Glutathione S-transferase P1 Polymorphisms Research Articles

Association analysis of glutathione‐S‐transferase P1 (GSTP1) polymorphism with urothelial cancer susceptibility and myelosuppression after M‐VAC chemotherapy

Glutathione-S-transferase P1 (GSTP1) detoxifies a wide range of endogenous and exogenous carcinogens and anticancer agents such as cisplatin and doxorubicin. The aim of this study was to examine the association between GSTP1 polymorphism and both urothelial cancer susceptibility and adverse events of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) chemotherapy in Japanese urothelial cancer patients. This cohort consisted of 179 urothelial cancer patients and 225 healthy controls matched for age and sex. GSTP1 Ile105Val polymorphism was identified by direct sequencing methods. Furthermore, the association of GSTP1 polymorphism and adverse events of M-VAC chemotherapy was investigated. A similar frequency of GSTP1 Ile105Val allele was observed in the urothelial cancer patients and in the control group. However, when the 46 patients who underwent systemic M-VAC chemotherapy were investigated, significantly more severe toxicity in leukocytopenia (P = 0.044, odds ratio +infinity, 95% confidence interval 0.9203- +infinity) and a prolonged duration of G-CSF administration (P = 0.013, odds ratio 8.625, 95% confidence interval 1.390-89.98) were observed in patients with the Val allele in comparison to those with the Ile allele. The GSTP1 Ile105Val polymorphism was not found to be significantly associated with urothelial cancer susceptibility but it may be associated with myelosuppressive adverse events in M-VAC chemotherapy. The 105Val might therefore be a useful marker for predicting myelosuppression in M-VAC chemotherapy.

Polymorphisms of glutathione S-transferase M1, T1 and P1 in patients with reflux esophagitis and Barrett’s esophagus

Reflux esophagitis (RE) and Barrett's esophagus (BE) belong to the most common esophageal complications of gastroesophageal reflux disease. Glutathione S-transferase (GST) enzymes play an important role in cellular protection against oxidative stress and toxic foreign chemicals. Therefore, we investigated the hypothesis that polymorphisms in genes for these detoxifying enzymes could influence susceptibility to RE and BE. GSTM1, GSTT1 and GSTP1 loci were analyzed by PCR-based methods in 64 patients with RE (and an additional group of 22 subjects with BE as the fourth grade of esophagitis) and 173 unrelated controls. There were no significant differences in the distributions of GSTM1 and GSTT1 genotypes between the controls and patients with RE or BE. Similarly, frequencies of GSTP1 alleles were non-significantly different between the control and RE groups. However, GSTP1 B allele carriers were more frequent among the patients with BE compared to those in the reflux esophagitis group (P=0.04, OR=2.10, 95% CI 0.99-4.44) and most significantly when compared to the controls (P=0.0067, Pcorr<0.05, OR=2.56, 95%CI 1.30-5.05). Although the GSTM1 and GSTT1 genes did not show any relationship with reflux disease, the GSTP1 gene might be one of the risk factors associated with susceptibility to RE, especially to BE.

Arsenic-related skin lesions and glutathione S-transferase P1 A 1578 G (Ile 105 Val) polymorphism in two ethnic clans exposed to indoor combustion of high arsenic coal in one village

