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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1222-1228
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Polymorphisms within glutathione S-transferase genes
(GSTM1, GSTT1, GSTP1) and risk of relapse in
childhood B-cell precursor acute lymphoblastic leukemia: a
case-control study
Martin Stanulla,
Martin Schrappe,
Annette
Müller Brechlin,
Martin Zimmermann, and
Karl Welte
From the Department of Pediatric Hematology and Oncology,
Children's Hospital, Hannover Medical School, Hannover, Germany.
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Abstract |
Glutathione S-transferases (GSTs) have been associated with outcome
in human cancers treated with cytotoxic chemotherapy. In a case-control
study, we investigated the association between polymorphisms within the
GSTM1, GSTT1, and GSTP1 genes and risk of
relapse in childhood acute lymphoblastic leukemia (ALL). Cases were
relapsed patients. Controls were successfully treated patients with a
minimum follow-up of 5 years. The null genotype (absence of both
alleles) for GSTM1 or GSTT1 conferred a 2-fold
(OR = 0.5, 95% CI = 0.23-1.07, P = .078) and
2.8-fold (OR = 0.36, 95% CI = 0.13-0.99, P = .048)
reduction in risk of relapse, respectively, relative to the presence of
the GSTM1 or GSTT1 gene. The GSTP1 Val105/Val105 genotype showed a 3-fold decrease
in risk of relapse (OR = 0.33, 95% CI = 0.09-1.23,
P = .099) in comparison to the combined category of
Ile105/Val105 and
Ile105/Ile105 genotypes. No particular
associations with relapse were observed for the GSTP1
polymorphism at codon 114. The risk of relapse when having 1 of the
low-risk genotypes (GSTM1 null, GSTT1 null,
GSTP1 Val105/Val105) decreased 1.9-fold
(OR = 0.53, 95% CI = 0.24-1.19, P = .123), and the
risk when having 2 or 3 low-risk genotypes 3.5-fold (OR = 0.29,
95% CI = 0.06-1.37, P = .118), compared with
individuals having no low-risk genotype (P for
trend = .005). Our results suggest that polymorphisms within genes
of the GST superfamily may be associated with risk of relapse in
childhood ALL.
(Blood. 2000;95:1222-1228)
© 2000 by The American Society of Hematology.
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Introduction |
Glutathione S-transferases (GSTs) are a family of
cytosolic enzymes involved in the detoxification of various exogenous
as well as endogenous reactive species.1,2 GSTs function as dimers by catalyzing the conjugation of mutagenic electrophilic substrates to glutathione. In humans, 4 major subfamilies of GSTs can
be distinguished and are designated as GST , GSTµ,
GST , and GST .3 Each of these
subfamilies is composed of several members, some of which display
genetic polymorphism. Within the GSTµ subfamily, the gene
coding for GSTM1 exhibits a deletion polymorphism, which in case of
homozygozity (GSTM1 null) leads to absence of phenotypic enzyme
activity.4 A similar mechanism is described for GSTT1 within the GST subfamily,5 whereas the gene
coding for GSTP1, a member of the GST subfamily, displays
polymorphisms within its coding region at codon 105 (Ile105Val) and
codon 114 (Ala114Val).6-10 The coding region polymorphisms
within GSTP1 have been suggested to confer different catalytic
activities.11,12
Important environmental carcinogens (eg, benzo[a]pyrene and
other polyaromatic hydrocarbons) are detoxified through the GST system.1,2,13 In this context, interindividual differences in GST enzyme activity mediated by polymorphic genes have been suggested to confer varying susceptibility to environmental
cancer.2,13 Several groups have investigated the
association of GSTM1, GSTT1, and GSTP1 genotype
status with various malignancies such as smoking-induced lung cancer
and bladder, breast, or gastrointestinal cancers.10,14-21 Some of these studies observed an increased risk for individuals with
GST genotypes with lower enzyme activities.10,14-16,19-21
GSTs may also confer resistance to cytotoxic chemotherapeutic agents used to treat cancer.22,23 However, in contrast to the role of GSTs in environmental carcinogenesis, GST genotypes conferring lower
enzyme activity may be of advantage for individuals undergoing chemotherapeutic treatment for neoplastic disease because reduced detoxification potentially enhances effectiveness of cytotoxic drugs.
Anticancer drugs that have been shown to be substrates for GSTs are,
for example, chlorambucil, melphalan, cyclophosphamide metabolites, and
steroids.22,24,25 Indirect evidence for a role of GSTs in
modulating drug effects through deactivation of drug-generated
hydroperoxides or other reactive oxygene species exists for adriamycin,
mitomycin C, carboplatin, and cisplatin.22,26,27
Childhood acute lymphoblastic leukemia (ALL) is the most common
malignant disease of childhood and can be cured in up to 70% of cases
by the application of intensive multiagent chemotherapeutic regimens.28,29 To assess whether genetic polymorphisms in
GST genes are associated with therapeutic success in childhood ALL, we
conducted a matched case-control study of relapsed and nonrelapsed patients selected from the multicenter ALL-BFM 86 and ALL-BFM 90 trials
of childhood ALL conducted by the Berlin-Frankfurt-Münster (BFM)
study group.30,31 The questions addressed in this study were as follows: (1) What are the frequencies and what is the interrelation of the GSTM1, GSTT1, and GSTP1
genotypes; (2) how are these genotypes related to important clinical
risk factors such as gender, age at diagnosis, initial white blood cell
count (WBC), and immunophenotype in childhood ALL; (3) what is the
association of specific GST genotypes with the risk of relapse; and (4)
what is the effect of GST genotype combinations on risk of relapse in
childhood ALL?
