Hawaiian ethnicity reported a significant reduction in risk for those with the A/A genotype compared with those with the G/G genotype in only a Japanese population. Also, the A/A genotype was associated with decreased risk of lung cancer among an American population.91 In subsequent Caucasian (or mostly Caucasians) studies,72,73,83,92 the A/A genotype was suggested as being a protective factor for lung cancer. However, the G/A and A/A genotypes combined was associated with increased risk of lung cancer among a subset of Caucasian men of > 64 years old (OR = 2.92, 95% CI = 1.33–6.43).72 A statistically significant reduced risk of lung cancer was observed for the G/A and A/A genotypes combined among Caucasian men (OR = 0.55, 95% CI = 0.36–0.84), but not among women (OR = 0.81, 95% CI = 0.55–1.26).92 The A/A genotype was nonsignificantly associated with increased risk of lung cancer among Caucasians.85 No evidence for an influence of genetic polymorphism in MPO on lung cancer risk was found in three Caucasian populations74,80,90 and one Chinese population.99
The 12 case-control studies of lung cancer among 15 ethnic groups and MPO genotype included 4285 lung cancer cases and 4656 controls. Although biological effects of each genotype have not been clarified, the previous meta-analysis suggested that the MPO activity was different among the three genotypes.83 We used the genetic model (lung cancer risks of the genotypes G/G, G/A, and A/A decrease in that order), which was applied to our meta-analysis of the studies on NQO1 polymorphism and lung cancer. The summary OR for the A/A genotype was 0.81 (95% CI = 0.64 - 1.02) (Table 4). The summary OR for the A/A genotype among Caucasian only studies with PHWE ≫0.05 was 0.70 (95% CI = 0.47 - 1.04). The Egger's test was statistically significant (P = 0.007) for publication bias but not the Begg's test (P = 0.21) in a sensitivity analysis among all studies with PHWE ≫ 0.05, because the largest study of Xu et al. showed null association.91 Although the results concerning the association between lung cancer and the MPO polymorphism are still a matter of debate, the OR of 0.7 suggests an important role for MPO in lung cancer etiology among Caucasians, possibly through activation of carcinogens and/or production of free radicals in or near the target cells.
Of the 12 reports on the MPO genotype and lung cancer risk, eight provide information on the MPO genotype and lung cancer risk in histologic types. A significant protection of the A/A and G/A genotypes combined was seen among adenocarcinoma (OR = 0.24, 95% CI = 0.10–0.58) and squamous cell carcinoma (OR = 0.39, 95% CI = 0.18–0.82) cases.74 In another study, a protective effect of the combined genotype was noted for adenocarcinoma (OR = 0.64, 95% CI = 0.42–0.96) cases and small cell carcinoma cases (OR = 0.43, 95% CI = 0.17–1.05), but not for squamous cell carcinoma cases (OR = 0.99, 95% CI = 0.54–1.82).92 The decreased risk was significant for squamous cell carcinoma patients with the combined genotype (OR = 0.42, 95%CI = 0.25–0.71) but not for those with adenocarcinoma (OR = 0.75, 95% CI = 0.47–1.20).99 The OR for the A/A genotype for squamous cell carcinoma was 0.49 (95% CI = 0.27–0.88).83 A reduction in risk, although not statistically significant (OR = 0.66, 95% CI = 0.28–1.52), was also observed for small cell carcinoma patients with the A/A genotype.83 Furthermore, a protective effect of the A/A and G/A genotypes combined was seen among patients with small cell carcinoma (OR = 0.58, 95% CI = 0.36 - 0.95) but not patients with squamous cell carcinoma (OR = 0.82, 95% CI = 0.56–1.21) and adenocarcinoma (OR = 0.81, 95% CI = 0.55–1.19).73 In contrast, the A/A genotype was associated with increased risk of squamous cell carcinoma (OR = 1.82, 95% CI = 0.8–4.1) and adenocarcinoma (OR = 1.36, 95% CI = 0.8–2.5).89 No significant association for the MPO genotype and patients with squamous cell carcinoma or adenocarcinoma was observed.82 There was also no clear evidence of lung cancer risk by histologic types.80 Stratification by histologic type yielded an OR of 0.91 (95% CI = 0.45–1.84) for adenocarcinoma and 1.33 (95% CI = 0.73–2.42) for squamous cell carcinoma (data not shown). These results may largely be affected by the study of Xu et al.90 (more than one third of cases and nearly two thirds of controls were included). Taken together, results on the MPO genotype and risk for different histologic types of lung cancer are conflicting and suggest that confounders that have not been controlled for may have interfered with the analysis.
