Genetic determinants of lung cancer short-term survival: the role of glutathione-related genes

Abstract

Purpose: Survival of lung cancer patients has been dismal. Glutathione enzymes are directly involved in the metabolism of platinum compounds, a group of important chemotherapeutic drugs in cancer treatment. We tested the hypothesis that genes encoding glutathione enzymes may predict lung cancer short-term survival. Methods: We studied DNA polymorphisms of 250 primary lung cancer patients at four glutathione-related loci: GSTP1, GSTM1, GSTT1 and γ-GCS that encode glutathione-S-transferase-π, glutathione-S-transferase-μ, glutathione-S-transferase-θ, and γ-glutamylcysteine synthetase, respectively. Pearson's χ²-square tests, Kaplan–Meier survival curves, log rank tests, and Cox regression models were applied in the analysis. Results: There were 150 (60%) men and 100 (40%) women in this study. Seventeen percent of the patients had never smoked cigarettes, and 61% had stopped smoking at least 6 months prior to their lung cancer diagnosis. Among never smokers, those with null (N) or low (L) genotype experienced a better 1-year-survival rate than those with a positive (P) or high (H) genotype. Patients with P or H at two loci (PP or PH) were compared with patients with N or L at one or both loci (other). Among never smokers, 1-year-survival rates were 60–78% for patients with PP or PH genotypes compared with 89–100% for other types. The survival advantage was greater among advanced-stage patients who were NL or NN than low-stage patients. Similar results were not observed among smokers. Conclusions: Glutathione-related genes may determine lung cancer survival. Our results, if confirmed, would suggest new directions to enhance cancer treatment, and provide easily measurable markers for clinicians to plan patient-specific therapy.

Introduction

Over the past half century, survival after a lung cancer diagnosis has improved little, particularly for patients with advanced disease [1], [2]. Currently, lung cancer treatment modalities are determined by tumor histology, disease stage, and influenced by a patient's performance status [1], [3]. If treated at all, patients with inoperable or advanced stage disease receive a variety of chemotherapeutic agents. Anti-cancer drugs typically have a very narrow therapeutic index, meaning a close margin between clinical effective dose and toxicity limit dose. For any given treatment regimen, tumor response rate and patients’ survival time are unpredictable, even after adjusting for disease stage, histology, and performance status. There are no host-specific measures on which to base an optimal choice of the type, dose, delivery schedule or combination of these drugs. Therefore, individualized dose optimization algorithms of chemotherapy agents are desperately needed to maximize treatment efficacy and minimize unwanted toxicity.

Glutathione (GSH) synthesis and GSH-dependent enzymes (GSH system) are directly involved in detoxification or inactivation of several groups of major anti-cancer drugs [4], [5], [6], [7], [8], [9]. Platinum-based compounds and alkylating agents are important drugs in lung cancer chemotherapy, and both are mainly inactivated through the GSH system. The key elements of this system, as shown in Fig. 1, are the amount of GSH itself and the enzymes that catalyze the conjugation of substrates to GSH. The important enzymes are γ-glutamylcystein synthetase (γ-GCS), glutathione-S-transferase-Pi (GSTπ), glutathione-S-transferase mu (GSTμ) and glutathione-S-transferase theta (GSTθ) [4], [8]. Two lines of evidence, from multiple cancer sites, indicate the important role of these enzymes in anticancer treatment sensitivity and responses [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34]. First, elevated GSH and/or GSH-dependent enzyme levels correlate with inferior treatment response [14], [15], [16], [17], [18], [19]. Secondly, inhibition or reduction of GSH and/or GSH-system increases treatment response rates [12], [20], [21], [22], [35]. Genetic polymorphisms with functional significance have been well characterized for GSH-related enzymes [36], [37], [38], [39], [40], [41], [42], [43], [44]. Testing for the presence of the genes which encode for these enzymes has the potential to offer clinicians a powerful tool in determining which patients are likely to respond to which drugs. In this study, we have tested the hypothesis that in patients with lung cancer, genotypes corresponding to low activity levels of critical enzymes in the GSH system are associated with improved short-term survival.