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Carcinogenesis Advance Access originally published online on February 6, 2008
Carcinogenesis 2008 29(6):1164-1169; doi:10.1093/carcin/bgn020
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A comprehensive analysis of phase I and phase II metabolism gene polymorphisms and risk of non-small cell lung cancer in smokers

Shanbeh Zienolddiny*,1,{dagger}, Daniele Campa2,{dagger}, Helge Lind1, David Ryberg1, Vidar Skaug1, Lodve B. Stangeland3, Federico Canzian4 and Aage Haugen1

1 Section of Toxicology, Department of Biological and Chemical Work Environment, National Institute of Occupational Health N-0033, Oslo, Norway
2 Department of Biology, University of Pisa, 56126 Pisa, Italy
3 Haukeland University Hospital, N-5021 Bergen, Norway
4 Department of Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

* To whom correspondence should be addressed. Tel: +47 23195284; Fax: +47 23195203; Email: shan.zienolddiny{at}stami.no


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Supplementary material
 Funding
 References
 
Lung cancer is a leading cause of cancer mortality worldwide with smoking and occupational exposure to carcinogenic compounds as the major risk factors. Susceptibility to lung cancer is affected by existence of polymorphic genes controlling the levels of metabolic activation and detoxification of carcinogens. We have investigated 105 single nucleotide polymorphisms (SNPs) in 31 genes from the phase I and phase II metabolism genes and antioxidant defense genes for association with the risk of non-small cell lung cancer (NSCLC) in a Norwegian population-based study. Our results indicate that several SNPs in the phase I genes, CYP1B1, CYP2D6, CYP2E1 and CYP3A4, are associated with the risk of NSCLC. Moreover, significant associations with multiple SNPs in the phase II genes ALDH2, COMT, EPHX1, SOD2, NAT1, NAT2, GSTM3, GSTP1, GSTT2 and MPO were also found. We prioritized our findings by use of two different recently developed Bayesian statistical tools, employing conservative prior probabilities of association. When we corrected for multiple testing using these statistical tools, three novel associations of NSCLC risk with SNPs in the CYP1B1 (Arg48Gly), COMT (Val158Met) and GSTT2 (Met139Ile) genes were found noteworthy. However, only four of the previously reported associations with polymorphisms in the GSTP1 (Ala14Val), SOD2 (Val16Ala), EPHX1 (His139Arg) genes and the NAT1 fast acetylator phenotype remained significantly associated with lung cancer.

Abbreviations: BFDP, Bayesian false-discovery probability; COMT, catechol-O-methyltransferase; FPRP, false-positive report probability; GST, glutathione S-transferase; NAT, N-acetyltransferases; NSCLC, non-small cell lung cancer; OR, odds ratio; SNP, single nucleotide polymorphism


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Supplementary material
 Funding
 References
 
Smoking and occupational exposure to potential carcinogenic compounds are the major risk factors for lung cancer (1). Since only ~1 in 10 smokers develop lung cancer, genetic predisposition may play a role in modulating the risk possibly through low-penetrance polymorphic genes. Epidemiologic studies have demonstrated that low-penetrance, high-prevalence polymorphic phase I and phase II enzymes of the cytochrome P450 system may alter susceptibility to lung cancer (2). It is hypothesized that genetic variations in these metabolism genes may play a role in how individuals will respond to carcinogenic compounds and hence affecting the risk of developing the disease.

More than 60 lung carcinogens have been identified in cigarette smoke (3). Many of these compounds are converted into reactive carcinogenic metabolites by phase I enzymes and are removed by phase II enzymes (4). In the lung, at least 57 cytochrome P450 enzymes are expressed, resulting in multiple species of reactive metabolites (5). The phase II enzymes, among which glutathione S-transferases (GSTs) and N-acetyltransferases (NATs), are responsible for removal of reactive metabolites (6,7). The most important enzymes in this pathway are GSTµ, GST {theta}, GST {pi} and glutathione peroxidase, all of which are polymorphic.

The aryl and heterocyclic amines are metabolized by NAT1 and NAT2, which act via N- and O-acetylation. The NAT genes are polymorphic in humans, resulting in fast, slow or intermediate acetylator phenotypes (8).