A total of 2402 patients with arsenic-related skin lesions, such as hyperkeratosis, hyperpigmentation or hypopigmentation, or even skin cancer in a few villages in Southwest Guizhou Autonomous Prefecture, China represent a unique case of endemic arsenism related with indoor combustion of high arsenic coal. This study aimed to investigate the cluster of arsenism cases and the possible relevant factors including GSTP1 polymorphism in two clans of different ethnic origin living in one village for generations. A questionnaire-based study was performed in 170 Miao clan P members, 10 of whom had arsenic-related skin diseases, and 153 Han clan G1 members, 50 of whom had arsenic-related skin diseases. The data were checked against the registration archives since the 1980s. At the same time, arsenic concentrations in samples of coal, indoor air, drinking water, corn and chilli pepper that were once baked over the stoves for desiccation, as well as in samples of urine and hair of clan members were determined. Glutathione S-transferase P1 (GSTP1) A1578G polymorphism was genotyped by a restriction fragment length polymorphism-based procedure. Arsenism morbidity in Miao clan P was significantly lower than in the neighbouring Han clan G1 [5.9 vs. 32.7%, odds ratio (OR)=0.13, 95% confidence interval (CI): 0.06-0.27, P<0.0001]. No sex differences were confirmed inside both clans. Analyses of the environmental samples indicated that Miao clan P members were exposed to higher amounts of arsenic via inhalation and food ingestion. Hair and urine samples also proved a higher arsenic body burden in ethnic Miao individuals. No corresponding differences by sex were found. Higher frequencies of combined mutant genotype G/G1578 and A/G1578 (OR=4.72, 95% CI: 2.34-9.54, P<0.0001) and of mutant allele G1578 (OR=3.22, 95% CI: 2.00-5.18, P<0.0001) were detected in diagnosed arsenism patients than in non-diseased individuals. The Miao individuals showed a lower percentage of combined mutant genotypes (30.6 vs. 52.7%, OR=0.40, 95% CI: 0.19-0.84, P=0.015) as well as of mutant allele G1578 (OR=0.46, 95% CI: 0.24-0.88, P=0.017) than their Han neighbours. Genetic predisposition influences dermal arsenism toxicity. The GSTP1 A1578G (Ile105Val) status might be a susceptibility factor for arsenic-related skin lesions.

Effects of arsenic exposure and genetic polymorphisms of p53, glutathione S-transferase M1, T1, and P1 on the risk of carotid atherosclerosis in Taiwan

To evaluate the joint effects between genetic polymorphisms of glutathione S-transferase M1, T1, P1, and p53 , and arsenic exposure through drinking well water on the risk of carotid atherosclerosis, 605 residents including 289 men and 316 women were recruited from a northeastern area of Taiwan. Carotid atherosclerosis was diagnosed by either a carotid artery intima-media thickness (IMT) of >1.0 mm, a plaque score of ≥1, or stenosis of >50%. A significant age- and gender-adjusted odds ratio of 3.3 for the development of carotid atherosclerosis was observed among the high-arsenic exposure group who drank well water containing arsenic at levels >50 μg/L. The high-arsenic exposure group with GSTP1 variant genotypes of Ile/Val and Val/Val, and with the p53 variant genotypes of Arg/Pro and Pro/Pro had 6.0- and 3.1-fold higher risks of carotid atherosclerosis, respectively. In addition, the high-arsenic exposure group with one or two variant genotypes of GSTP1 and p53 had 2.8- and 6.1-fold higher risks of carotid atherosclerosis, respectively, and showed a dose-dependent relationship. A multivariate-adjusted odds ratio of 3.4 for the risk of carotid atherosclerosis among study subjects with the two variant genotypes of GSTP1 and p53 was also found. Our study showed the joint effects on the risk of carotid atherosclerosis between the genetic polymorphisms of GSTP1 and p53, and arsenic exposure.

Relationships Between Genetic Polymorphisms and Anticancer Drug Cytotoxicity Vis-à-Vis the NCI-60 Panel

The National Cancer Institute (NCI)-60 panel consists of 60 human tumor cell lines initially established for screening thousands of molecules for antiproliferative activity. It has been powerful for deciphering the relationships between anticancer drug cytotoxicity and cell molecular characteristics. We tested its potential interest for establishing relationships between the polymorphism of genes involved in drug metabolism and transport or in DNA repair, and drug cytotoxicity extracted from NCI databases. Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) techniques, three frequent single nucleotide polymorphisms (SNPs) were analyzed: Lys751Gln in the Xeroderma pigmentosum complementation group D (XPD, ERCC2) gene, Asp1104His in the Xeroderma pigmentosum complementation group G (XPG, ERCC5) gene and Ile105Val in the glutathione S-transferase P1 (GSTP1) gene. The allelic frequencies of the variants were 33% for ERCC2, 23% for ERCC5 and 39% for GSTP1. The ERCC2 polymorphism appeared to be a strong determinant of the in vitro cytotoxicity of most anticancer agents, with lower half maximal inhibitory concentration (IC50) values in variant homozygous lines than in common homozygous or heterozygous cell lines. Unexpectedly, the cytotoxicity of taxanes appeared markedly dependent upon the ERCC2 genotype, with threefold lower mean IC50 values in variant homozygous cell lines. The ERCC5 genotype appeared to be important only for taxanes, with fourfold higher IC50 values in variant homozygous cell lines. The GSTP1 polymorphism was related to the cytotoxicity of several drug classes, especially topoisomerase inhibitors, antimetabolites and N7 alkylating agents. The NCI-60 panel is capable of providing clues and tracks for the establishment of clinically useful relationships between a given genotype and the cytotoxicity of an anticancer agent.

