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Lack of Association between NADPH Quinone Oxidoreductase 1 (NQO1) Gene C609T Polymorphism and Lung Cancer: A Case-Control Study and a Meta-Analysis

  • Shujie Guo,

    Affiliation State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

  • Min Gao,

    Affiliation Department of Respiratory, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China

  • Xiaobo Li,

    Affiliation State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

  • Yuqiong Li,

    Affiliation State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

  • Shaoli Chu,

    Affiliation Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

  • Dingliang Zhu,

    Affiliation State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

  • Wenquan Niu

    niuwenquan@yahoo.cn

    Affiliation State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Lack of Association between NADPH Quinone Oxidoreductase 1 (NQO1) Gene C609T Polymorphism and Lung Cancer: A Case-Control Study and a Meta-Analysis

  • Shujie Guo, 
  • Min Gao, 
  • Xiaobo Li, 
  • Yuqiong Li, 
  • Shaoli Chu, 
  • Dingliang Zhu, 
  • Wenquan Niu
PLOS
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Abstract

Background

The association between NAD(P)H:quinone oxidoreductase 1 (NQO1) gene C609T polymorphism (rs1800566) and lung cancer has been widely evaluated, and a definitive answer so far is lacking. We first conducted a case-control study to assess this association in northeastern Han Chinese, and then performed a meta-analysis to further address this issue.

Methodology/Principal Findings

This case-control study involved 684 patients clinically diagnosed as lung cancer and 602 age-matched cancer-free controls from Harbin city, Heilongjiang province, China. Genotyping was conducted using the PCR-LDR (ligase detection reactions) method. Meta-analysis was managed by STATA software. Data and study quality were assessed in duplicate. Our case-control association study indicated no significant difference in the genotype and allele distributions of C609T polymorphism between lung cancer patients and controls, consistent with the results of the further meta-analysis involving 7286 patients and 9167 controls under both allelic (odds ratio (OR) = 0.99; 95% confidence interval (CI): 0.92–1.06; P = 0.692) and dominant (OR = 0.98; 95% CI: 0.89–1.08; P = 0.637) models. However, there was moderate evidence of between-study heterogeneity and low probability of publication bias. Further subgroup analyses by ethnicity, source of controls and sample size detected no positive associations in this meta-analysis.

Conclusions

Our study in northeastern Han Chinese, along with the meta-analysis, failed to confirm the association of NQO1 gene C609T polymorphism with lung cancer risk, even across different ethnic populations.

Introduction

Lung cancer is one of the common malignancies, and nearly 1.3 million new cases are diagnosed annually worldwide [1], [2]. Evidence is mounting suggesting that the cause of lung cancer is multifactorial, and part is due to genetic defects. In the last decade, exhaustive efforts have been devoted to unraveling the genetic underpinnings of lung cancer; however, its driving genes and genetic determinants that attribute to the development of lung cancer so far remain elusive.

The gene encoding NAD(P)H:quinone oxidoreductase 1 (NQO1) is a promising candidate in the pathogenesis of lung cancer [3], [4]. NQO1 is a cytosolic enzyme, and catalyzes the reduction of two electrons of quinoid compounds to generate the less-toxic hydroquinones, which can alleviate cancer carcinogenesis [5], [6]. In tissues of human lung cancer, NQO1 gene was observed to be over-expressed [5], [7][9]. It is therefore of added interest to identity genetic defects of NQO1 gene responsible for its enzyme activity, further accountable for lung carcinogenesis. The transition of C to T at position 609 (rs1800566) of NQO1 gene can lead to reduced activity of quinone reductase [10][12]. The C609T polymorphism has been widely evaluated in association with lung cancer across various ethinicities, yet with conflicting results, possibly due to the insufficient sample sizes, genetic backgrounds, and selection of study populations.

In this study, we first decided to assess the assocation of C609T polymorphism of NQO1 gene with lung cancer risk in a large northeastern Han Chinese population. Then, given the accumulating data and to shed some light on current uncertain claims, we sought to conduct a comprehensive meta-analysis of this association from both English and Chinese literature.

