An association between a NQO1 genetic polymorphism and risk of lung cancer

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Abstract

NAD(P)H:quinone oxidoreductase (NQO1) is a detoxification enzyme that protects against the regeneration of reactive oxygen species chemically induced by oxidative stress, cytotoxicity, mutagenicity, and carcinogenicity. The protection conferred by NQO1 protein reduces certain environmental carcinogens, such as nitroaromatic compounds, heterocyclic amines, and possible cigarette smoke condensate. The gene coding for NQO1 has a genetic polymorphism (C  T) at nucleotide position 609 (i.e. amino acid codon 187) of the NQO1 cDNA. This polymorphism was shown to reduce NQO1 enzyme activity, thereby diminishing the protection provided by NQO1. Therefore, we hypothesized that individuals with the variant NQO1 genotype are at higher risk for lung cancer. Using a case-control study, we genotyped the NQO1 variants successfully by PCR–RFLP in 826 lung cancer patients and 826 healthy control subjects matched for age, sex, ethnicity, and smoking status. The frequency of the NQO1 T-allele was statistically significantly different among three ethnic groups (p < 0.001). In further analysis of Caucasians, the variant NQO1 genotypes (CT and TT) were associated with a marginally increased lung cancer risk (OR = 1.19; 95% CI: 0.95–1.50). The elevated lung cancer risk was only evident in younger individuals (age <62 years old) (OR = 1.46; 95% CI: 1.04–2.05), women (OR = 1.89; 95% CI: 1.33–2.68), and never smokers (OR = 1.80; 95% CI: 1.03–3.13). Furthermore, we found a statistically significant trend in the development of lung cancer at an early age in women with increasing copies of the variant allele (p = 0.03). These results suggest that the NQO1 variant genotype may modulate lung cancer risk, especially in younger individuals (age < 62), women, and never smokers.

Introduction

With an estimate of 193,770 new diagnoses and 160,440 deaths in 2004, lung cancer is the most fatal neoplasm in the United States [1]. Extensive epidemiological data clearly establish cigarette smoking as the major cause of this malignancy [2]. Although up to 90% of lung cancer is attributable to smoking, only 10% of smokers develop lung cancer [3]. This observation suggests that individual variation in the metabolism of tobacco carcinogens may determine susceptibility to lung cancer [4]. A number of genetic polymorphisms associated with the capacity to metabolically alter tobacco procarcinogens have been found to vary markedly across individuals. Some of these polymorphisms have been linked with lung cancer risk [5], [6].

NAD(P)H:quinone oxidoreductase 1 (NQO1) is an important flavoprotein that catalyzes the 2-electron reduction of quinones to hydroquinones [7]. In doing so, NQO1 prevents the generation of free radicals and reactive oxygen, thus protecting the cells from oxidative damage [8]. This pathway is thought to be the major mechanism responsible for modifying the toxicity of quinones, including those arising from the formation of DNA adducts induced by benzo(a)pyrene 3,6-quinone, one of the most potent polycyclic aromatic hydrocarbons present in tobacco smoke [9]. Alternatively, NQO1 is known to activate some environmental procarcinogens, such as nitroaromatic compounds and heterocyclic amines [10], [11], [12], present in tobacco smoke. Therefore, NQO1 exerts both detoxification and activation functions, depending on the substrate.

The NQO1 gene is located on chromosome 16q22. The polymorphic variant is a C  T transition at nucleotide position 609 (amino acid codon 187) that results in a proline-to-serine amino acid substitution in the protein. The reference number of this SNP in the database of the National Center for Biotechnology Information (NCBI) is rs1800566. Genotype–phenotype studies of the NQO1 variant alleles have been performed using both cell systems and tissues, and NQO1 protein has been detected in normal lung respiratory epithelium, suggesting a protective role against lung damage [13]. Three genotypes of NQO1 are known to be associated with different enzymatic activities: C/C is the homozygous wild-type with normal activity, C/T is heterozygous with reduced activity, and T/T is the homozygous variant with only 2–4% of the enzyme activity of the wild-type [14], [15], [16], [17], [18].

Several studies have examined the relationship between the NQO1 genetic polymorphism and lung cancer risk, but the conclusions have been inconsistent [19], [20], [21], [22]. In this case-control study, we compared the NQO1 variant allele frequency in patients with lung cancer and control subjects matched by age, sex, ethnicity, and smoking status. Furthermore, we obtained risk estimates for NQO1 variant alleles stratified by demographic variables. Because of its potential role in the modulation of tobacco procarcinogens, we hypothesized that subjects with the NQO1 variant allele associated with reduced enzymatic activity are at higher risk for lung cancer.

Section snippets

Study subjects

For this study, we selected cases from an ongoing lung cancer study enrolling patients with newly diagnosed, untreated lung cancer at The University of Texas M.D. Anderson Cancer Center. There were no age, histologic, or stage restrictions, and all cases were histologically confirmed. A pool of control subjects was recruited from the largest private multi-specialty physician group in the Houston metropolitan area [23]. The controls did not have a previous diagnosis of any type of cancer and

Results

Distributions of characteristics for the study subjects are presented in Table 1. The study population consisted of 826 lung cancer cases and 826 controls. In terms of age, sex, ethnicity, and smoking status, the cases and controls were well matched. As expected, cases smoked more packs of cigarettes per year than controls (42.06 versus 33.50, p < 0.001).

Table 2 illustrates the NQO1 genotype distributions among the various ethnic groups. The polymorphisms were generally in Hardy–Weinberg

Discussion

The NQO1 enzyme is known to play a major role in the detoxification of xenobiotics, including benzo(a)pyrene [27], and evidence suggests that this enzyme is induced as part of the response to tobacco smoke [28]. Although NQO1 has been detected at high levels in normal respiratory epithelium, this enzyme has not been detected in certain lung tumors [29], suggesting that the lack of NQO1 may play a role in the pathology of this disease. Furthermore, variant alleles of this enzyme, produced by a

Acknowledgement

This research was supported by National Cancer Institute grants CA55769 and CA86390.

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