Combined Effects of the Glutathione S-transferase P1 (GST-P1) Gene Polymorphism and Environmental Tobacco Smoke (ETS) Exposure on the Development of Asthma

RATIONALE: Since GST-P1 is the main cytosolic GST enzyme in lung epithelium involved in metabolizing tobacco metabolic intermediates and reactive oxygen species (ROS), we examined the GST-P1 polymorphism in the CCAAPS population as a determinant of ETS metabolism and the development of asthma.

Distribution of glutathione S-transferase M1, P1 and T1 genotypes in different age-groups of Finns without diagnosed cancer

Background: Xenobiotic metabolizing enzymes (XMEs) are important detoxifiers of hazardous environmental agents, and their polymorphisms may therefore modify the risk of environmentally induced cancers. Consequently, the XME polymorphisms have been extensively studied in this context during recent years. Particular attention has been given to the polymorphisms of glutathione S-transferase (GST) M1, P1 and T1 genes. Previous studies have provided abundant data indicating these polymorphisms as important modifiers of individual susceptibility to cancers of environmental origin. It can be postulated that if the at-risk genotypes of these genes were real risk factors for the environmental cancers, their prevalence would presumably decrease with age in cancer-free part of the population. Methods: We tested the hypothesis in a population based group of 2105 Finns (1051 men, 1054 women) in five age strata (27, 37, 47, 57 and 67 years of age), all without clinically diagnosed cancer. Results: For GSTM1 genotype, a significant interaction was seen between gender and age among never smokers ( p = 0.003). Currently smoking men tended to be less likely (OR 0.57, 95% CI 0.31–1.03), and currently smoking women more likely (OR 1.70, 95% CI 0.97–2.97) homozygotes for the GSTP1*B allele compared with never smokers. Moreover, the likelihood of being a concurrent carrier of the putatively protective genotypes of all of the three studied GSTs was almost three-fold (OR 2.80, 95% CI 1.10–7.12) in heavy smokers in the two oldest age-groups compared with the other genotypes. Conclusions: Our findings based on a novel study design provide support to the previous case–control studies suggesting that GST genotypes modify individual risk of environmentally-induced cancers.

Polymorphisms of glutathione S-transferase M1, T1, and P1 in patients with HBV-related liver cirrhosis, chronic hepatitis, and normal carriers

Objectives: Persistent hepatitis B virus (HBV) infection often leads to the development of chronic hepatitis and cirrhosis. The role of host genetic factors in chronic HBV infection is not fully understood. We studied the influence of glutathione S-transferase (GST) M1, T1, and P1 polymorphisms in patients with different stages of HBV infections. Methods: The sample population included 41 HBV normal carriers, 37 patients with chronic hepatitis, and 38 patients with cirrhosis (infected with HBV) compared to a control group ( n = 59). PCR-based procedures were performed in the studied populations to confirm the genotypes of GSTT1, M1, and P1. Odds ratio analysis tests were used for statistical evaluation. Results: We found that the frequency of GSTP1-Val (105)/Val (105) genotype was significantly higher in patients with liver cirrhosis (27%) than HBV normal carriers (2.4%; OR 14.8, 95% CI 1.8–122.5) and the frequency GSTP1-Val (105)/Ile (105) genotype was significantly higher in patients with liver cirrhosis (59.5%) than HBV normal carriers (19.5%; OR 6.1, 95% CI 2.1–16.7). The genotype GSTP1-Val (105)/Val (105) was more frequent in patients with chronic hepatitis (19.4%) than HBV normal carriers (2.4%; OR 9.65, 95% CI 1.1–82.8). Patients with cirrhosis also had a higher frequency of the GSTM1 null genotype (71.1%) than HBV normal carriers (27.5%; OR 6.5, 95% CI 2.4–17.4) and the GSTM1 null genotype was more frequent in patients with chronic hepatitis (64.9%) than HBV normal carriers (27.5%OR 4.9, 95% CI 1.8–12.8). The frequency of GSTT1 genotype was similar in all groups. Conclusion: These results suggest that in HBV infection, inheritance of the null GSTM1 and GSTP1-Val (105) polymorphisms involves a host genetic factor that is relevant to disease progression.

