Elsevier

Lung Cancer

Volume 40, Issue 1, April 2003, Pages 25-32
Lung Cancer

Association between glutathione S-transferase p1 polymorphisms and lung cancer risk in Caucasians: a case-control study

https://doi.org/10.1016/S0169-5002(02)00537-8Get rights and content

Abstract

Glutathione transferases (GSTs), a multiple gene family of phase II enzymes, catalyze detoxifying endogenous reactions with glutathione and protect cellular macromolecules from damage caused by cytotoxic and carcinogenic agents. Glutathione S-transferase p1 (GSTP1), the most abundant GST isoform in the lung, metabolizes numerous carcinogenic compounds including benzo[a]pyrene, a tobacco carcinogen. Previous studies suggest that genetic polymorphisms of GSTP1 exon 5 (Ile105Val) and exon 6 (Ala114Val) have functional effects on the GST gene product resulting in reduced enzyme activity. Individuals with reduced GST enzymatic activity may be at a greater risk for cancer due to decreased detoxification of carcinogenic and mutagenic compounds. Utilizing a hospital-based case-control study, we investigated the association between GSTP1 polymorphisms at exons 5 and 6 with lung cancer risk. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to successfully genotype the GSTP1 exons 5 and 6 polymorphism in 582 Caucasian lung cancer cases and 600 frequency matched Caucasian controls. There was no association between the exon 5 variant genotypes (A/G+G/G) and overall lung cancer risk (OR=1.09; 95% CI 0.82–1.45) nor when stratified by age, gender, and smoking status. However, the exon 6 variant genotypes (C/T+T/T) were associated with a statistically significant elevated lung cancer risk (OR=1.40; 95% CI 1.06–1.92). Additionally, there was an increase in lung cancer risk for the exon 6 variant genotypes in younger individuals (<62 years) (OR=1.63; 95% C.I. 1.07–2.49) but no effect in older individuals (OR=1.14; 95% CI 0.72–1.81). A statistically significant increased risk of lung cancer was also observed for the exon 6 variant genotypes among men (OR=2.17; 95% CI 1.41–3.33), but not among women (OR=0.80; 95% CI 0.51–1.28). Among ever smokers, the exon 6 variant genotypes were associated with an elevated lung cancer risk (OR=1.58; 95% CI 1.14–2.19), which was not evident for never smokers (OR=0.53; 95% CI 0.21–1.33). These data demonstrate that the GSTP1 exon 6 polymorphism, but not the exon 5 polymorphism, is associated with lung cancer risk that is especially evident in men, younger individuals, and ever smokers.

Introduction

Glutathione transferases (GSTs), a multiple gene family of phase II enzymes, catalyze detoxifying endogenous reactions with glutathione and protect cellular macromolecules from damage caused by cytotoxic and carcinogenic agents [1], [2]. The cytosolic GST isozymes are comprised of 6 gene families and are classified according to their biochemical characteristics: alpha (GSTA), mu (GSTM), theta (GSTT), pi (GSTP), omega (GSTMO) and one membrane-associated microsomal GST [2], [3], [4]. The GST gene families, including glutathione S-transferase p1 (GSTP1), contain several polymorphic loci, which prompts the hypothesis that allelic variants associated with less effective detoxification of potential carcinogens can confer an increased susceptibility to cancer [5]. GSTP1 is widely expressed in different human epithelial tissue [6] and is the most abundant GST isoform in the lung [7]. Thus, GSTP1 may be of importance for the detoxification of inhaled carcinogens [8] including benzo[a]pyrene, a tobacco carcinogen.