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Patients and methods |
Patients
This study uses data from the ALL-BFM 86 and ALL-BFM 90 trials in
childhood ALL, conducted by the BFM study group. In these multicenter
trials, pediatric patients up to 18 years from up to 96 different
treatment centers in Germany, Austria, and Switzerland were enrolled
after informed consent was obtained. Design, conduct, analysis, and
results of the ALL-BFM 86 and ALL-BFM 90 trials are described in detail
elsewhere.30-32 In both trials, treatment was stratified
into 3 branches (standard, intermediate, and high risk), primarily
according to the leukemic cell mass estimate and treatment response.
The leukemic cell mass estimate, the so-called risk factor, is a
composite variable calculated from the initial blast count in the
peripheral blood and the sizes of liver and spleen below the costal
margin in cm (risk factor = 0.2 × log (no. of blood blasts/µL + 1) + 0.06 × liver size + 0.04 × spleen size). Treatment
response is based mainly on the in vivo prednisone response. Prednisone
poor response is defined as the presence of  1000/µL peripheral
blood blasts on treatment day 8 after a 7-day monotherapy with
prednisone and a single intrathecal application of methotrexate on
treatment day 1. In ALL-BFM 86 standard risk patients had < 1000/µL
peripheral blood blasts on treatment day 8, a risk factor of < 0.8, no central nervous system (CNS) disease, and no mediastinal mass.
Intermediate risk was defined as < 1000/µL peripheral blood blasts
on treatment day 8, a risk factor 0.8, or a risk factor < 0.8 and
CNS disease and/or presence of a mediastinal mass. High-risk patients
had 1000/µL peripheral blood blasts on treatment day 8, or > 5%
blasts in the bone marrow at treatment day 40, or acute
undifferentiated leukemia. In ALL-BFM 90 standard-risk patients had < 1000/µL peripheral blood blasts on treatment day 8, a risk factor of < 0.8, no CNS disease, no mediastinal mass, and no T-cell ALL.
Intermediate risk was defined as < 1000/µL peripheral blood blasts
on treatment day 8, a risk factor 0.8, or a risk factor < 0.8 and
CNS disease and/or presence of a mediastinal mass or T-cell ALL.
High-risk patients had 1000/µL peripheral blood blasts on
treatment day 8, or 5% blasts in the bone marrow at treatment day
33, or were positive for a t (9;22) or bcr/abl fusion RNA. Treatment in
both trials used standard drugs (eg, prednisone, vincristine,
daunorubicin, L-asparaginase, cyclophosphamide, ifosfamide, cytarabine,
6-mercaptopurine, 6-thioguanine, and methotrexate) and, in parts of the
study group, cranial radiotherapy. With the exception of high-risk
patients in ALL-BFM 90, all patients received induction, consolidation,
and reinduction treatment, followed by maintenance therapy. Some
patients in the intermediate-risk group in ALL-BFM 86 received a late
intensification protocol. High-risk patients in ALL-BFM 90 were treated
on a shorter induction regimen and continued on an intensive rotational
consolidation schedule but did not receive the regular reinduction protocol.
Study design
Of 998 protocol patients enrolled in the ALL-BFM 86 trial, 472 patients (348 successfully treated patients; 124 relapsed patients) and, of the 2178 protocol patients enrolled in the ALL-BFM 90 trial,
575 patients (465 successfully treated patients; 110 relapsed patients)
had spare, unstained peripheral blood or bone marrow smears available,
obtained at 1 or more time points during the treatment period. The
smears were stored at  20°C and were wrapped in parafilm.
Exclusion criteria for patients in this study were preexisting
neoplastic disease, preexisting immunologic or hematologic disorders,
genetic syndromes, initial CNS disease, and deviations from the therapy
protocol. This left 406 patients from trial ALL-BFM 86 (308 successfully treated patients; 98 relapsed patients) and 539 patients
from trial ALL-BFM 90 (440 successfully treated patients; 99 relapsed
patients). Of the remaining total of 197 relapsed patients, all with an
available remission peripheral blood or bone marrow smear were included
as cases into the study group if they could be matched to a
successfully treated patient with an available remission peripheral
blood or bone marrow smear (control individual) according to the
following criteria: sex, age at diagnosis (± 6 months), WBC at
diagnosis (± 10 000/µL), immunophenotype, trial, risk group, and
treatment arm within the branch (risk group) of the respective
trial. The latter criterion assured similarity of treatment between
cases and controls. Controls had to have a minimum follow-up of 5 years. In case of relapses occurring later than 5 years of diagnosis,
the follow-up for the control subject had to be at least as long as the
time from date of initial diagnosis to date of relapse diagnosis in the
case subject. If more than 1 control subject was available, the subject
with the closest initial WBC at diagnosis with reference to the case
subject was chosen. Remission peripheral blood or bone marrow smears
were used to avoid misclassification of genotypes in the study subjects caused by genetic instability-mediated, possible leukemic
clone-specific alterations within the investigated GST genes.
This procedure led to the identification of 64 case subjects and 64 individually matched control subjects.