Glutathione S-transferase M1, T1, and P1 polymorphisms and prostate cancer risk in middle-aged men

The glutathione S-transferase (GST) enzymes detoxify several carcinogens. Genetic polymorphisms in GSTM1, T1, and P1 (Ile105Val) have been associated with prostate cancer, however, results have been inconsistent across studies. Data from a population-based case-control study in King County, Washington, were used to further evaluate the relationships between these GST polymorphisms and prostate cancer. Incident cases (n = 590) were 40-64 years old, diagnosed from 1993 through 1996, and identified via the SEER cancer registry. Controls (n = 538) were identified via random digit dialing, and frequency age-matched to cases. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Risk of prostate cancer was moderately increased among Caucasians with the GSTM1-null genotype (OR = 1.54; 95% CI 1.19-2.01). There were no associations for either GSTT1 or P1(Ile105Val). The association between the GSTM1-null genotype and prostate cancer was not different according to cancer aggressiveness defined by stage at diagnosis and Gleason score. Among GSTM1-null Caucasians, the relative risk of prostate cancer increased linearly with increasing pack-years of smoking (P-value for trend = 0.007), with the highest ORs observed for smokers of >30 pack-years. Findings suggest that the GSTM1-null genotype defines a subgroup of men at higher risk of prostate cancer, particularly if they are heavy smokers.

Prediction of Progression to Cirrhosis by a Glutathione S-Transferase P1 Polymorphism in Subjects With Hereditary Hemochromatosis

Oxidative stress plays an important pathogenic role in hereditary hemochromatosis (HHC) and chronic hepatitis C virus infection (CHC). Several enzymes involved in the degradation of reactive oxidants and xenobiotics, such as glutathione S-transferase P1 (GSTP1) and manganese superoxide dismutase (MnSOD), reveal polymorphisms that affect their antioxidant capacity and may therefore modulate the progression to cirrhosis. Our objective was to establish the role of the functional polymorphisms of GSTP1 (codon 105 Ile-->Val) and MnSOD (codon 16 of precursor protein Ala-->Val) on the evolution of cirrhosis in patients with HHC and CHC. One hundred seventy-two patients with HHC who were homozygous for the C282Y mutation and 285 patients with CHC underwent liver biopsy and genotyping for the GSTP1 and MnSOD polymorphisms. In HHC, the GSTP1 Val/Val genotype was more common in patients with than in those without cirrhosis (14.8% vs 2.1%, P = .009), whereas the distribution of MnSOD variants was not different. Logistic regression analysis identified GSTP1 Val/Val genotype, serum ferritin level, male sex, and age as independent predictors for the presence of cirrhosis. The odds ratio for the GSTP1 Val/Val genotype for the development of cirrhosis was 3.85 (95% confidence interval, 1.18-12.62; P = .03). However, in patients with CHC, the GSTP1 and MnSOD genotypes were not associated with cirrhosis. Cirrhosis is more likely to develop in C282Y homozygotes with the GSTP1 Val/Val genotype than in those with non-Val/Val genotypes, which in part explains the variable phenotypic expression of HHC and highlights the central role of oxidative stress in its pathogenesis.

