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 » Introduction
 » Subjects and Methods
 » Results
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  Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 4  |  Page : 490-495
 

Glutathione S transferase (GSTP 1, GSTM 1, and GSTT 1) gene polymorphisms in Egyptian patients with acute myeloid leukemia


1 Department of Clinical Pathology, Kasr El Eini School of Medicine, Cairo University, Egypt
2 Department of Nuclear Medicine and Oncology, Kasr El Eini School of Medicine, Cairo University, Egypt

Date of Web Publication10-Mar-2016

Correspondence Address:
Aml S Nasr
Department of Clinical Pathology, Kasr El Eini School of Medicine, Cairo University
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.178408

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 » Abstract 


BACKGROUND: The super family of glutathione S-transferases (GSTs) is composed of multiple isoenzymes with significant evidence of functional polymorphic variation. GSTs detoxify potentially mutagenic and toxic DNA-reactive electrophiles, including metabolites of several chemotherapeutic agents, some of which are suspected human carcinogens. Polymorphisms within the phase II metabolizer enzymes GST T1, GST M1, and GST P1 affect the body's ability to detoxify a range of potential leukemogens encountered in the environment. AIM OF WORK: To address how differences in the human GST isoenzyme expression patterns influence cancer susceptibility, prognosis, and treatment. PATIENTS AND METHODS: A total of 50 patients with acute myeloid leukemia (AML), as well as 50 age and sex matched apparently healthy volunteers were genotyped for GSTP 1, GSTM 1, and GSTT 1 gene polymorphisms using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and conventional polymerase chain reaction (PCR), respectively. RESULTS: For GSTP1 313 A → G (GSTP1 Ile105Val) polymorphism, It was found that the wild genotype (AA) was significantly higher among control subjects (P value = 0.0277), while the frequency of heteromutant genotype (AG) and mutant G allele (AG + GG) was significantly higher among patients (P value = 0.0402, P value = 0.0277, respectively). For GSTM1 and GSTT1gene, we found statistically significantly higher frequency among patients regarding homozygous gene deletion (P value = 0.0005). CONCLUSION: We demonstrated that GSTM1 null or GSTT1 null genotypes may be considered independent risk factors for AML with no impact on prognosis and GSTP1 * 105 genotype is a prognostic factor, adding independent information to the routine laboratory parameters and cytogenetic and molecular alterations of the tumor cells.


Keywords: Acute myeloid leukemia, glutathione S-transferases, polymerase chain reaction, restriction fragment length polymorphism, risk


How to cite this article:
Nasr AS, Sami RM, Ibrahim NY, Darwish DO. Glutathione S transferase (GSTP 1, GSTM 1, and GSTT 1) gene polymorphisms in Egyptian patients with acute myeloid leukemia. Indian J Cancer 2015;52:490-5

How to cite this URL:
Nasr AS, Sami RM, Ibrahim NY, Darwish DO. Glutathione S transferase (GSTP 1, GSTM 1, and GSTT 1) gene polymorphisms in Egyptian patients with acute myeloid leukemia. Indian J Cancer [serial online] 2015 [cited 2019 Dec 10];52:490-5. Available from: http://www.indianjcancer.com/text.asp?2015/52/4/490/178408





 » Introduction Top


Accepted causes of acute leukemia, such as benzene, ionizing radiation, and cytotoxic therapy, only account for a minority of cases. Other environmental and occupational exposures have been implicated, including smoking, but the results have been inconsistent and the associated risks are small. Deoxyribonucleic acid (DNA) damage in the hemopoietic precursor cell is the essential prerequisite for the development of leukemia and the body has developed a series of mechanisms aimed at preventing such damage.[1]

Glutathione S-transferases (GSTs) are a family of enzymes that carry out a wide range of functions in cells. GSTs also play a role in detoxification of a variety of endogenous and exogenous electrophilic compounds, such as the removal of reactive oxygen species and regeneration of S-thiolated proteins that are products of oxidative stress and the detoxification of carcinogenic compounds.[2]