Reactive oxygen/nitrogen species (ROS/RNS) in tobacco smoke may also contribute to lung carcinogenesis. Several studies indicate that oxidative stress is an important mechanism in cancer development. Interindividual genetic susceptibility in antioxidant defense enzymes may be relevant in lung cancer. The potential role of ROS/RNS species in generation of oxidative stress and DNA damage is supported by experimental evidence (3). The level of oxidative stress in the lungs is modulated by enzymes such as myeloperoxidase, catechol-O-methyltransferase (COMT), manganese superoxide dismutase, microsomal epoxide hydrolase and NAD(P)H:quinone oxidoreductase. In addition to the release of ROS/RNS species, they may also activate procarcinogens such as benzo[a]pyrene in tobacco smoke (9). Polymorphisms in these genes may affect gene expression or enzyme activities and thereby affecting the cancer risk.

In this study, we have performed a comprehensive analysis of 105 SNPs in 31 genes from phase I and phase II xenobiotic-metabolizing enzymes and oxidative pathways in a case–control study on lung cancer among Norwegian smokers. The false-positive report probability (FPRP) and Bayesian false-discovery probability (BFDP) are two Bayesian statistical tools recently developed to deal with multiple testing problems in association studies. In order to correct for the large number of statistical tests, we prioritized our findings by using both methods, employing conservative prior probabilities of association.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Supplementary material
 Funding
 References
 
Study subjects
The study population, with details and criteria for inclusion or exclusion of cases and controls into the ongoing lung cancer case–control study of Norwegian Caucasians, have been described previously (10,11). The characteristics of non-small cell lung cancer (NSCLC) patients and healthy controls included in the present study are summarized in Table I. A total of 365 NSCLC patients were treated by surgery at the university hospitals in Oslo or Bergen between 1986 and 2001. Diagnosis of NSCLC was confirmed by two pathologists. Patients were enrolled in the study consecutively whenever practically feasible. Less than 5% of the patients declined to participate in the project resulting in an overall response rate of >95% among the patients asked to participate in the study. Further, 11 cases (3%) were excluded from the study because of more advanced tumors (metastasis). Controls were recruited from a general health survey conducted by the National Health Surveys in the Oslo area (HUBRO) of the general population. The purpose of the surveys was to monitor the health status of the general population. A total of 8100 persons participating in the year 2000–2001 HUBRO study were asked to participate in the present study, and ~50% of the subjects contacted agreed to be included in the control group. Among them, 413 smokers without any known history of cancer were randomly selected and frequency matched with the cases on age, smoking dose (pack-years) and male:female ratio. Cases and controls were interviewed by trained health personnel using questionnaires containing comparable information on demographic and lifestyle details. All subjects were informed about the project and gave written consent to participate in the study and to allow their biological samples to be genetically analyzed. The study was conducted in accordance with guidelines set up by the Regional Ethical Committee and the Data Inspectorate of Norway.


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  		Table I. Characteristics of NSCLC cases and controls

 
DNA extraction
DNA was extracted from biological samples either with DNA isolation kits (Qiagen, Germany) or standard proteinase K digestion, phenol–chloroform extraction and ethanol precipitation.

SNP selection and genotyping
A total of 105 SNPs in 31 genes related to carcinogen metabolism and detoxification were chosen (Table II). The SNPs chosen for this study have been associated with cancers induced by environmental factors as well as smoking, having a frequency ≥5% in Caucasians and proven or inferred biological activity. Genotyping was performed by the arrayed primer extension as described previously (10,11). Briefly, the arrayed primer extension procedure consists of a sequencing reaction primed by an oligonucleotide anchored with its 5' end to a glass slide and terminating just one nucleotide before the polymorphic site. This method is suitable not only for SNPs but also for small insertion/deletion polymorphisms. Since both sense and anti-sense strands are sequenced, two oligonucleotides were designed for each polymorphism. The arrayed primer extension genotyping assay has been thoroughly validated and published previously (12,13). The quality control of genotyping was checked by reanalysis of genotyping of the subjects, independently by two persons.