517 Polymorphisms of glutathione S-transferase M1, T1 and P1 in patients with HBV related liver cirrhosis, chronic hepatitis and normal carriers

517 Polymorphisms of glutathione S-transferase M1, T1 and P1 in patients with HBV related liver cirrhosis, chronic hepatitis and normal carriers

Association of Genetic Polymorphism of Glutathione S-transferase M1, T1, P1 and Susceptibility to Bladder Cancer

Objective: Glutathione- S-transferases (GSTs) are active in the detoxification of wide variety of endogenous or exogenous carcinogens. We examined the association of the GST gene polymorphism with sporadic bladder cancer patients in Northern India. Material and methods: The study constituted of 106 bladder cancer cases and 370 age-matched controls. The GSTT1 and GSTM1 null genotypes were identified by multiplex PCR and GSTP1313 A/G by Polymerase Chain Reaction/Restriction Fragment Length Polymorphism method (PCR/RFLP). Results: We observed non-significant association in null alleles of the GSTM1 ( p = 0.611, OR = 1.12, 95% CI = 0.72–1.74 and GSTT1 ( p = 0.135, OR = 1.45, 95% CI = 0.89–2.37) with risk of bladder cancer. However, the G/G genotype of the GSTP1 gene polymorphism was highly significant when compared to controls ( p = 0.000, OR = 7.12, 95% CI = 3.14–16.16). The combined analysis of the three risk genotypes demonstrated further increase in the risk of bladder cancer ( p = 0.000, OR = 7.29 95% CI = 2.81–18.93). Conclusion: Our study demonstrated that GSTP1313 G/G polymorphism is a strong predisposing risk factor for bladder cancer. Combination of three GST genotypes association exhibiting gene-gene interaction further substantiates the increased risk of bladder cancer.

Glutathione S-Transferase M1, T1 and P1 Polymorphisms and Bladder Cancer Risk in Egyptians

Previous studies suggest that bladder cancer risk may vary with GST genotype but these results are inconsistent. The aim of this study was to explore whether GSTM1, GSTT1 and GSTP polymorphisms were associated with increased bladder cancer risk in an Egyptian population. GSTM1, GSTT1 and GSTP1 genotype frequencies were determined in bladder cancer cases (n=72) and healthy controls with no history of malignancies (n=82) using PCR-based techniques. The GSTT1*2 genotype was particularly associated with increased risk (OR 2.71, 95%CI 1.27–5.73) and the GSTM1*2 genotype to a lesser extent (OR 1.63, 95%CI 0.85–3.10). 18.1% of cases but only 7.3% of controls were GSTP1*B*B homozygotes (OR 2.38, 95%CI 0.83–6.87). The presence of two or more a priori at-risk genotypes was associated with increased bladder cancer risk (OR 2.42; 95%CI 1.47–3.97). These results suggest that polymorphisms in the GST genes are associated with increased risk of bladder cancer among Egyptians.

Glutathione S-transferase M1, T1 and P1 polymorphisms and bladder cancer risk in Egyptians

Previous studies suggest that bladder cancer risk may vary with GST genotype but these results are inconsistent. The aim of this study was to explore whether GSTM1, GSTT1 and GSTP polymorphisms were associated with increased bladder cancer risk in an Egyptian population. GSTM1, GSTT1 and GSTP1 genotype frequencies were determined in bladder cancer cases (n=72) and healthy controls with no history of malignancies (n=82) using PCR-based techniques. The GSTT1*2 genotype was particularly associated with increased risk (OR 2.71, 95%CI 1.27-5.73) and the GSTM1*2 genotype to a lesser extent (OR 1.63, 95%CI 0.85-3.10). 18.1% of cases but only 7.3% of controls were GSTP1*B*B homozygotes (OR 2.38, 95%CI 0.83-6.87). The presence of two or more a priori at-risk genotypes was associated with increased bladder cancer risk (OR 2.42; 95%CI 1.47-3.97). These results suggest that polymorphisms in the GST genes are associated with increased risk of bladder cancer among Egyptians.