Genotype analysis
Peripheral blood or bone marrow was carefully scraped off the frozen
microscopic slides by using sterile surgical scalpel blades. The
material was then transferred to microcentrifuge tubes. After each
patient, surgical blades, laboratory bench covers, and gloves of the
person performing the isolation procedure were changed. DNA was then
isolated by using a polymerase chain reaction (PCR) template isolation
system (Boehringer Mannheim, Mannheim, Germany) and the DNA yield
estimated by measuring the optical density at 260 nm in a
spectrophotometer. Genotypes for GSTM1 and GSTT1 were
determined by PCR as previously described by Chen et al.33
This assay places individuals in 2 categories for each GSTM1
and GSTT1, one being either homozygous or heterozygous for GSTM1 or GSTT1 and the other having a homozygous
deletion of GSTM1 (GSTM1 null) or GSTT1
(GSTT1 null). Thus, the assay cannot distinguish between
heterozygotes and homozygotes for GSTM1 and GSTT1, but places them into 1 category. The GSTP1 codon 105 genotype was analyzed according to Harries et al.10 This assay
distinguishes homozygotes for the Ile105 allele,
heterozygotes (Ile105/Val105), and homozygotes
for the Val105 allele. The GSTP1 codon 114 genotype was analyzed according to Harris et al34 using the
restriction enzyme AciI instead of Cac8I. In this assay homozygotes for
the Ala114 allele, heterozygotes
(Ala114/Val114), and homozygotes for the
Val114 allele can be distinguished. Negative controls in
both PCR assays consisted of similar reaction mixtures as regular samples, but did not contain DNA. Twenty-nine subjects with an available additional remission peripheral blood or bone marrow smear
were genotyped twice for the 4 investigated GST genotypes. No
deviations from initial genotyping results were observed.
Statistical analysis
For descriptive purposes, frequencies of characteristics and common
factors affecting risk of relapse were obtained at the beginning of the
analysis. To investigate the interrelationships between GSTM1,
GSTT1, and GSTP1 genotypes, and their associations with
sex, age at diagnosis, WBC at diagnosis, immunophenotype, and risk
group, Spearman correlation coefficients were computed. The association
between GST genotypes and occurrence of relapse was examined with
conditional logistic regression analysis to calculate odds ratios (OR)
and their 95% confidence intervals (CI). GST genotypes and genotype
combinations were used as categorical variables in the analyses.
Computations were performed with SAS software (SAS-PC Version 6.04, SAS
Institute, Cary, NC).
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Results |
Table 1 shows the distribution of matching variables
and genetic analyses (DNA index and karyotype) in relapsed case
subjects and successfully treated control subjects. Case and control
group showed equal distributions of the matching variables. Thirty-five matched pairs were selected from the ALL-BFM 86 trial and 29 pairs from
the ALL-BFM 90 study. There was a higher percentage of males compared
with females. At diagnosis, the majority of patients were from 1 to 9 years of age and, with the exception of a single matched pair, all
patients presented with an initial WBC of < 50 000/µL.
Phenotypically, 54 matched pairs were common (c)-ALLs (diagnostic
criteria: terminal deoxynucleotidyl transferase [TdT]+,
CD19+, CD10+, cytoplasmic
IgM , cell surface Ig) and 10 pairs were pre-B-ALLs (diagnostic criteria: TdT+,
CD19+, CD10 ±, cytoplasmic IgM+, cell
surface Ig). All subjects selected were either part
of the standard-risk group (23 matched pairs) or the intermediate-risk
group (41 matched pairs). No study subject was a prednisone
poor-responder or part of the high-risk group. For DNA
index (ratio of DNA content of leukemic
G0/G1 cells to normal diploid cells) and
karyotype analyses, most of the patients in both groups had no
information available. Table 2 displays the
characteristics of relapses in the 64 case subjects of this study. Most
of the treatment failures occurred between 2 and 5 years after the date
of initial diagnosis and were isolated bone marrow relapses or combined
relapses in the bone marrow and CNS. Table
3 shows the treatment protocols of standard- and intermediate-risk patients in ALL-BFM 86 and 90. Drugs that are known GST substrates are indicated as well as potential or indirect substrates of GSTs. In addition to a previously described association (P < .05) between the GSTP1 codon 105 and codon 114 genotypes,34 which is due to the almost
absent Ile105/Val114 haplotype (see below), no
particular correlations among the GSTM1, GSTT1, and
GSTP1 genotypes or between the genotypes and sex, age at
diagnosis, WBC at diagnosis, immunophenotype, and risk group were
observed (data not shown).
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Table 1.
Characteristics of relapsed case subjects and
successfully treated matched control subjects with acute lymphoblastic
leukemia selected from trials ALL-BFM 86 and ALL-BFM 90
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Figure 1 explains the PCR assays used for
genotype analyses. Genotype prevalences in the entire study population
were as follows: GSTM1 present: 50%, GSTM1 null: 50%;
GSTT1 present: 85.2%, GSTT1 null: 14.8%;
GSTP1 Ile105/Ile105: 50.8%,
GSTP1 Ile105/Val105: 38.3%,
GSTP1 Val105/Val105: 10.9%; and
GSTP1 Ala114/Ala114: 78.1%, GSTP1 Ala114/Val114: 21.1%,
GSTP1 Val114/Val114: 0.8%. Table
4 shows the distribution of GSTM1,
GSTT1, and GSTP1 genotypes in case and control subjects
and the association of these genotypes with the occurrence of relapse.
The risk of relapse for study subjects being GSTM1 null
conferred a statistically nonsignificant 2-fold protection from relapse
compared with individuals being either heterozygous or homozygous for
GSTM1 (OR = 0.50; 95% CI = 0.23-1.07; P = .078).