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Table 1. The baseline characteristics of our study population in case-control study.

https://doi.org/10.1371/journal.pone.0047939.t001

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Table 2. The alleles and genotype distributions of NQO1 gene C609T polymorphism between cases (n = 682) and controls (n = 597).

https://doi.org/10.1371/journal.pone.0047939.t002

Methods

Study Population

The design of this study has been described previously [13]. Briefly, this was a hospital-based case-control study with a total of 1286 subjects consecutively recruiting from three hospitals in Harbin city, Heilongjiang province, China. The study population included 684 patients clinically diagnosed as lung cancer and 602 age-matched cancer-free controls, and all subjects were local residents of Han descent. This study was approved by the Ethics Committee of Harbin Medical University, and was conducted according to the Declaration of Helsinki Principles. All subjects signed the written informed consent.

Diagnostic Criteria and Demographic Characteristics

Lung cancer was diagnosed by chest radiograph and either high resolution computed tomography (CT) or enhanced CT or positron emission computed tomography (PET)-CT scan, which was confirmed by clinical doctors of respiratory medicine. Those who were susceptible to lung cancer were further pathologically confirmed by biopsy, and those with normal CT or enhanced CT or PET-CT results were treated as cancer-free controls in this study. Clinical subtypes of lung cancer included squamous cell cancer, adenocarcinoma, small cell cancer and unspecified lung cancer. Age and gender were recorded at enrollment. The status of cigarette smoking and alcohol drinking were defined at the time of the survey. Smoking was expressed by percent of ever or current smoking. Drinking was categorized as never, ever or current drinking. Here, current drinking referred to consumption of at least one alcoholic drink during the past 30 days.

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Table 3. The baseline characteristics of all qualified studies in this meta-analysis.

https://doi.org/10.1371/journal.pone.0047939.t003

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Table 4. The baseline characteristics of all qualified studies in this meta-analysis (Continued).

https://doi.org/10.1371/journal.pone.0047939.t004

Genotyping

Blood samples (1 mL) were collected, and genomic DNA was extracted from white blood cells using the TIANamp Blood DNA Kit (Tiangen Biotect [Beijing] Co., LTD). Genotyping was conducted using the PCR-LDR (ligase detection reactions) method by ABI 9600 system (Applied Biosystems, USA) [14]. Cycling parameters were as the following: 94°C for 2 min; 35 cycles of 94°C for 15 s; 60°C for 15 s; 72°C for 30 s; and a final extension step at 72°C for 5 min. Two specific probes to discriminate the specific bases and one common probe were synthesized (available upon request). The common probe was labeled at the 3′ end with 6-carboxy-fluorescein and phosphorylated at the 5′ end. The reacting conditions of LDR were: 94°C for 2 min, 20 cycles of 94°C for 30 s and 60°C for 3 min. After reaction, 1 mL LDR reaction products were mixed with 1 mL ROX passive reference and 1 mL loading buffer, and then denatured at 95°C for 3 min, and chilled rapidly in ice water. The fluorescent products of LDR were differentiated using ABI sequencer 377 (Applied Biosystems, USA).

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Figure 2. Funnel plots of NQO1 gene C609T polymorphism with lung cancer under both allelic (A) and dominant (B) models.

https://doi.org/10.1371/journal.pone.0047939.g002

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Figure 3. Begg’s and filled funnel plots for studies investigating the effect of NQO1 gene C609T polymorphism on lung cancer under both allelic (A and B) and dominant models (C and D).

https://doi.org/10.1371/journal.pone.0047939.g003

Statistical Analysis

Comparisons between lung cancer patients and controls were conducted by unpaired t-test for continuous variables and by χ2 test for categorical variables. To avoid gross genotyping error, C609T polymorphism was checked for consistency with Hardy-Weinberg equilibrium by χ2 test. In view of age-matched patients and controls, genotypes were compared by conditional logistic regression analysis under assumptions of additive, dominant and recessive models of inheritance, respectively. Statistical significance was accepted as P<0.05.

Meta Analysis

This meta-analysis is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline (please see PRISMA checklist: Table S1) [15].