There are four cytosolic families of GSTs, including GST α, GST µ, GST θ, and GST π.[3] Gene clusters of GST µ (GSTM1, M2, M3, M4, and M5) and GST θ (GSTT1 and T2) are located on chromosomes 1 and 22, respectively.[4] Independent gene deletions exist at both GSTM1 and GSTT1 loci, resulting in a lack of active protein in 50% and 20% of Caucasians, respectively.[5] GSTπ or GSTP1, encoded by a single locus (GSTP1) on chromosome 11, is also subject to polymorphic variation.[6] Codon 105 residue forms part of the GSTP1 active site for binding of hydrophobic electrophiles, and the Ile–Val substitution affects substrate specific catalytic activity and thermal stability of the encoded protein.[7]

Polymorphisms within genes that encode GSTs have been associated with susceptibility to nonmalignant [8] and malignant human diseases,[9] including acute myeloid leukemia (AML).[1] Presumably, altered cancer risk because of polymorphic variation is mediated by differential ability to conjugate and detoxify both endogenously formed and exogenously derived electrophiles and their metabolites. Due to their multiple functions, polymorphic variants of GST enzymes may account for interindividual differences in outcome of chemotherapy. There are several reports on the role of GSTM1 and/or GSTT1 deletions as prognosticators in acute leukemia.[10],[11].

The role of environmental mutagens and procarcinogens in the pathogenesis of this disease is strongly suspected.[12] This led to hypothesize that interpersonal variation in the capacity to metabolize and excrete carcinogens might influence the predisposition to this malignancy. To test this hypothesis, the aim of our study was to investigate the role of polymorphisms of some enzymes involved in conjugation/detoxification (phase II) of xenobiotic compounds in the incidence of AML in Egyptian patients.


 » Subjects and Methods Top


The current study was carried out on 50 patients with AML, in the period between July 2008 and April 2009, among cases referred to nuclear medicine and oncology unit with follow up period of 18 months, as well as 50 age and sex matched apparently healthy volunteers. Cases were diagnosed according to World Health Organization (WHO) criteria.[13] The diagnosis of AML was based on morphological and phenotypic data. Subtypes according to the French–American–British classification were available for all the patients, 12 patients with M1,15 with M2,13 with M3,5 with M4,3 with M5,1 with M6, and 1 with M7.

Patients were 21 males and 29 females. Age ranged from 21 to 65 years. Fifty age and sex matched apparently healthy adults were enrolled as control group These individuals were volunteers who had no medical history of any type of cancer or other diseases and were not related to the patients. They were 19 male and 31 females. Their ages ranged between 18 and 77 years. All patients and controls were analyzed for clinical and laboratory findings, including full history taking, clinical examination, routine laboratory investigations, lactate dehydrogenase (LDH) abdominal ultrasound for detection of organomegaly and lymphadenopathy. The patients were subjected as well to cytochemical and immunophenotypic analysis to confirm diagnosis and to divide the patients into their subtypes. Written informed consent was obtained from all the participants before including them in the study.

Genotyping for detection of GSTP1, GSTM1, and GSTT1 polymorphisms was performed for both patients and controls. Three milliliters of blood were withdrawn from all the subjects included in the study in a sterile ethelenediaminetetraacetic acid (EDTA) vacutainer. DNA was extracted from the whole blood using DNA extraction kit (QIAamp Blood Kit (Cat. No. 51106; Qiagen Inc., Valencia, CA)) according to the manufacturer's instructions.