The GSTT1 null genotype conferred a statistically significant
2.8-fold reduction in risk of relapse relative to the presence of the
GSTT1 gene (OR = 0.36, 95% CI = 0.13-0.99, P = .048). For GSTP1, the
Ile105/Val105 and the
Ile105/Ile105 genotypes did not differ with
respect to their association with risk of relapse (OR = 1.0 for
Ile105/Val105 relative to
Ile105/Ile105). Thus, both groups were combined
in 1 category to increase the variability for the assessment of risk of
the Val105/Val105 genotype. A 3-fold decrease
in risk of relapse (OR = 0.33, 95% CI = 0.09-1.23, P = .099) was associated with the
Val105/Val105 genotype in comparison to the
combined category (Ile105/Val105 and
Ile105/Ile105). No particular association with
relapse was observed for the GSTP1 polymorphism at codon 114. The OR for a combined category of Ala114/Val114 and Val114/Val114 genotypes with reference to
the Ala114/Ala114 genotype was 0.85 (95%
CI = 0.38-1.88, P = .682).
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| Fig 1.
Genotype analyses of GSTM1, GSTT1, and
GSTP1.
Left panel: Agarose gel electrophoresis of PCR products from a
multiplex PCR experiment for simultaneous assessment of GSTM1
and GSTT1 status.33 The PCR products amplified from
the GSTM1 and GSTT1 loci are 219 bp and 480 bp in size,
respectively. A 268 bp fragment from the  -globin locus was
coamplified for internal control purposes. Lane 1 shows an individual
with a homozygous deletion of GSTM1 and GSTT1. Lane 2 shows an individual in which GSTM1 can be detected but
GSTT1 is homozygously deleted. In lane 3, GSTM1 is
absent while a PCR product from the GSTT1 locus can be
detected. In lane 4 both GSTM1 and GSTT1 are present.
M = DNA size standard. Middle and right panel: Detection of
GSTP1 codon 105 and codon 114 genotypes by agarose gel
electrophoresis of PCR products after digestion with the restriction
endonucleases BsmAI and AciI, respectively.10,34 The
sequence polymorphism at GSTP1 codon 105 creates a restriction
site for BsmAI within the resulting 176 bp PCR product, leading to the
generation of 2 fragments of 91 bp and 85 bp, respectively. Thus, in
individuals homozygous for this polymorphism
(Val105/Val105) the 176 bp PCR product is
completely digested into 2 fragments (lane 1). Lane 2 displays a
heterozygous individual (Ile105/Val105), and in
lane 3 an individual homozygous for the Ile105-coding
allele is shown. The polymorphism at GSTP1 codon 114 leads to
the loss of an AciI restriction site. Thus, individuals homozygous for
the Val114 allele only show the undigested 217 bp PCR
product (lane 1). Heterozygous individuals
(Ala114/Val114) show the undigested product and
2 additional fragments (121 bp and 96 bp) resulting from its digestion
(lane 2), and individuals homozygous for Ala114 are
characterized by the sole presence of the digestion products of 121 bp
and 96 bp (lane 3). M = DNA size standard.
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Table 4.
Distribution of GSTM1, GSTT1, GSTP1 genotypes
and their association with the occurrence of relapse in 64 case
subjects and 64 successfully treated matched control subjects with
acute lymphoblastic leukemia from ALL-BFM trials 86 and 90
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Four different haplotypes have been described for
GSTP1.7-9 GSTP1*A has Ile at codon 105 and
Ala at codon 114. GSTP1*B has Val at codon 105 and Ala at codon
114. GSTP1*C has both Val at codon 105 and 114, and
GSTP1*D has Ile at position 105 and Val at position 114. The
PCR genotyping method used in this study does not allow precise
determination of GSTP1 haplotypes, but haplotypes can be
estimated according to their order of occurrence.9 GSTP1*A is by far the most common haplotype, followed by
GSTP1*B and GSTP1*C. The GSTP1*D haplotype is
very rare. Table 5 shows the distribution
of estimated GSTP1 haplotypes in our study population. Our sample size of 128 patients combined with the distribution of
GSTP1 haplotypes over the 6 categories did not allow a
reasonable, matched assessment of the association of GSTP1
haplotypes with risk of relapse. However, the most protection from
relapse with reference to the GSTP1*A/GSTP1*A category
was conferred by the GSTP1*B/GSTP1*B and
GSTP1*B/GSTP1*C genotypes with an OR of 0.50 (P = .418) and 0.33 (P = .317), respectively. These
2 genotypes carry Val at codon 105 in both of their alleles. The ORs
for the GSTP1*A/GSTP1*B and
GSTP1*A/GSTP1*C categories in comparison to the
GSTP1*A/GSTP1*A category were 0.70 (P = .465)
and 1.00 (P > .99), respectively. Thus,
although hampered by small numbers, in haplotype analyses, patients
homozygous for Val at codon 105 seemed to have the greatest protection
from relapse.
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Table 5.
Distribution of estimated GSTP1 haplotypes in 64 case subjects and 64 successfully treated matched control subjects with
acute lymphoblastic leukemia from ALL-BFM trials 86 and 90
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Regarding binding properties of specific substrates by GSTs in the
body, it was suggested that, besides specific substrates, GST isozymes
display overlapping limited substrate specifity toward a variety of
substances.22 Such an overlap in substrate specificity suggests that different GST genotype combinations may confer varying levels of GST activity. For this reason, we investigated the
association of GST genotype combinations with risk of relapse in our
study population of children with ALL. The reference category consisted of study subjects who did not have any of the genotypes that were shown
to be protective in the above described analyses of GSTM1, GSTT1, and GSTP1 genotypes. These were individuals with
GSTM1 present, GSTT1 present, and GSTP1
genotypes other than GSTP1
Val105/Val105. GSTM1 null, GSTT1
null, and GSTP1 Val105/Val105
(corresponding to GSTP1 haplotypes
GSTP1*B/GSTP1*B and GSTP1*B/GSTP1*C) were considered as protective GST genotypes (low-risk genotypes). In Table
6, the distribution of low-risk GST
genotypes and their association with risk of ALL relapse is shown. The
risk of relapse when having 1 low-risk GST genotype decreased 1.9-fold
(OR = 0.53, 95% CI = 0.24-1.19, P = .123) and the risk
when having 2 or 3 low-risk genotypes decreased 3.5-fold (OR = 0.29,
95% CI = 0.06-1.37, P = .118), compared with the reference
group (no low-risk genotype). The decrease of risk with increasing
numbers of low-risk genotypes was statistically significant (P
for trend = .005).