HuGE Navigator and PubMed, as well as Wanfang database (http://www.wanfangdata.com.cn) were searched up to July 2012 for articles investigating the association between C609T polymorphism and lung cancer risk. The subject terms used were “lung cancer” or “lung neoplasm” and “NAD(P)H:quinone oxidoreductase” or “NQO1”, annexed with “gene” or “allele” or “genotype” or “variant” or “polymorphism” or “mutation”. Articles written in English or Chinese language and studies performed in human subjects were identified. The search result was supplemented by reviews of reference lists for all relevant studies and review articles. In addition, if there were shared or duplicated samples between studies, we recruited those with the large sample size.

Studies were qualified if they met the following criteria: (i) on a retrospective or nested case-control design; (ii) adopt validated genotyping method; (iii) provide genotype counts of NQO1 gene C609T polymorphism between patients with lung cancer and controls.

Study quality was evaluated by using a quality assessment score explored for genetic association studies by Thakkinstian et al [16]. Total scores ranged from 0 (worst) to 12 (best). The criteria for quality assessment of genetic association between NQO1 gene C609T polymorphism examined with lung cancer are described in Table S2.

In the meta-analysis, the random effects model using the DerSimonian and Laird method was employed to combine the individual effect size estimates to calculate pooled weighted ORs, and the estimate of heterogeneity was determined using the Mantel-Haenszel model. Between-study heterogeneity was explored by the χ2 test, and heterogeneity was assessed by the inconsistency index I2 statistic (ranging from 0 to 100%) which is defined as the percentage of the observed between-study variability that is due to heterogeneity rather than to random error [17].

Publication bias was assessed by the Begg’s funnel plot, Egger’s test and the trim and fill method [18]. For the I2 and Egger’s statistics, statistical significance was set at 0.1. All statistical analyses were managed by STATA software (version 11.0).

Results

Baseline Characteristics

The demographics and risk factors of the study population are summarized in Table 1. Cases and controls were well matched by age. Male gender, smoking and drinking were associated with increased risk for lung cancer. Among all lung cancer patients, the subtype of adenocarcinoma, squamous cell cancer, small cell cancer, and unspecified cancer accounted for 37.54%, 32.26%, 20.83%, and 9.38%, respectively.

Single-locus Analysis

The success rates of genotyping for C609T polymorphism were 99.71% and 99.17% in patients and controls, respectively. Genotype distributions of examined polymorphism respected Hardy-Weinberg equilibrium in controls (P>0.05). There was no significant difference in the genotype and allele distributions of C609T polymorphism between lung cancer patients and controls, and this non-significance was also mirrored under assumptions of the additive (OR = 0.99; 95% CI: 0.85–1.17; P = 0.634), dominant (OR = 1.01; 95% CI: 0.81–1.33; P = 0.607) and recessive (OR = 1.04; 95% CI: 0.80–1.34; P = 0.791) models (Table 2).

Eligible Articles for Meta-analysis

The initial search yielded 83 potentially relevant articles. After applying the inclusion/exclusion criteria, 22 articles were eligible for inclusion. A flow chart schematizing the process of selecting and excluding articles with specific reasons is shown in Figure 1. The retrieved articles were published between 1997 and 2011, with 20 articles written in English and two in Chinese.

Study Characteristics

Since more than one study group was included in some articles, we treated them separately. In total, 30 separate studies plus the present study encompassing a total of 7286 patients with lung cancer and 9167 controls were finally meta-analyzed, with 12 studies performed in Asians [19][29], 12 in Caucasians [19], [30][39], 4 in African-Americans [33], [35], [38], [40], and 3 in mixed ethnicities [19], [31], [40]. 18 studies reported matching information on age between patients and controls. The quality score of individual studies ranged from 2 to 10 (mean: 7.6) out of a maximal score of 12. The frequencies of 609T allele varied widely, which were exceedingly higher in Asians than in Caucasians for both patients (28.44 to 54.21% versus 14.23–21.96%) and controls (30.88 to 46.60% versus 12.41–20.47%). Baseline characteristics of qualified studies are shown in Table 3 and Table 4.