Human glutathione S-transferase A1, T1, M1, and P1 polymorphisms and susceptibility to prostate cancer in the Japanese population

The incidence of prostate cancer is increasing in low-risk populations such as Japanese. One of the causes of this increase is considered to be associated with the Western diet, especially the high intake of red meat and fat. Glutathione S-transferase (GST) A1, T1, M1, and P1 are phase II enzymes that are important for activation and detoxification of chemical carcinogens. In this study, 190 Japanese male patients with prostate cancer and 294 healthy controls, frequency-matched for age, were compared for frequencies of GSTA1, GSTT1, GSTM1, and GSTP1 genotypes. Among smokers, the frequency of the GSTA1*A/*B or *B/*B genotype in patients with prostate cancer (27.8%) showed a statistically significant increase compared with the control group frequency (18.2%; odds ratio [OR] =1.72; 95% CI, 1.01-2.94). In addition, the frequency of GSTT1 nondeletion genotype was associated with prostate cancer among smokers (OR =1.68; 95% CI, 1.06-2.68). The OR of carrying the combined genotyping of GSTA1*A/*B or *B/*B and GSTT1 nondeletion was 2.08 (95% CI, 1.14-3.80) with the combined genotyping of GSTA1*A/*A and GSTT1 null as a reference. On the other hand, no significant associations were observed for genotypes of GSTM1 and GSTP1 I105V. These findings suggest that the GSTA1 and GSTT1 polymorphisms are associated with prostate cancer susceptibility, especially among smokers.

The Tyr113His polymorphism in exon 3 of the microsomal epoxide hydrolase gene is a risk factor for perinatal mortality.

A genetic predisposition to impaired detoxification of oxidative or chemical stress could play a role in the etiology of perinatal mortality. In this pilot study we investigated the risk of perinatal mortality in relation to genetic polymorphism in microsomal epoxide hydrolase (EPHX) and glutathione S-transferase P1 (GSTP1) in women who experienced perinatal mortality caused by placental pathology, congenital disorders and complications of premature delivery and their male partners. Genomic DNA of couples (72 females and 46 males) with a history of perinatal mortality and control couples (71 females and 66 males) with no complications in their obstetric history were analyzed for the presence of the polymorphisms in exon 3 of EPHX (Tyr113His) and GSTP1 (Ile105Val). A similar distribution of the GSTP1 polymorphism was found in all subjects investigated. In women who experienced perinatal mortality, we demonstrated a higher prevalence of the EPHX His113/His113 genotype, which could result in a lower enzyme activity, compared with controls (25% vs. 9%; chi2 = 5.7 and p < 0.02), with an odds ratio (95% confidence interval) of 3.5 (1.1-12.7). Our results suggest that the maternal Tyr113His polymorphism in EPHX may be a risk factor for perinatal mortality. However, more research is needed to determine the implication of this finding.

Genetic Polymorphism of Glutathione S-transferase P1 and Breast Cancer Risk

To evaluate the potential association between the GSTP1 genotype and the development of breast cancer, a hospital based case-control study was conducted on Korean women. The study population consisted of 171 histologically confirmed incident breast cancer cases and 171 age-matched controls with no present or previous history of cancer. PCR-RFLP was used for the GSTP1 genotyping and statistical evaluations were performed using an unconditional logistic regression model. Postmenopausal women with the GSTP1 Val allele were found to have a reduced risk of breast cancer (OR = 0.3, 95 % CI = 0.10-0.74). A significant interaction was observed between the GSTP1 genotype and alcohol consumption (p for interaction = 0.01); compared with never-drinking women with Ile/Ile genotype, ever-drinking women with the GSTP1 Val allele had almost a three-fold risk of breast cancer (OR = 2.9, 95 % CI = 1.05-7.85), whereas never-drinking women with Val allele had half this risk (OR = 0.5, 95 % CI = 0.27-0.93). Our findings suggest that the GSTP1 polymorphism influences individual susceptibility to breast cancer in the Korean women and this effect may be modified by alcohol consumption.