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Table 6.
Distribution of potential glutathione S-transferase
low-risk genotypes and their association with the occurrence of relapse
in 64 case subjects and 64 successfully treated matched control
subjects with acute lymphoblastic leukemia from ALL-BFM trials 86 and
90
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Discussion |
In our study population, the prevalence of the
GSTM1 and GSTT1 null genotype was 50.0% and
14.8%, respectively. Thus, our findings within the whole study
sample are not different from the results observed by Chen et
al35 in a study on GSTM1 and GSTT1
genotypes in childhood ALL. In their study, the GSTM1 null genotype was detected in 55.2% of white childhood ALL patients and
53.5% of normal controls, and the GSTT1 null genotype was found in 14.1% of white childhood ALL patients and 15.0% of their controls. To our knowledge, there are no reported genotype frequencies for GSTP1 in childhood ALL. However, the GSTP1 genotype
distributions (Ile105/Ile105: 50.8%,
Ile105/Val105: 38.3%,
Val105/Val105: 10.9%; and
Ala114/Ala114: 78.1%,
Ala114/Val114: 21.1%,
Val114/Val114: 0.8%) observed in our study
population fall within the same range described for white populations
in studies conducted on GSTP1 genotype frequencies and, for
example, risk of breast cancer or other
malignancies.9,10,19
In the analysis of the relationships of GSTM1,
GSTT1, and GSTP1 genotypes with important clinical risk
factors such as gender, age, and WBC at diagnosis, and immunophenotype
in childhood ALL, we did not detect any particular associations. This
is in accordance with the above mentioned study by Chen et
al35 who reported on a suggestive association of the GST
double null genotype (GSTM1 and GSTT1 null) with WBC at
diagnosis and DNA index (ploidy), but did not find any significant
relationship. We were not able to appropriately address the question of
an association between DNA ploidy measurements and GST genotypes
because a major part of our patients had no data available (see Table
1). In a study by Hall et al,36 however, on protein
expression of µ class GST and event-free survival in childhood ALL,
no obvious associations between GST µ expression and prognostic
features were observed either.
In the past, several studies addressed the association of GST
protein expression and leukemia outcome.36-40 For example,
in the above mentioned study by Hall et al,36 a 3-fold
increased risk of childhood ALL relapse (95% CI = 1.25-7.26) in
patients expressing µ class GST compared with nonexpressing patients
was observed. In contrast, very little information is available on the
role of GST genotypes in leukemia. To our knowledge, this is the first
study to show a statistically significant association between GST
genotypes and outcome in childhood ALL. In our study, the null genotype
for GSTM1 or GSTT1 conferred a 2-fold (OR = 0.5, 95%
CI = 0.23-1.07, P = .078) and 2.8-fold (OR = 0.36, 95% CI = 0.13-0.99, P = .048) reduction in risk of relapse,
respectively, relative to the presence of the GSTM1 or
GSTT1 gene. For GSTP1, the
Val105/Val105 genotype showed a 3-fold decrease
in risk of relapse (OR = 0.33, 95% CI = 0.09-1.23,
P = .099) in comparison to the combined category of
Ile105/Val105 and
Ile105/Ile105 genotypes. Thus, we detected a
statistically significant association of the GSTT1 genotype
with risk of relapse, and strongly suggestive results for the
GSTM1 and GSTP1 codon 105 genotypes. The biologic
plausability of our results is supported by a statistically significant
(P for trend = 0.005) decrease in risk of relapse with
increasing number of low-risk genotypes (GSTM1 null,
GSTT1 null, GSTP1
Val105/Val105). With regard to the small sample
size in our study and the relatively low prevalence of the
GSTT1 null and the GSTP1
Val105/Val105 genotypes (Table 4), as well as
the small group of patients with 2 or 3 low-risk genotypes (Table 6),
our results encourage the prospective evaluation of the contribution of
GST genotypes to therapeutic outcome in larger patient populations.
Such prospective studies should also include assays to evaluate if
patients who are heterozygous for GSTM1 or GSTT1 do
differ from patients homozygous for GSTM1 or
GSTT1. In addition, a potential modulatory effect of
the GSTM1*A and GSTM1*B alleles on therapeutic outcome
would be of investigative interest. These 2 distinct GSTM1
alleles have recently been suggested to confer varying susceptibility
to, for example, breast and bladder cancer, and may therefore also
display different enzyme activities.41,42 This information
may help clarify the issue of the potential existence of variability
with regard to therapeutic outcome in GSTT1 and GSTM1
positive patient populations and increase our knowledge on the
role of GST genotypes in childhood ALL.