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Table 5. Subgroup analyses of NQO1 gene 609C/T polymorphism with the risk of lung cancer, and exploration of between-study heterogeneity and publication bias.

https://doi.org/10.1371/journal.pone.0047939.t005

Meta-analysis Results

After combining all qualified studies, we found null association of NQO1 gene C609T polymorphism with lung cancer under both allelic (OR = 0.99; 95% CI: 0.92–1.06; P = 0.692) and dominant (OR = 0.98; 95% CI: 0.89–1.08; P = 0.637) models, and this association suffered from significant evidence of heterogeneity between studies (allelic and dominant models: I2 = 32.1% and 43.7%) (Figure 2). However, there was low probability of publication bias for both models (PEgger = 0.608 and 0.81) (Figure 3).

To account for potential sources of heterogeneity, we conducted a set of subgroup analyses according to ethnicity, source of controls and sample size (Table 5). Despite the wide divergence of 609T allele, the risk estimates were comparable in magnitude between Asians and Caucasians. Notably, 609T allele was associated with a 13% reduced, albeit nonsignificant, risk for lung cancer in African-Americans (95% CI: 0.66–1.16; P = 0.341), without heterogeneity (I2 = 0.0%) or publication bias (PEgger = 0.192). Upon stratification by source of controls, risk magnitude was relatively stronger in hospital-based studies than in population-based studies, whereas heterogeneity and publication bias tangled the former. Restricting analysis to studies with ≥500 patients still detected no material changes in risk estimates in both allelic and dominant models, indicating the robustness of our results.

Discussion

Although numerous studies have regarded NQO1 gene C609T polymorphism as a promising candidate for lung cancer, our case-control study in northeastern Han Chinese, along with the meta-analysis, failed to confirm this relation, even across different ethnic populations. This non-significance was also reflected in larger sample-size studies, which are less prone to chance results, indicating the robustness of our findings. To the authors’ knowledge, this is the most comprehensive meta-analysis investigating the genetic susceptibility of NQO1 gene C609T polymorphism to lung cancer.

With the increase of genetic association studies, it is highly encouraged to synthesize available data to resolve persistent difficulties in obtaining robust, replicable results. Considering the fact that most common genetic defects usually make a small-to-moderate contribution to future disease risk, this study urges the necessity of very large sample sizes to drive sufficiently precise estimates between genetic variation and disease. Several individual studies have reported positive signals of NQO1 gene C609T polymorphism with lung cancer [19], [20], [22], [23], [26], [29], [39], [40]; contrastingly, as illustrated in our overall findings among 16453 subjects, there was no detectable risk, even in populations of different descents. However, it is worth noting that the protective effect conferred by 609T allele was appreciably obvious in African-Americans. Considering the relatively few studies were conducted in African-Americans and most of these studies were small, there is an indication of possible benefit, reinforcing additional large studies to confirm or refute this finding. Even though, we cannot rule out a possible significant effect of 609T allele in lung carcinogenesis, and it is also possible that the potential role of the examined polymorphism is diluted or masked by other gene-gene or gene-environment interactions.

Several strengths distinguishing the present investigation merit adequate consideration. First, this is to date the largest synthesis exploring the association of NQO1 gene C609T polymorphism with lung cancer. Second, the results of the present case-control study were in line with that of the corresponding meta-analysis, and restricting analyses to larger studies generated the similar findings. Third, our results are less prone to selection bias in view of low probability of publication bias.

In addition, some limitations should be considered when interpreting our findings. First, the cross-sectional design of included studies in this meta-analysis may preclude comments on causality, and a survival bias could not be excluded. Second, as with all meta-analyses, publication bias might have occurred because our analyses were based entirely on published studies from English- and Chinese-language journals. Third, although the adopted random-effects model takes both a between-study variance and the within-study variances into account, this model cannot be regarded as a panacea for heterogeneity [41]. Moreover, as stated by Higgins et al [42], the assumption of true quantities from the individual studies following a certain probability distribution in a random-effect model is somewhat arbitrary and makes the interpretation of its predictions difficult. Fourth, data on circulating levels of NQO1 protein or its catalyzed products were unavailable, precluding a more robust assessment of sources of heterogeneity, and making us incapable of comparing their levels across genotypes. Fifth, we focused on only one polymorphism in NQO1 gene, and did not cover other susceptibility genes or polymorphisms. Given these limitations, we cannot jump to a conclusion until further verification of our findings in vitro, in vivo and in large prospective studies.