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  		Table II. List of all genes, polymorphisms and corresponding dbSNP reference numbers

 
Statistical analysis
Differences in demographic variables, smoking and grouped genotypic frequencies between the cases and control subjects were evaluated by using the chi-square test. All reported P values are two sided with P < 0.05 considered as significant. Hardy–Weinberg equilibrium was estimated in controls for each polymorphism with P = 0.01 as the thereshold. The association between the variant genotypes and risk of lung cancer was estimated by computing odds ratios (ORs) and their 95% confidence intervals from unconditional logistic regression analysis using the SPSS (version 13.01) statistical package. Age, sex and cumulative smoking dose (pack-years) were used as covariates. Homozygosity for the more frequent allele among controls was set as the reference group.

Phenotype analysis
For the genes NAT1 and NAT2, we grouped subjects according to their possible phenotype. NAT1 and NAT2 were grouped as described by Wikman et al. (14) or as reported in the database http://louisville.edu/medschool/pharmacology/NAT.html. According to this classification, the NAT1*10 haplotype is associated with a ‘fast’ acetylator phenotype, NAT1*4 and NAT1*11 are considered to give a ‘normal’ acetylator phenotype and NAT1*14 and NAT1*15 are the ones associated with a ‘slow’ acetylator phenotype. Subjects carrying one fast and one slow allele were grouped as normal acetylators. For NAT2, the haplotypes *4, *12 and *13 are all considered associated with a fast acetylator phenotype, whereas the haplotypes *5, *6 and *7 are considered as slow acetylators. Thus, subjects were grouped according to their status as ‘fast acetylators’ when they carried at least one fast allele and ‘slow acetylators’ when they carried two slow alleles.

Multiple testing and false-positive rate
To evaluate the possibility of false positives, we used the FPRP. The FPRP statistical tool was introduced by Wacholder et al. (15) as a means to assess whether the strength of an association is ‘noteworthy’, in the case of multiple hypothesis testing. In addition to FPRP, we also used the BFDP, which is a recent, further development of FPRP (16). Both methods use a Bayesian approach in the form of a priori hypothesis of the noteworthy of the association. The more conservative an a priori probability of association is chosen, the lesser the possibility of false association, possibly at the cost of losing some true associations.

Prior probability is likely to be influenced by the known biological knowledge of the gene, the functional significance of the variants and the available epidemiological evidence. It remains a subjective measure that may vary from one investigator to another based on the importance they assign to the different pieces of evidence. For this reason, we have assigned to each SNP a single value of prior probability according to the following criteria: (i) we considered that a prior probability of 0.1 might be acceptable when there was a very strong biological plausibility with consistent previous epidemiological evidence for association; (ii) a prior probability of 0.01 may be appropriate when either the biological knowledge or epidemiological data were missing or inconclusive and (iii) finally a prior probability of 0.001 may be appropriate when the biological knowledge and epidemiological data were both missing or inadequate. We have not considered lower prior probabilities because they are more appropriate for genome-wide scans. We have then performed a single analysis of FPRP and BFDP for each SNP. For both tests, we chose the noteworthiness thresholds (FPRP ≤ 0.2 and BFDP ≤ 0.8) following the original papers (15,16). We considered ‘noteworthy’ only those associations that passed both tests. We have set very conservative prior probabilities compared with what commonly have been used (17).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Supplementary material
 Funding
 References
 
The relevant characteristics of the cases and controls are shown in Table I. Cases and controls were similar in terms of gender distribution and smoking habits. In order to get a comprehensive picture of the individual risk of lung cancer in smokers, we analyzed a rather large number of polymorphisms in xenobiotic-metabolizing enzyme genes (Table II) using a moderate-sized sample of only NSCLC histology.

Out of the 18 SNPs associated with increased or decreased risk of NSCLC (Table III), 3 SNPs are novel findings not reported previously to be associated with NSCLC risk. The risk for the variant allele of CYP1B1 in exon 2 (Arg48Gly) was pronounced with an OR of 4.45 (95% confidence interval, 2.51–7.49, P = 0.007) in homozygotes. The exonic SNP in the COMT gene (Val158Met) was associated with an increased risk of lung cancer. The Met139Ile SNP in GSTT2 had significant protective effect. The remaining 15 polymorphisms have been reported previously to be associated with the risk of NSCLC and are listed in Table III.