In the only other study addressing the association of GST
genotypes and outcome in childhood ALL, Chen et al35
reported on GSTM1 and GSTT1 genotypes and their impact
on event-free survival (EFS), hematologic remission, and time to
isolated CNS relapse in 161 childhood ALL patients from 3 consecutive
trials conducted at St Jude Children's Research Hospital. Except for a
tendency of higher CNS relapse-free survival at 5 years among patients with the GSTM1 null genotype (P = .054), no
particular associations between GSTM1 and GSTT1
genotypes, and outcome of childhood ALL were detected in that
study.35 Because 2 different study designs were used, the
diverging results between the study by Chen et al35 and
ours could be explained several ways. In our study, case and control
groups were highly homologous concerning the matching factors, assuring
similarity between both groups with regard to treatment and all
clinical prognostic features used for patient stratification in the
ALL-BFM 86 and 90 trials. However, the matching criteria set forth in
our study led to the selection of a particular subgroup of the entire
ALL patient population. Thus, our results are not generalizable to all
childhood ALL patients, but are restricted to B-cell precursor ALL of
standard- and intermediate-risk. In contrast, Chen et al35
looked at 161 patients derived from 3 consecutive trials representing a
selection from the St Jude Children's Research Hospital trials of
childhood ALL Total XI, Total XII, and Total XIIIA. This strategy led
to the analysis of a more diverse patient population and to more
generalizable results. However, a possible effect of GST genotypes in
certain subgroups may have been diluted. Another reason could be the
different drug regimens applied in the trials at St Jude Children's
Research Hospital and in the ALL-BFM trials. Unfortunately, our study
population was too small to appropriately assess the association of GST
genotypes and site of relapse. With regard to the results of Chen et
al35 (tendency of higher CNS relapse-free survival among
patients with the GSTM1 null genotype) and the notion of
tissue-specific expression of GSTs,1,36 this is an
important question for the future. Another important aspect for future
studies will be the contribution of GST genotypes to leukemia outcome
under consideration of cytogenetically and/or molecular genetically
defined patient populations. This, because GST genotypes, may be
associated with leukemogenesis in specific, cytogenetically, and/or
molecular genetically defined leukemia subsets.43-45 If
such an association exists, the evaluation of GST genotypes in
association with leukemia outcome will have to take cytogenetic and/or
molecular genetic information into account. Unfortunately, in our
patient population cytogenetic data were only available for 34.4%,
making an analysis in a matched setting impossible.
One last issue to be discussed relates to the mechanism
by which GSTs modulate response to cytotoxic chemotherapy. On one hand, GST-family isozymes have relatively low binding affinities to
specific substrates, and on the other hand, they recognize and/or detoxify a broad range of substrates.22 As a
consequence, a variety of anticancer drugs are proven or potential
substrates or binding partners of GSTs. However, the mechanism by which
GSTs may modulate resistance to anticancer drugs is still a matter of
debate. The major mechanism suggested is still the conjugation with
glutathione.1 Other studies propose additional
possibilities, involving the binding of drugs and/or their
removal from the cell.46,47 Growing understanding of the
mechanism of action will help design clinical studies for a more
specific assessment of the role of GSTs in drug resistance. Another
open question is the contribution of specific GST isozymes to the
metabolism of distinct anticancer drugs. For example, to our knowledge
GSTT1 has not yet been associated with the detoxification or
binding of any of the anticancer drugs used in ALL-BFM 86 and ALL-BFM
90. Although overlapping substrate specificities may infer involvement
of GSTT1 in the detoxification or binding of at least some of
the drugs previously described as substrates for other GST isozymes,
this issue remains unproven. The results of the current study should
inspire further studies that evaluate such specific substrate
associations for GSTT1 and other GST isozymes, as well.
In conclusion, our results suggest an association of GST genotypes with
therapeutic outcome in childhood precursor B-cell ALL. However, the
contribution of genetic interindividual variability in the GST system
has to be evaluated in larger, well-characterized patient populations.
Nevertheless, GST genotypes may be useful for the future development of
individual patient risk profiles to optimize cancer chemotherapeutic regimens.
| |
Acknowledgments |
We thank all the participants of the ALL-BFM 86 and 90 studies for
their cooperation and Nicolai Götz for excellent data management.
We are particularly thankful to Edelgard Odenwald for her careful
organization of spare bone marrow and peripheral blood smears.
| |
Footnotes |
Submitted April 19, 1999; accepted October 18, 1999.
M.St. is a recipient of a "Kind-Philipp-Rückkehrstipendium"
through the "Kind-Philipp-Stiftung" within the "Stifterverband für die Deutsche Wissenschaft," Essen, Germany.
Supported in part by the "Madeleine
Schickedanz-Kinderkrebs-Stiftung," Fürth, Germany, and the
Lions Club, Rinteln, Germany.
Reprints: Karl Welte, Department of Pediatric Hematology and
Oncology, Children's Hospital, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; e-mail:
welte.karl{at}mh-hannover.de.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
References |
1.
Ketterer B.
The protective role of glutathione transferases in mutagenesis and carcinogenesis.
Mutat Res.
1988;202:343[Medline]
[Order article via Infotrieve].
2.
Hengstler JG, Arand M, Herrero ME, Oesch F.
Polymorphisms of N-acetyltransferases, glutathione S-transferases, microsomal epoxide hydrolase, and sulfotransferases: influence on cancer susceptibility.
Recent Results Cancer Res.
1998;154:47[Medline]
[Order article via Infotrieve].
3.
Mannervik B, Awasthi YC, Board PG, et al.
Nomenclature for human glutathione transferases.
Biochem J.
1992;282:305.
4.
Seidegard J, Vorachek WR, Pero RW, Pearson WR.