To sum up, this case-control study in northeastern Han Chinese, along with the comprehensive meta-analysis, failed to confirm the association of NQO1 gene C609T polymorphism with lung cancer risk, even across different ethnic populations. Nevertheless, for practical reasons, we hope that this study will not remain just another endpoint of research instead of a beginning to establish the background data to further investigate the molecular mechanisms of NQO1 gene and lung cancer.

Supporting Information

Table S1.

Checklist of items to include when reporting a systematic review or meta-analysis (diagnostic review consisting of cohort studies).

https://doi.org/10.1371/journal.pone.0047939.s001

(DOC)

Table S2.

Criteria for quality assessment of genetic association of NQO1 gene C609T polymorphism with lung cancer.

https://doi.org/10.1371/journal.pone.0047939.s002

(DOC)

Author Contributions

Conceived and designed the experiments: SG WN. Performed the experiments: GS XL YL. Analyzed the data: SG WN. Contributed reagents/materials/analysis tools: SC DZ MG. Wrote the paper: SG WN.

References

  1. 1. Shibuya K, Mathers CD, Boschi-Pinto C, Lopez AD, Murray CJ (2002) Global and regional estimates of cancer mortality and incidence by site: II. Results for the global burden of disease 2000. BMC Cancer 2: 37.
  2. 2. Chao C, Zhang ZF, Berthiller J, Boffetta P, Hashibe M (2006) NAD(P)H:quinone oxidoreductase 1 (NQO1) Pro187Ser polymorphism and the risk of lung, bladder, and colorectal cancers: a meta-analysis. Cancer Epidemiol Biomarkers Prev 15: 979–987.
  3. 3. Rosvold EA, McGlynn KA, Lustbader ED, Buetow KH (1995) Identification of an NAD(P)H:quinone oxidoreductase polymorphism and its association with lung cancer and smoking. Pharmacogenetics 5: 199–206.
  4. 4. Heller G, Zielinski CC, Zochbauer-Muller S (2010) Lung cancer: from single-gene methylation to methylome profiling. Cancer Metastasis Rev 29: 95–107.
  5. 5. Schlager JJ, Powis G (1990) Cytosolic NAD(P)H:(quinone-acceptor)oxidoreductase in human normal and tumor tissue: effects of cigarette smoking and alcohol. Int J Cancer 45: 403–409.
  6. 6. Joseph P, Jaiswal AK (1994) NAD(P)H:quinone oxidoreductase1 (DT diaphorase) specifically prevents the formation of benzo[a]pyrene quinone-DNA adducts generated by cytochrome P4501A1 and P450 reductase. Proc Natl Acad Sci U S A 91: 8413–8417.
  7. 7. Smitskamp-Wilms E, Giaccone G, Pinedo HM, van der Laan BF, Peters GJ (1995) DT-diaphorase activity in normal and neoplastic human tissues; an indicator for sensitivity to bioreductive agents? Br J Cancer 72: 917–921.
  8. 8. Marin A, Lopez de Cerain A, Hamilton E, Lewis AD, Martinez-Penuela JM, et al. (1997) DT-diaphorase and cytochrome B5 reductase in human lung and breast tumours. Br J Cancer 76: 923–929.
  9. 9. Malkinson AM, Siegel D, Forrest GL, Gazdar AF, Oie HK, et al. (1992) Elevated DT-diaphorase activity and messenger RNA content in human non-small cell lung carcinoma: relationship to the response of lung tumor xenografts to mitomycin Cl. Cancer Res 52: 4752–4757.
  10. 10. Misra V, Grondin A, Klamut HJ, Rauth AM (2000) Assessment of the relationship between genotypic status of a DT-diaphorase point mutation and enzymatic activity. Br J Cancer 83: 998–1002.