GSTP1 313 A → G polymorphism:

For GSTP1 polymorphism, we used a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method following the protocol from Harries et al.[14], using the following primers, Forward (5' ACC CCA GGG CTC TAT GGG AA 3') and Reverse (5' TGA GGG CAC AAG AAG CCC CT 3'). The PCR was carried out in a total volume of 25 µL containing 12.5 ml Master mix (Fermentas, Lot: #K0171), 2 ml forward primer (20 pmole), 2 ml reverse primer (20 pmole), 3.5 ml nuclease-free water and 5 ml Genomic extracted DNA. PCR cycling conditions were: an initial denaturation step at 95°C for 5 minutes, and 30 cycles of the following: 94°C for 30 sec, 55°C for30 sec, and 72°C for 30 sec. A final extension step of 72°C for 5 min was done to complete the elongation processes. The PCR products (20 µL) were incubated with 5 units BsmAI (New England Biolabs, Hertfordshire, United Kingdom) for 4 hours at 37°C and loaded on a 2.5% agarose gel stained with ethidium bromide. The wild-type (313 AA) showed a single band at 176 bp. The presence of the 'G' allele introduces a restriction site. Three bands of 176, 91, and 85 bp were seen heterozygous (313AG). The homozygous (313 GG) had two bands of 91 and 85 bp. The size of the amplified product was read with a DNA ladder of different molecular weights (fermentas, NoLimits™ 100 bp DNA Fragment, catalogue number SM1441).

Homozygous deletions of GSTM1, resulting in absence of specific enzymes, were studied using conventional polymerase chain reaction (PCR) technique,[15] including the housekeeping gene BCL-2 as internal control. The primers used for GSTM1 were as follows: 5-GAACTCCCTGAAAAGCTAAAGC-3 and 5-GTTGGGC TCAAATATACGGTGG-3. The primers used for BCL-2 were as follows; 5-GCAATTCCGCATT TAATTCATGG-3 and 5-GAAACAGGCCACGTAAAGCAAC-3. PCR reaction was carried out in a total volume of 25 μl reaction containing 12.5 ml Master mix (Fermentas, Lot: #K0171), 2 ml forward primer (20 pmole), 2 ml reverse primer (20 pmole), 3.5 ml nuclease-free water and 5 ml Genomic extracted DNA. After denaturation for 4 min at 94°C, the PCR was performed for 35 cycles of 30 sec at 94°C, 1 min at 59°C and 1 min at 72°C. The last elongation step was extended to 7 min. The presence of GSTM1 allele, identified by a 219-bp fragment, or its complete deletion (null genotype), was analyzed by electrophoresis on a 2.5% agarose gel. The absence of amplifiable GSTM1 indicates a null genotype. BCL-2 gave a band at 154 bp fragment.

Homozygous deletions of GSTT1, resulting in absence of specific enzymes, were studied using conventional PCR technique,[15] including the housekeeping gene BCL-2 as internal control. The primers used for GSTT1 were as follows: 5-TTCCT TACTGGTCCTCACATCTC-3 and 5-TCACCGGATCATGGCCAGCA-3. The primers used for BCL-2 were as follows: 5-GCAATTCCGCATT TAATTCATGG-3 and 5-GAAACAGGCCACGTAAAGCAAC-3. The primers used for GSTT1 were as PCR was performed in 25 μL reaction containing 12.5 ml Master mix (Fermentas, Lot: #K0171), 2 ml forward primer (20 pmole), 2 ml reverse primer (20 pmole), 3.5 ml nuclease-free water and 5 ml Genomic extracted DNA. After denaturation for 4 min at 94°C, PCR was performed for 35 cycles of 15 sec at 94°C, 30 sec at 60°C and 45 sec at 72°C with an elongation step for 7 minutes. The presence of GSTT1 alleles, identified by a 480 bp fragment or its complete deletion (null genotype), was analyzed by electrophoresis on a 2.5% agarose gel. The absence of amplifiable GSTT1 indicates a null genotype. BCL-2 gave a band at 154 bp fragment.

All patients included in the study were treated according to the protocol of the nuclear medicine and oncology department, Cairo University, using ongoing induction and consolidation regimens for treatment of adult AML cases.