GENE-ENVIRONMENT INTERACTIONS
NQO1 Pro187Ser polymorphism
The excess small cell lung cancer risk associated with the presence of the Ser allele was apparent in heavy smokers where the OR for the Ser/Ser and Pro/Ser genotypes combined was 12.5 (95% CI = 2.10–75.5); in light smokers the OR was 0.90 (95% CI = 0.08–9.60).26 In contrast, the frequency of NQO1 genotypes did not differ significantly between smokers and nonsmokers.60 Current smokers with the Ser/Ser genotype had a smaller lung cancer risk than current smokers with the Pro/Pro and Pro/Ser genotypes combined; the OR for the Ser/Ser genotype versus the Pro/Pro genotype was 0.38 (95% CI = 0.19–1.00).46 However, there was no statistically significant interaction between NQO1 genotypes and smoking.46 The ORs for the Ser/Ser genotype were 0.42 (95% CI = 0.18–1.10) in smokers and 0.34 (95% CI = 0.08–1.33) in nonsmokers.54 Therefore, the result showed that the association of the NQO1 polymorphism with lung adenocarcinoma risk appeared to be equal both in smokers and nonsmokers.54 The NQO1 genotype distribution in cases was similar to that found among controls in never, light and heavy smokers with ORs close to unity within each smoking group.29 Only one26 of five studies26,29,46,54,60 suggested a possible interaction between NQO1 genotypes and smoking upon investigation. Significant interaction can be seen when accurate categorization of tobacco exposure is used instead of a ternary variable, such as never, ex- and current smokers.
MPO G-463A polymorphism
Four studies suggested the existence of an interaction between MPO genotype and cigarette smoking.72,73,92,99 The association between MPO genotype and lung cancer risk was modified by duration of smoking (P for interaction = 0.014).72 Among heavy smokers (≫ 26 pack-years) with the G/A and A/A genotypes combined, the OR for squamous cell carcinoma was 6.22 (95% CI = 1.72–22.47), against 1.39 (95% CI = 0.29–6.57) among light smokers with the combined genotype.99 No such gene-smoking interaction was observed for adenocarcinoma, however.99 There was a protective effect for the G/A and A/A genotypes combined in ever smokers (OR = 0.63, 95% CI = 0.45–0.87), but no effect in never smokers (OR = 1.14, 95% CI = 0.42–3.11).92 A significant protective effect for individuals with the G/A and A/A genotypes combined with the lowest tertile of < 30 pack-years (OR = 0.39, 95% CI = 0.19–0.82). The cross-product interaction term between MPO genotype and pack-years was significant (P for interaction = 0.025).92 A protective effect for the A/A genotype was also found only in groups with lower tobacco consumption (OR = 0.43, 95% CI = 0.25–0.74), and heavy smoking abolished the MPO-related effect (OR = 1.03, 95% CI = 0.69–1.55).73 Three studies79,83,90 found no evidence of interaction between MPO genotypes and smoking. Two of these three studies measured tobacco smoking as a binary variable, such as nonsmokers and smokers. Assessment of gene-environment interaction should begin with appropriate measurement of tobacco smoking and large sample size.
GENE-GENE INTERACTIONS
NQO1 Pro187Ser polymorphism
Interactions between NQO1 and other genes have been investigated in three studies.29,53,54 The combined NQO1 Pro/Pro and GSTT1 null genotypes showed a significant association with lung adenocarcinoma risk. When using the NQO1 Ser/Ser and GSTT1 non-null genotypes combined as a reference, the OR for the NQO1 Pro/Pro and GSTT1 null genotypes combined was 4.61 (95% CI = 1.59–13.34).54 A gene-gene interaction was suggested between NQO1 and T3801C/A2455G (Ile462Val) polymorphisms combined of CYP1A1.29 The OR for squamous cell carcinoma was higher in the group with the combined variant genotypes of NQO1 and CYP1A1 (OR = 3.54, 95% CI = 0.88–14.3) compared with the ORs in the groups with only one of the NQO1 variant genotype (OR = 1.69, 95% CI = 0.85–3.39) and only one of the CYP1A1 variant genotype (OR = 1.36, 95% CI = 0.46–3.90). However, no evidence was seen for effects of gene-gene interactions (all possible combinations of two genotypes for NQO1, CYP1A1, GSTM1, and GSTT1) on lung cancer risk.53 In addition to adequate sample size, assessment of gene-gene interaction also depends upon the proper statistical evaluation of interaction on the multiplicative and additive models. Again, if such gene-gene interaction indeed exists, it may be hampered by the small sample size.