  11. 11. Siegel D, McGuinness SM, Winski SL, Ross D (1999) Genotype-phenotype relationships in studies of a polymorphism in NAD(P)H:quinone oxidoreductase 1. Pharmacogenetics 9: 113–121.
  12. 12. Kuehl BL, Paterson JW, Peacock JW, Paterson MC, Rauth AM (1995) Presence of a heterozygous substitution and its relationship to DT-diaphorase activity. Br J Cancer 72: 555–561.
  13. 13. Guo S, Li X, Gao M, Kong H, Li Y, et al. (2012) Synergistic Association of PTGS2 and CYP2E1 Genetic Polymorphisms with Lung Cancer Risk in Northeastern Chinese. PLoS One 7: e39814.
  14. 14. Niu W, Zhang Y, Ji K, Gu M, Gao P, et al. (2010) Confirmation of top polymorphisms in hypertension genome wide association study among Han Chinese. Clin Chim Acta 411: 1491–1495.
  15. 15. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151: 264–269, W264.
  16. 16. Thakkinstian A, McEvoy M, Minelli C, Gibson P, Hancox B, et al. (2005) Systematic review and meta-analysis of the association between {beta}2-adrenoceptor polymorphisms and asthma: a HuGE review. Am J Epidemiol 162: 201–211.
  17. 17. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327: 557–560.
  18. 18. Duval S, Tweedie R (2000) Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 56: 455–463.
  19. 19. Chen H, Lum A, Seifried A, Wilkens LR, Le Marchand L (1999) Association of the NAD(P)H:quinone oxidoreductase 609C–>T polymorphism with a decreased lung cancer risk. Cancer Res 59: 3045–3048.
  20. 20. Lin Y, Lu X, Shao M, Liang Y, Li Y (2000) NAD(P)H: quinone oxidoredictase gene polymorphism and susceptibility of lung cancer. J Thorac Oncol 6: 1826–1832.
  21. 21. Yin L, Pu Y, Liu TY, Tung YH, Chen KW, et al. (2001) Genetic polymorphisms of NAD(P)H quinone oxidoreductase, CYP1A1 and microsomal epoxide hydrolase and lung cancer risk in Nanjing, China. Lung Cancer 33: 133–141.
  22. 22. Sunaga N, Kohno T, Yanagitani N, Sugimura H, Kunitoh H, et al. (2002) Contribution of the NQO1 and GSTT1 polymorphisms to lung adenocarcinoma susceptibility. Cancer Epidemiol Biomarkers Prev 11: 730–738.
  23. 23. Hamajima N, Matsuo K, Iwata H, Shinoda M, Yamamura Y, et al. (2002) NAD(P)H: quinone oxidoreductase 1 (NQO1) C609T polymorphism and the risk of eight cancers for Japanese. Int J Clin Oncol 7: 103–108.
  24. 24. Lin P, Hsueh YM, Ko JL, Liang YF, Tsai KJ, et al. (2003) Analysis of NQO1, GSTP1, and MnSOD genetic polymorphisms on lung cancer risk in Taiwan. Lung Cancer 40: 123–129.
  25. 25. Lan Q, Mumford JL, Shen M, Demarini DM, Bonner MR, et al. (2004) Oxidative damage-related genes AKR1C3 and OGG1 modulate risks for lung cancer due to exposure to PAH-rich coal combustion emissions. Carcinogenesis 25: 2177–2181.
  26. 26. Liang GY, Pu YP, Yin LH (2004) Studies of the genes related to lung cancer susceptibility in Nanjing Han population, China. Yi Chuan 26: 584–588.
  27. 27. Chan EC, Lam SY, Fu KH, Kwong YL (2005) Polymorphisms of the GSTM1, GSTP1, MPO, XRCC1, and NQO1 genes in Chinese patients with non-small cell lung cancers: relationship with aberrant promoter methylation of the CDKN2A and RARB genes. Cancer Genet Cytogenet 162: 10–20.