Induction of remission: Patients were ]subjected to 7-3 protocol [16] for induction of remission: Novantrone: 12 mg/m 2, IV on days 1 and 3. Arabinofuranosyl Cytidine (ARA) – C: 100 mg/m 2, continuous IV infusion, from days l to 7. If remission is not achieved, this protocol was repeated again. If no or minimal response, patients were shifted to high dose chemotherapy. Induction therapy for acute promyelocytic leukemia (PML) included oral administration of all-trans-retinoic acid (ATRA) 45 mg/m 2/day PO until complete remission (CR) induces remission in 70–90% of patients with M3 AML. ATRA induces terminal differentiation of the leukemic cells followed by restoration of nonclonal hematopoiesis.

Consolidation [17]: High dose ARA-C for 4 cycles. ARA-C: 2 g/m 2, over 2 hours infusions, every 12 hours on days 1–4.

Statistics

A predesigned Statistical Package for Social Science Version 17 (SPSS, IBM SPSS software) file was used for data entry and analysis. The following tests were used unpaired t-test, with 95% confidence intervals (95% CI), Odds ratio to access the risk conferred by a particular allele and genotype. A P value < 0.05 was considered to be statistically significant. Cox regression analysis was used to study relapse free survival and overall survival.


 » Results Top


Our study was carried out on 50 patients with AML, as well as 50 age and sex matched apparently healthy volunteers (as a control group).

Patients included in our study were 21 males (42%) and 29 females (58%). Their age ranged between 21 and 65 years with a mean value of 41.8 ± 11.2. Control group were 19 males (38%) and 31 females (62%). Age ranged between 18 and 77 years with a mean value of 45.6 ± 15.3 years. There were no statistically significant differences between the two groups as regard to age (P = 0.159) or sex (P = 0.838).

Clinical characteristics of patients were summarized in [Table 1] and [Table 2].
Table 1: Clinical characteristics of patients

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Table 2: laboratory data of patients and controls

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There were highly statistically significant differences between them as regard to the hemoglobin level and platelet count (P value < 0.0001), but there were no statistically significant differences regarding the total leukocytic count (P value = 0.319), performed liver functions (P value = 0.0437), or kidney functions results (P value = 0. 0.0929).

Some additional laboratory tests and procedures were performed for the patients to diagnose AML, assess staging and prognostic state.

In the patient group, the serum LDH level ranged between 249 and 478 mg/dl with a mean of 412.8 ± 74.5, bone marrow aspirate blast percentage ranged between 23% and 98%, X-rays and computed tomography (CT) were free in 44 patients (88%) and were involved in 6 patients (12%). Cerebrospinal fluid (CSF) analysis was free in 47 patients (94%) and was involved in 3 patients (6%).

As regard to the flow cytometry results, CD19 was negative in 50 patients (100%), CD13 and 33 were positive in 50 patients (100%), Glycophorin A was positive in 1 patient (2%) and negative in 49 patients (98%), Human leucocyte antigen DR (HLA-DR) was positive in 37 patients (74%) and was negative in 13 patients (26%).

After chemotherapy, 35 patients (70%) achieved complete remission while 15 patients (30%) achieved only partial remission, 47 patients (94%) needed red blood cells and platelet transfusion, while 3 patients (6%) did not need neither red blood cells nor platelet transfusion. Drug adverse reactions as myelosuppression, infections or toxicity developed in 47 patients (94%). Among 50 patients, 41 (82%) achieved CR, whereas 7 (14%) were resistant during the follow-up period of 18 months. Death was the adverse outcome in 2 patients (4%). The duration of relapse free survival ranged between 0 and 18 months with a mean value of 11.4 ± 6.9.