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  		Table III. List of polymorphisms associated with the risk of NSCLC

 
Since a large number of polymorphisms were tested for association with NSCLC risk, the issue of false-positive findings is important. Standard adjustments for multiple testing, such as Bonferroni correction, are too conservative as they assume that tests are independent, which is usually not the case when multiple polymorphisms in the same gene are considered. We have, therefore, applied recently developed FPRP and BFDP statistical tools to evaluate noteworthiness of the associations by following the recommendations suggested by Wacholder et al. (15) in using a threshold for noteworthiness of 0.2. By applying these methods, only seven polymorphisms remained significantly associated at noteworthy levels (Table IV). Four of them including NAT1 fast acetylator, GSTP1, EPHX1 and SOD2 are well-known players in lung cancer genetic susceptibility, suggesting the robustness of our method, whereas the CYP1B1 (Arg48Gly), COMT (Val158Met and GSTT2 (Met139Ile) are the novel associations described in this report.


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  		Table IV. Prior probabilities, the FPRP and BFDP values for each individual SNP

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Supplementary material
 Funding
 References
 
We have genotyped 105 polymorphisms in 31 genes involved in carcinogen and xenobiotic metabolism in 748 Norwegian lung cancer cases and controls. Eighteen SNPs were associated with the risk of NSCLC but only six, namely EPHX1 His139Arg, SOD Val16Ala, GSTP1 Ala114Val, CYP1B1 Arg48Gly, GSTT2 Met139Ile and COMT Val158Met passed our false-positive detection criteria set in the FPRP and BFDP tests (Table IV). Moreover, NAT1 fast acetylator phenotype passed the FPRP/BFDP test. Out of the seven associations we found, four were already known and have been reported in lung cancer studies. The fact of having confirmed them after the FPRP and the BFDP filtering supports the robustness of our a priori hypothesis.

We report three novel associations with NSCLC. The CYP1B1 Arg48Gly was found to modify risk of lung cancer in homozogote subjects carrying two Gly alleles (Table III). Several CYP1B1 variants (including Gly48) exhibit higher enzymatic activity when compared with the most common Arg48 form (18). The CYP1B1, an extrahepatic enzyme highly expressed in human lung (19), is inducible by cigarette smoking (20), B[a]P and dioxin (21). This enzyme is involved in the metabolic activation of chemically diverse procarcinogens to reactive metabolites that cause DNA damage (22). CYP1B1 is overexpressed in a wide range of human cancers, including breast, colon, lung, esophagus, skin, lymph node, brain and testis cancer. The importance of CYP1B1 in chemical carcinogenesis is well documented using Cyp1b1-null (Cyp1b1–/–) mice. Embryonic fibroblast cells derived from Cyp1b1-deficient mice were found to be resistant to 7,12-dimethylbenz(a)anthracene-mediated tumorigenesis and were protected from 7,12-dimethylbenz(a)anthracene-induced malignant lymphomas (23,24) and preleukemia (25), but the incidences of adenomas and adenocarcinomas of the lung were increased as compared with wild-type mice.

We found an association between carriers of the 158Met allele of the COMT gene with increased risk of lung cancer. This SNP has been the subject of several molecular epidemiological studies because of the important role of the COMT enzyme in various pathways, including the metabolism of catecholamines and catechol estrogens. The substitution of valine by methionine at codon 158 affects the activity of the COMT enzyme. Individuals with the Val/Val genotype have a 3- to 4-fold higher activity of the COMT enzyme than those with Met/Met genotype, whereas heterozygous subjects exhibit intermediate enzyme activity (26). Thus, the carriers of the Met genotype may be subjected to a lowered protective activity, thereby promoting DNA damage and tumor progression. This is plausible since the enzyme prevents quinone formation and redox cycling and therefore might protect DNA from oxidative damage. Despite the large number of studies evaluating the relationship between Val158Met polymorphism and diseases, the influence of this polymorphism on lung cancer risk has not been reported.