  28. 28. Yang M, Choi Y, Hwangbo B, Lee JS (2007) Combined effects of genetic polymorphisms in six selected genes on lung cancer susceptibility. Lung Cancer 57: 135–142.
  29. 29. Eom SY, Zhang YW, Kim SH, Choe KH, Lee KY, et al. (2009) Influence of NQO1, ALDH2, and CYP2E1 genetic polymorphisms, smoking, and alcohol drinking on the risk of lung cancer in Koreans. Cancer Causes Control 20: 137–145.
  30. 30. Lewis SJ, Cherry NM, Niven RM, Barber PV, Povey AC (2001) Polymorphisms in the NAD(P)H: quinone oxidoreductase gene and small cell lung cancer risk in a UK population. Lung Cancer 34: 177–183.
  31. 31. Xu LL, Wain JC, Miller DP, Thurston SW, Su L, et al. (2001) The NAD(P)H:quinone oxidoreductase 1 gene polymorphism and lung cancer: differential susceptibility based on smoking behavior. Cancer Epidemiol Biomarkers Prev 10: 303–309.
  32. 32. Alexandrie AK, Nyberg F, Warholm M, Rannug A (2004) Influence of CYP1A1, GSTM1, GSTT1, and NQO1 genotypes and cumulative smoking dose on lung cancer risk in a Swedish population. Cancer Epidemiol Biomarkers Prev 13: 908–914.
  33. 33. Bock CH, Wenzlaff AS, Cote ML, Land SJ, Schwartz AG (2005) NQO1 T allele associated with decreased risk of later age at diagnosis lung cancer among never smokers: results from a population-based study. Carcinogenesis 26: 381–386.
  34. 34. Lawson KA, Woodson K, Virtamo J, Albanes D (2005) Association of the NAD(P)H:quinone oxidoreductase (NQO1) 609C->T polymorphism with lung cancer risk among male smokers. Cancer Epidemiol Biomarkers Prev 14: 2275–2276.
  35. 35. Saldivar SJ, Wang Y, Zhao H, Shao L, Lin J, et al. (2005) An association between a NQO1 genetic polymorphism and risk of lung cancer. Mutat Res 582: 71–78.
  36. 36. Skuladottir H, Autrup H, Autrup J, Tjoenneland A, Overvad K, et al. (2005) Polymorphisms in genes involved in xenobiotic metabolism and lung cancer risk under the age of 60 years. A pooled study of lung cancer patients in Denmark and Norway. Lung Cancer 48: 187–199.
  37. 37. Sorensen M, Autrup H, Tjonneland A, Overvad K, Raaschou-Nielsen O (2005) Genetic polymorphisms in CYP1B1, GSTA1, NQO1 and NAT2 and the risk of lung cancer. Cancer Lett 221: 185–190.
  38. 38. Cote ML, Yoo W, Wenzlaff AS, Prysak GM, Santer SK, et al. (2009) Tobacco and estrogen metabolic polymorphisms and risk of non-small cell lung cancer in women. Carcinogenesis 30: 626–635.
  39. 39. Timofeeva M, Kropp S, Sauter W, Beckmann L, Rosenberger A, et al. (2010) Genetic polymorphisms of MPO, GSTT1, GSTM1, GSTP1, EPHX1 and NQO1 as risk factors of early-onset lung cancer. Int J Cancer 127: 1547–1561.
  40. 40. Wiencke JK, Spitz MR, McMillan A, Kelsey KT (1997) Lung cancer in Mexican-Americans and African-Americans is associated with the wild-type genotype of the NAD(P)H: quinone oxidoreductase polymorphism. Cancer Epidemiol Biomarkers Prev 6: 87–92.
  41. 41. Spector TD, Thompson SG (1991) The potential and limitations of meta-analysis. J Epidemiol Community Health 45: 89–92.
  42. 42. Higgins JP, Thompson SG, Spiegelhalter DJ (2009) A re-evaluation of random-effects meta-analysis. J R Stat Soc Ser A Stat Soc 172: 137–159.