Results of genotype distribution: Concerning the results of PCR-RFLP for GSTP1 313 A → G (GSTP1 Ile105Val) polymorphism in the patient group, 20 patients (40%) were homozygous for wild allele (105Ile/105Ile) (AA), 18 patients (36%) were heterozygous for mutant allele (105Ile/105Val) (AG), and 12 patients (24%) were homozygous for mutant allele (105Val/105Val) (GG). For the control group, 32 cases (64%) had AA genotype, 8 cases (16%) had AG genotype, while 10 cases (20%) had GG genotype. It was found that the wild genotype (AA) was significantly higher among control subjects (P value = 0.0277), while the frequency of heteromutant genotype (AG) and mutant G allele (AG + GG) was significantly higher among patients (P = 0.0402, P = 0.0277, respectively).

The frequency of deletions in the GSTM1 gene (GSTM1 * 0) in patients was 48% (24/50). For the control group, seven patients (14%) had homozygous gene deletion with statistically significantly higher frequency among patients (P value = 0.0005). The frequency of deletions in the GSTT1 gene (GSTT1 * 0) in patients was 60% (30/50). For the control group, four patients (8%) had homozygous gene deletion with statistically significantly higher frequency among patients (P = 0.0005).

That is to say that the frequency of deletions in the GSTM1 gene (GSTM1 * 0) was statistically significantly higher among patients (P = 0.0005). Statistically significantly higher frequency of deletions in the GSTT1 gene (GSTT1 * 0) was also found among patients (P = 0.0005).

The results of genotype frequency are summarized in [Table 3].
Table 3: Genotype and allele frequencies in patients and control groups for GSTP1 313 A → G, GSTM1 and GSTT1 gene deletions

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GST genotypes and response to induction therapy: After chemotherapy, 35 patients (70%) achieved complete remission, while 15 patients (30%) achieved only partial remission, 47 patients (94%) needed red blood cells and platelet transfusion, while 3 patients (6%) did not need neither red blood cells nor platelet transfusion. Drug adverse reactions as myelosuppression, infections or toxicity developed in 47 patients (94%).

GST genotypes and survival: Among 50 patients, 41 (82%) achieved CR, whereas 7 (14%) were resistant during the follow-up period of 18 months. Death was the adverse outcome in 2 patients (4%). The duration of relapse free survival ranged between 0 and 18 months with a mean value of 11.4 ± 6.9. At a median follow-up of 18 months, the univariate analysis stratified for treatment/age group revealed that the GSTP1 * 105 genotype was significantly associated to relapse free survival (RFS) (P = 0.04) and overall survival (OS) (P value = 0.02). Patients with the variant Val allele had a better risk for RFS and OS. GSTT1 or GSTM1 genotypes analyses showed no significant impact on RFS or OS. [Table 4]
Table 4: Summarizes GST genotypes and survival

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Proportional hazards regression analysis was performed to evaluate differences of OS and RFS between genotypes after adjusting for patient characteristics with prognostic significance. GST genotypes, LDH and WBC levels, and age groups were included in a multivariable analysis. The Cox model for OS is based on the data of 48 patients with complete information for all parameters included, whereas the Cox model for relapse-free model is based on 41 patients. In these models, the GSTP1 * 105 genotype was a significant unfavorable variable for RFS and OS. [Table 5]
Table 5: Cox regression analysis for relapse--free and overall survival

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From this analysis it was clear that there were statistically significant hazard ratios (HRs) in patients > 60 years, with high LDH level and high white blood cells (WBCs) counts, in the presence of GSTP 1 GG allele mutation, and this was strongly related to better overall survival and relapse free survival of patients.


 » Discussion Top


GSTs are phase II detoxification enzymes involved in the metabolism of carcinogens and anticancer drugs, known also to interact with kinase complexes during oxidative or chemical stress-induced apoptosis. We were interested whether their polymorphic variants may account for susceptibility and differences in outcome of patients with AML following chemotherapy. We studied three GST genes (GSTP1/M1/T1) on 50 Egyptian patients with AML, as well as 50 age and sex matched apparently healthy volunteers (as a control group) with a follow-up period of 18 months.