Hereditary differences in the expression of the human glutathione transferase active on trans-stilbene oxide are due to a gene deletion.
Proc Natl Acad Sci U S A.
1988;85:7293[Abstract/Free Full Text].
5.
Pemble S, Schroeder KR, Spencer SR, et al.
Human glutathione S-transferase theta (GSTT1): cDNA cloning and the characterization of a genetic polymorphism.
Biochem J.
1994;300:271.
6.
Board PG, Webb GC, Coggan M.
Isolation of a cDNA clone and localization of the human glutathione S-transferase 3 gene to chromosome bands 11q13 and 12q13-14.
Ann Hum Genet.
1989;53:205[Medline]
[Order article via Infotrieve].
7.
Ali-Osman F, Akande O, Antoun G, Mao J-X, Buolamwini J.
Molecular cloning, characterization, and expression in Escherichia coli of full length cDNAs of three human glutathione S-transferase pi gene variants.
J Biol Chem.
1997;272:10,004[Abstract/Free Full Text].
8.
Lo HW, Ali-Osman F.
Genomic cloning of hGSTP1*C, an allelic human Pi class glutathione S-transferase gene variant, and functional characterization of its retinoic acid response elements.
J Biol Chem.
1997;272:32,743[Abstract/Free Full Text].
9.
Watson MA, Stewart RK, Smith GBJ, Massey TE, Bell DA.
Human glutathione S-transferase P1 polymorphisms: relationships to lung tissue enzyme activity and population frequency distribution.
Carcinogenesis.
1998;19:275[Abstract/Free Full Text].
10.
Harries LW, Stubbins MJ, Forman D, Howard GCW, Wolf CR.
Identification of genetic polymorphisms at the glutathione S-transferase Pi locus and association with susceptibility to bladder, testicular and prostate cancer.
Carcinogenesis.
1997;18:641[Abstract/Free Full Text].
11.
Zimniak P, Nanduri B, Pikula S, et al.
Naturally occurring human glutathione S-transferase GSTP-1 isoforms with isoleucin and valine in position 104 differ in enzymic properties.
Eur J Biochem.
1994;224:893[Medline]
[Order article via Infotrieve].
12.
Hu X, Xia H, Srivastava SK, et al.
Activity of four allelic forms of glutathione S-transferase hGSTP1-1 for diol epoxides of polycyclic aromatic hydrocarbons.
Biochem Biophys Res Commun.
1997;238:397[Medline]
[Order article via Infotrieve].
13.
Perera F.
Molecular epidemiology: insights into cancer susceptibility, risk assessment, and prevention.
J Natl Cancer Inst.
1996;88:496[Abstract/Free Full Text].
14.
Seidegard J, Pero RW, Markowitz MM, Roush G, Miller DG, Beattie EJ.
Isoenzyme(s) of glutathione transferase (class Mu) as a marker for the susceptibility to lung cancer: a follow-up study.
Carcinogenesis.
1990;11:33[Abstract/Free Full Text].
15.
Nazar-Stewart V, Motulsky AG, Eaton DL, et al.
The glutathione S-transferase mu polymorphism as a marker for susceptibility to lung carcinoma.
Cancer Res.
1993;53:2313[Abstract/Free Full Text].
16.
Bell DA, Taylor J, Paulson DF, Robertson CN, Mohler JF, Lucier GW.
Genetic risk and carcinogen exposure: a common inherited defect of the carcinogen-metabolism gene glutathione S-transferase M1 (GSTM1) that increases susceptibility to bladder cancer.
J Natl Cancer Inst.
1993;85:1159[Abstract/Free Full Text].
17.
Ambrosone CB, Freudenheim JL, Graham S, et al.
Cytochrome P450 1A1 and glutathione S-transferase (M1) genetic polymorphisms and postmenopausal breast cancer risk.
Cancer Res.
1995;55:3483[Abstract/Free Full Text].
18.
Kelsey KT, Hankinson SE, Colditz GA, et al.
Glutathione S-transferase class mu deletion polymorphism and breast cancer: results from prevalent versus incident cases.
Cancer Epidemiol Biomarkers Prev.
1997;6:511[Abstract].
19.
Helzlsouer KJ, Selmin O, Huang H-Y, et al.
Association between glutathione S-transferase M1, P1, and T1 genetic polymorphisms and development of breast cancer.
J Natl Cancer Inst.
1998;90:512[Abstract/Free Full Text].
20.
Strange RC, Matharoo B, Faulder GC, et al.
The human glutathione S-transferases: a case-control study of the incidence of the GST1 theta phenotype in patients with adenocarcinoma.
Carcinogenesis.
1991;12:25[Abstract/Free Full Text].
21.
Deakin M, Elder J, Hendrickse C, et al.
Glutathione S-transferase GSTT1 genotypes and susceptibility to cancer: studies of interactions with GSTM1 in lung, oral, gastric and colorectal cancers.
Carcinogenesis.
1996;17:881[Abstract/Free Full Text].
22.
Tew KD.
Glutathione-associated enzymes in anticancer drug resistance.
Cancer Res.
1994;54:4313[Abstract/Free Full Text].
23.
Iyer L, Ratain MJ.
Pharmacogenetics and cancer chemotherapy.
Eur J Cancer.
1998;34:1493.
24.
Yuan Z-M, Smith PB, Brundrett RB, Colvin M, Fenselau C.
Glutathione conjugation with phosphoramide mustard and cyclophosphamide.
Drug Metab Dispos.
1991;19:625[Abstract].
25.
Listowsky I.