A statistically significant association between the missense Met139Ile substitution in GSTT2 gene and NSCLC was observed. We set a very stringent prior probability (0.001) for this polymorphism since little is known about this SNP and the risk of lung cancer. However, Coggan et al. (27) suggest that it may influence the enzyme function. The polymorphic residue 139 is located in the helix 5 region of the protein and occupies a hydrophobic pocket that is bounded by Phe110, Tyr181, Pro176, Pro113 and Leu183 residues. The substitution of isoleucine in this position is very unlikely to have a direct effect on the enzyme's function; however, subtle secondary effects cannot be excluded.

Finally, we confirm that NAT1 fast acetylator phenotype, the Arg carriers of the His139Arg polymorphism of the EPHX1 gene and the carriers of the Ala allele of the Val16Ala SOD2 gene were associated with higher lung cancer risk (28,29). We also found an increased risk for carriers of the Val allele of the GSTP1 Ala114Val, as reported previously (30). However, this result should be interpreted with caution since the numbers for the rare homozygotes at this polymorphism are small. For the NAT1 fast acetylator phenotype, there is a large body of evidence showing an association of polymorphisms in this gene and risk of several cancer types and our results are in agreement with most of the data reported in previous studies (14).

Our study failed to replicate some previously reported associations (supplementary table is available at Carcinogenesis Online). For example, the nucleotide change of C to T at position 677 (C677T rs1801133) in the methylenetetrahydrofolate reductase (MTHFR) gene resulting in an amino acid substitution of alanine to valine at codon 222 (A222V) has been most studied and found associated with lung cancer risk in some studies (31,32). Functional studies have shown that minor allele results in thermolability and diminished enzyme activity, lower folate levels as well as lower methylation levels (33–36). The CYP1A1 (MspI) polymorphism has been extensively studied in relation to lung cancer in many ethnic groups with conflicting results (37–40). This polymorphism has been associated experimentally with increased catalytic activity (41) and higher levels of hydrophobic DNA adducts (42,43). The two CYP1B1 (A119S, m2 rs1056827) and CYP1B1 (V432L, m3 rs1056836) polymorphisms have been studied in relation to lung cancer risk with negative results (44,45) as well as positive results (46).

One of the possible limitations of this study is the moderate sample size and thus the possibility of potential confounding false positives. For this reason, we applied two Bayesian approaches to filter out false-positive associations by setting very stringent prior probabilities. It should also be noted that we could not replicate some of the previously reported associations. One of the reasons may be that with 335 cases and 413 controls, we had <80% power of finding ORs <1.8 (for polymorphisms with minor allele frequency between 5 and 15%) or <1.5 (for more common polymorphisms). Therefore, if a real association characterized by low OR was reported previously, our study would be underpowered to replicate it. Moreover, one specific difference between ours and previous reports is that all our study subjects were smokers. This may mask some of the associations observed in other studies that had a large proportion of non-smokers. For example, one can speculate that smoking reduces folate levels to a point where the difference caused by the methylenetetrahydrofolate reductase A222V polymorphism becomes unrelevant.

In conclusion, in this comprehensive study of 105 polymorphisms in 31 xenobiotic-metabolizing enzymes genes, we found seven strong and robust associations. Four of them are already well known to be associated with risk of lung cancer and form our proof of principle that both the technique used and the statistics worked out properly. The other three are novel and promising candidates as markers for genetic susceptibility to lung cancer in smokers.


   Supplementary material
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Supplementary material
Funding
 References
 
Supplementary table can be found at http://carcin.oxfordjournals.org/


   Funding
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Supplementary material
 Funding
References
 
Norwegian Research Council; The Cancer Society of Norway; International Agency for Research on Cancer, Lyon, France.


   Footnotes
 
{dagger} These authors contributed equally to the manuscript. Back


   Acknowledgments
 
We greatly acknowledge collaboration of Dr Anne Naalsund, National University Hospital, Oslo, in recruiting parts of the patients. We also acknowledge the assistance of Mr Erik B. Eide and Mrs Tove Andreassen.

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Supplementary material
 Funding
 References
 

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Received September 12, 2007; revised December 21, 2007; accepted January 14, 2008.


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