MPO G-463A polymorphism
Only two studies examined whether the association between MPO genotype and lung cancer risk was modified by other genes.83,85 The MPO G/A genotype interacted with the presence of GSTT1 (OR = 0.12, 95% CI = 0.02–0.71) and of both GSTM1 and GSTT1 genotypes (OR = 0.02, 95% CI = 0.01–0.50) to significantly decrease lung cancer among males but not in females.85 On the other hand, no differences in risks associated with MPO genotypes were found according to GSTM1, CYP1A1 T3801C, or CYP1A1 A2455G (Ile462Val) genotype.83 Nointeraction would either suggest that these proteins do not participate in the same pathway or, more likely, that there are backup or redundant mechanisms that compensate for the diminished or altered function of different enzymes.
Among smokers who smoked ≪ 25 pack-years, a significant reduction in risk for lung cancer was observed among individuals who had the MPO G/A genotype combined and the presence of GSTT1, compared with who had the MPO G/G genotype and GSTT1 null genotype (OR = 0.03, 95% CI = 0.01–0.79).85 Gene-gene-environment interaction was suggested despite the limited power for assessing three-way interaction. This finding must be interpreted with caution and needs to be validated in larger studies.
Laboratory testing
Methods of genotyping for NQO1 146 and MPO 79 by means of the polymerase chain reaction and restriction fragment length polymorphism techniques have been described previously.
POPULATION TESTING
To date, there is insufficient evidence implicating NQO1 or MPO in the etiology of lung cancer to make population testing an issue.
OTHER POTENTIAL PUBLIC HEALTH APPLICATONS
At this writing, the available data are insufficient to support any public health recommendations.
DISCUSSION AND RECOMMENDATIONS FOR RESEARCH
The variant allele of NQO1 Pro187Ser was associated with a 22% to 30% decrease in lung cancer risk among Asians. However, there are several conflicting reports on the association between this polymorphism and lung cancer risk among various populations. Although the reasons for the inconsistencies in the studies are not clear, possible explanations are as follows: (1) low frequency of the "at risk" genotype, which reduces the statistical power and (2) small size of the studies. Ethnic differences in roles of the polymorphism may be caused by gene-gene interactions, different linkages to the polymorphisms determining lung cancer risk and different lifestyles. On the other hand, the variant allele of MPO G-463A polymorphism was associated with decreased risk (30%) of lung cancer among Caucasians because most studies have been done on them. Thus, both polymorphisms appear to be candidates for lung cancer susceptibility genes. Although the summary risk for developing lung cancer in individuals with at each "at risk" genotype may be small, lung cancer is such a common malignancy that even a small increase in risk translates to a large number of excess lung cancer cases in the population. Therefore, polymorphisms, even those not significantly associated with lung cancer, should be considered an important public health issue.
Research into the role of NQO1 and MPO polymorphisms in lung cancer is not in the last stages. The etiology of lung cancer cannot be explained by allelic variability at a single locus. Advances in identification of new variants and in high-throughput genotyping techniques will facilitate analysis of multiple polymorphisms within the genes with the same pathway.147 Therefore, it is likely that the defining feature of future epidemiologic studies will be the simultaneous analysis of large samples of cases and controls.148,149 The major burden of lung cancer in the population probably results from complex interaction between many genetic and environmental factors over time. The effects of polymorphisms are best represented by their haplotypes. Recently developed haplotype-based methods were not used in the studies we reviewed; however, it can be anticipated that in future association studies on lung cancer, the development of new approaches will facilitate the evaluation of haplotypic effects, either for selected polymorphisms physically close to each other or for multiple genes within the same drug-metabolism pathway.
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Kiyohara, C., Yoshimasu, K., Takayama, K. et al. NQO1, MPO, and the risk of lung cancer: A HuGE review. Genet Med 7, 463–478 (2005). https://doi.org/10.1097/01.gim.0000177530.55043.c1
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DOI: https://doi.org/10.1097/01.gim.0000177530.55043.c1
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