Alterations in the structure, function or expression levels of GSTP1 due to genetic polymorphisms could alter the ability to detoxify carcinogens and modulate lung cancer risk. Previous studies have suggested that genetic polymorphisms of GSTP1 exon 5 (Ile105Val) and exon 6 (Ala114Val) have a functional relevance on the GST gene product resulting in reduced enzyme activity [9], [10], [11]. Therefore, individuals with these variant GSTP1 genotypes that result in reduced GST enzymatic activity may be at greater risk for cancer due to decreased detoxification of carcinogenic and mutagenic compounds. The proteins encoded by the GSTP1 alleles have been previously isolated and shown to differ significantly in their ability to metabolize a variety of carcinogens [12]. Board et al. [13] first identified the GSTP1 polymorphisms and subsequent in vitro studies [9], [10] demonstrated that the single nucleotide substitutions in exons 5 and 6 reduce enzyme activity. Waston et al. [10] reported that individuals with the 105 Val allele of exon 5 had significantly lower GST enzyme activity; however, GST activity was not significantly lower in individuals with the 114 Val allele of exon 6. Ali-Osman et al. [11] provided further evidence that the GSTP1 locus is polymorphic by identifying three different full-length cDNA designated GSTP1*A (105Ile/114Ala), GSTP1*B (105Val/114Ala) and GSTP1*C (105Val/114Val) [19].

Previous epidemiologic studies have suggested that cancer risks are modified by genetic polymorphisms that alter the detoxifying capability of the GST isoforms [12], [14], [15], [16], [17], [18]. A meta-analysis by Vineis et al. [19] reported that carriers of the GSTM1 null genotype had a 1.2-fold (95% CI 1.1–1.4) increased risk of lung cancer among Caucasians and a 1.5-fold (95% CI 1.2–1.7) increased risk among Asians compared to the GSTM1 positive individuals. There were insufficient data to draw conclusions for GSTM3 and GSTT1. In individuals who lacked the GSTM1 gene, the GSTM3 and GSTP1 at risk genotypes conferred nearly a threefold risk of lung cancer (OR=2.7; 95% CI 1.2–6.0) in heavy smokers [20]. With regard to GSTP1, Ryberg et al. [21] reported a significantly higher frequency of the G/G genotype and a lower frequency of A/A genotype of GSTP1 exon 5 in lung cancer patients. Additionally, interaction has been reported for GSTM1/GSTM3 and GSTP1 exon 5 for lung cancer risk in smokers [22], [23]. However, no correlation has been found between GSTP1 exon 5 genotypes and lung cancer risk in other studies [8], [24], [25], [26]. Two of the studies also examined the relationship between GSTP1 exon 6 and lung cancer risk, but no main effects were found [8], [25]. The objective of this hospital-based case-control study was to examine the association of the GSTP1 genotypes of exons 5 and 6 with lung cancer risk.

Section snippets

Study population and data collection

For this analysis there were a total of 1182 Caucasian subjects available of whom 582 were cases and 600 were controls. The lung cancer cases were newly diagnosed, previously untreated, histologically confirmed and recruited between 1995 and 2000 from The University of Texas M.D. Anderson Cancer Center, Houston, Texas. M.D. Anderson staff interviewers performed a daily review of computerized appointment schedules for patient clinics that treat lung cancer patients (the thoracic medical and

Results

Because of the small numbers of minority subjects with the GSTP1 genotype data available at the time of this analysis, we restricted the analysis to Caucasians (582 lung cancer cases and 600 controls). The mean age was 60.9 years (standard deviation (S.D.) 10.1) for the cases and 60.4 years (S.D. 10.3) for the controls (P=0.315) (Table 1). There were no significant differences between the cases and controls in terms of smoking status, gender or mean cigarette pack-years.

Genotype data for the

Discussion

Previous studies have investigated the potential role of the GSTP1 genotypes as a risk factor in various cancer sites including the breast, bladder, prostate, head and neck, colorectal, and lung [12], [14], [23], [28], [29], [30], [31], [32], [33], [34], [35], [36]. However, these findings have not demonstrated a consistent association for lung cancer. For example, Saarikoski et al. [8] found no association between the GSTP1*A, GSTP1*B, or GSTP1*C variants and lung cancer among 208 Finnish

Acknowledgements

This study was supported by National Cancer Institute Grants CA 74880, CA 55769, CA 68437, and CA 86390. Yunfei Wang was supported by the International Association for the Study of Lung Cancer Prevention Fellowship. Matthew B. Schabath was also supported, in part, by a National Cancer Institute cancer prevention fellowship (NCI grant R25 CA57730, Robert M. Chamberlain, Ph.D., Principal Investigator).

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