The relationship of the human glutathione S-transferase P1 polymorphism and chemotherapeutic sensitivity in head and neck squamous carcinoma

GSTP1, which encodes GSTPi, has a polymorphic site at codon 105 (exon 5), where an adenosine-to-guanine (A-G) transition causes an isoleucine-to-valine substitution (I105V). Recent studies have found that subjects with the valine allele display a significantly lower enzyme activity and less effective capability of detoxification. We hypothesized that head and neck squamous cell carcinoma (HNSCC) might respond differently to chemotherapeutic agents, especially cisplatin (CDDP) because of the presence of GSTP1 I105V polymorphism. Seventeen types of HNSCC cell lines were investigated with the MTT method, western blot, RT-PCR and direct sequence to examine the relationship between the sensitivity to CDDP and expression of GSTPi. There was a significant degree of difference in cell death among each cell line in the sensitivity test with CDDP, however, we did not find differences in the band density of the protein and mRNA expression levels of GSTPi. In the direct sequence examination we detected 4 subjects heterozygous of polymorphism GSTP1. The frequency was 23.5% in the 17 cell lines examined, and all 4 subjects showed a good response to CDDP treatment. A heterozygous polymorphism might alter the function of the GSTPi due to significantly lower enzyme activity and less effective capability of detoxification. Two other subjects which showed a good response to CDDP treatment did not show any polymorphism. These results indicated that there is another locus that reduces GSTPi activity, and that the mechanisms of CDDP resistance was multifactorial. Further study is required to conclude whether the GSTP1 I105V polymorphism might be useful as a predictive marker for multi-drug resistance.

Association between glutathione S-transferase (GST) P1 polymorphisms and survival of patients with advanced non-small cell lung cancer (NSCLC)

7009 Background: Glutathione S-transferase (GST) P1 is a detoxification enzyme with substrate specificity for both exogenous carcinogens and therapeutic compounds. Genetic polymorphisms of GSTP1 exon 5 (Ile105Val) and exon 6 (Ala114Val) appear to reduce this enzyme's activity. Previously, we reported that the exon 6 variant genotypes were associated with an increased risk of lung cancer, particularly among men, younger patients, and ever smokers. Increased cancer risk is due to reduced detoxification capacity of carcinogens. The variant genotype may also be associated with better chemotherapy response due to reduced inactivation of chemotherapy agents, and thus better survival in advanced-stage NSCLC patients, a group that is more likely to receive platinum-based chemotherapy. Methods: Stage III and IV NSCLC cases enrolled in a molecular epidemiology study at our institution were identified and genotyped for GSTP1 exons 5 and 6 by PCR-RFLP. There were 425 subjects. Results: Patients with the exon 6 variant genotype (C/T + T/T) had significantly better survival compared to patients with the wildtype genotype (CC) (P=0.037). The median survival time was 16.1 months for patients with the variant genotypes and 11.4 months for those with the wildtype. The better survival was especially apparent in patients who were younger than 55 years old (P=0.020), male (P=0.037), and ever smokers (P=0.032) but not in patients who were older than 55 years females, and never smokers. When we performed multivariate analysis using a Cox proportional hazards model, we detected a reduced hazard ratio (HR) of death associated with the exon 6 variant genotype of 0.8 (95% CI 0.55–1.16). This protective association was statistically significant among younger patients (< 55 years) (HR 0.47, 95% CI 0.23–0.94) and among males (HR 0.65, 95% CI 0.39–1.07). Conclusions: GSTP1 exon 6 variant genotypes may be associated with improved survival among stage III and IV NSCLC patients, particularly in subsets of younger patients, males, and ever smokers. Further studies are warranted. No significant financial relationships to disclose.

Association between glutathione S-transferase (GST) P1 polymorphisms and survival of patients with advanced non-small cell lung cancer (NSCLC)

7009 Background: Glutathione S-transferase (GST) P1 is a detoxification enzyme with substrate specificity for both exogenous carcinogens and therapeutic compounds. Genetic polymorphisms of GSTP1 exon 5 (Ile105Val) and exon 6 (Ala114Val) appear to reduce this enzyme's activity. Previously, we reported that the exon 6 variant genotypes were associated with an increased risk of lung cancer, particularly among men, younger patients, and ever smokers. Increased cancer risk is due to reduced detoxification capacity of carcinogens. The variant genotype may also be associated with better chemotherapy response due to reduced inactivation of chemotherapy agents, and thus better survival in advanced-stage NSCLC patients, a group that is more likely to receive platinum-based chemotherapy. Methods: Stage III and IV NSCLC cases enrolled in a molecular epidemiology study at our institution were identified and genotyped for GSTP1 exons 5 and 6 by PCR-RFLP. There were 425 subjects. Results: Patients with the exon 6 varian...