Several studies associating the presence of the GSTM1 and GSTT1 polymorphisms with lymphoid and myeloid leukemias have been performed.[18],[19],[20] The GSTT1 null genotype was reported to increase the risk of myelodysplastic syndrome and acute leukemia [21],[22],[23] although other studies failed to confirm these findings.[24],[18]

A number of mechanisms have evolved to protect the integrity of DNA from both endogenous and exogenous damage. The GSTs play a critical role in the system, which protects against reactive oxygen species, the breakdown of peroxidized lipid and oxidized DNA. GST levels can be induced by exposure to foreign substances in vivo suggesting that they form part of an adaptive system to chemical stress. The GSTs are involved in the metabolism of many carcinogens and environmental pollutants and thus the polymorphisms at the GST loci are good candidates as leukemia predisposition genes.[1]

To determine the importance of GST genotypes in prognosis of AML, patients were followed for 18 months. We found no significant difference between null GSTM1 or GSTT1 genotypes compared with normal genotypes regarding RFS or OS but patients with GSTP1*105 Val mutant allele had significantly better and longer RFS and OS. Our results were comparable with those by Voso et al.,[25] who found that GSTT1 and GSTM1 genotypes had no significant impact on RFS or OS but multivariable Cox regression models revealed a significant better RFS and OS for the GSTP1 * 105 Val.

An Iranian study by Mohammed et al.,[26] studied GSTs null genotypes in AML and found that there was no significant difference in the OS and in RFS between different groups.

These observations suggest that the inherited absence of the GSTT1 and GSTM1 carcinogen detoxification pathway may be related to carcinogenesis but it is not an important determinant of prognosis in AML. Another study by Stella et al.,[10] showed that patients with the GSTM1-negative genotype had similar survival compared with those possessing at least one GSTM1allele but patients with the GSTT1- negative genotype had reduced survival compared with those possessing at least one GSTT1 allele. Results of Weiss et al.,[27] showed that there were no statistically significant differences in OS by any GSTT1or GSTM1 genotypes and adjustment for other covariates such as age, race, gender, cytogenetic risk group, previous cancer, FAB, WBC count, blast percentage and AML onset did not appreciably alter the HR estimates in Cox regression analysis. Similarly, Davies et al.[10] observed in a population of 306 children with AML or MDS that those patients with the GSTT1 null genotype had reduced survival compared with those with at least one GSTT1 present allele. Patients with GSTM1 null genotypes had similar survival to those possessing at least one GSTM1 allele. These conflicting results may be attributable to chance, owing to the small sample sizes in several of the previous studies. Dosage and type of chemotherapy regimen may also play a role in the discrepant results.

AML patients studied by Voso et al.,[25] who had deletions of GSTM1or GSTT1 or both had a lower probability to achieve CR on induction therapy as compared with patients with intact GST genes. The reasons underlying this finding are unclear. Expression of GST enzymes has been linked to in vitro and in vivo chemoresistance of tumor and leukemic cells.[28] One might expect that a GST deficiency caused by the null genotype results in better response to chemotherapy. Stanulla et al.[11] also showed a reduced risk of relapse in childhood B-cell acute lymphoblastic leukemia (ALL) patients having GSTM1 null or GSTT1 null genotype, whereas in the study of Chen et al.,[22] no impact of GST genotypes was seen on patient response to therapy and outcome. The difference between our results and others may indicate that gene polymorphisms may exert only small effects and many studies on gene polymorphisms are underpowered, especially at short follow-up times.

In conclusion, we demonstrate that GSTM1null orGSTT1 null genotypes may be considered independent risk factors for AML with no impact on prognosis and GSTP1 * 105 genotype is a prognostic factor, adding independent information to the routine laboratory parameters.

 
 » References Top

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]

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