High capacity binding by glutathione S-tranferases and glucocorticoid resistance. In:
Tew KD,Pickett CB,Mantle TJ,Mannervik B,Hayes JD, eds.
Structure and Function of Glutathione Transferases. Boca Raton, FL: CRC Press; 1993:199.
26.
Nakagawa K, Saijo N, Tsuchida S, et al.
Glutathione S-transferase as a determinant of drug resistance in transfectant cell lines.
J Biol Chem.
1990;265:4296[Abstract/Free Full Text].
27.
Black SM, Beggs JD, Hayes JD, et al.
Expression of human glutathione S-transferase in Saccharomyces cerevisiae confers resistance to the anticancer drugs adriamycin and chlorambucil.
Biochem J.
1990;268:309[Medline]
[Order article via Infotrieve].
28.
Pui C-H.
Childhood leukemias.
N Engl J Med.
1995;332:1618[Free Full Text].
29.
Kersey JH.
Fifty years of studies of the biology and therapy of childhood leukemia.
Blood.
1997;90:4243[Free Full Text].
30.
Reiter A, Schrappe M, Ludwig W-D, et al.
Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients: results and conclusions of the multicenter trial ALL-BFM 86.
Blood.
1994;84:3122[Abstract/Free Full Text].
31.
Schrappe M, Reiter A, Sauter S, et al.
Konzeption und Zwischenergebnis der Therapiestudie ALL-BFM 90 zur Behandlung der akuten lymphoblastischen Leukämie bei Kindern und Jugendlichen: Die Bedeutung des initialen Therapieansprechens in Blut und Knochenmark.
Klin Pädiatr.
1994;206:208[Medline]
[Order article via Infotrieve].
32.
Schrappe M, Reiter A, Welte K, et al.
Risk adapted treatment in childhood acute lymphoblastic leukemia: data from the Berlin-Frankfurt-Münster group. In:
Büchner T,Hiddemann W,Wörmann B,Schellong G,Ritter J,Creutzig U, eds.
Hematology and Blood Transfusion. Vol 38. Acute Leukemias VI: Prognostic Factors and Treatment Strategies. New York, NY: Springer; 1997:601.
33.
Chen C-L, Liu Q, Relling MV.
Simultaneous characterization of glutathione S-transferase M1 and T1 polymorphisms by polymerase chain reaction in American whites and blacks.
Pharmacogenetics.
1996;6:187[Medline]
[Order article via Infotrieve].
34.
Harris MJ, Coggan M, Langton L, Wilson SR, Board PG.
Polymorphism of the Pi class glutathione S-transferase in normal populations and cancer patients.
Pharmacogenetics.
1998;8:27[Medline]
[Order article via Infotrieve].
35.
Chen C-L, Liu Q, Pui C-H, et al.
Higher frequency of glutathione S-transferase deletions in black children with acute lymphoblastic leukemia.
Blood.
1997;89:1701[Abstract/Free Full Text].
36.
Hall AG, Autzen P, Cattan AR, et al.
Expression of µ class glutathione S-transferase correlates with event-free survival in childhood acute lymphoblastic leukemia.
Cancer Res.
1994;54:5251[Abstract/Free Full Text].
37.
Joncourt F, Oberli A, Redmond SMS, et al.
Cytostatic drug resistance: parallel assessment of glutathione-based detoxifying enzymes, O6-alkylguanine-DNA-alkyltransferase and P-glycoprotein in adult patients with leukemia.
Br J Haematol.
1993;85:103[Medline]
[Order article via Infotrieve].
38.
Sauerbrey A, Zintl F, Volm M.
P-glycoprotein and glutathione S-transferase in childhood acute lymphoblastic leukaemia.
Br J Cancer.
1994;70:1144[Medline]
[Order article via Infotrieve].
39.
Russo D, Marie JP, Zhou DC, et al.
Evaluation of the clinical relevance of the anionic glutathione S-transferase (GST) and multidrug resistance (mdr-1) gene coexpression in leukemias and lymphomas.
Leuk Lymphoma.
1994;15:453[Medline]
[Order article via Infotrieve].
40.
Ribrag V, Massade V, Faussat AM, et al.
Drug resistance mechanisms in chronic lymphocytic leukemia.
Leukemia.
1996;10:1944[Medline]
[Order article via Infotrieve].
41.
Charrier J, Maugard CM, Le Mevel B, Bignon YJ.
Allelotype influence at glutathione S-transferase M1 locus on breast cancer susceptibility.
Br J Cancer.
1999;79:346[Medline]
[Order article via Infotrieve].
42.
Brockmöller J, Kerb R, Drakoulis N, Staffeldt B, Roots I.
Glutathione S-transferase M1 and its variants A and B as host factors of bladder cancer susceptibility: a case-control study.
Cancer Res.
1994;54:4103[Abstract/Free Full Text].
43.
Shpilberg O, Dorman JS, Shahar A, Kuller LH.
Molecular epidemiology of hematological neoplasms-present status and future directions.
Leukemia Res.
1997;21:265[Medline]
[Order article via Infotrieve].
44.
Schröder KR, Wiebel FA, Reich S, Dannappel DMBH, Hallier E.
Glutathione S-transferase (GST) theta polymorphism influences background SCE rate.
Arch Toxicol.
1995;69:505[Medline]
[Order article via Infotrieve].
45.
Wiencke JK, Pemble S, Ketterer B, Kelsey KT.
Gene deletion of glutathione S-transferase theta: correlation with induced genetic damage and potential role in endogenous mutagenesis.
Cancer Epidemiol Biomarkers Prev.
1995;4:253[Abstract].
46.
Lautier D, Canitrot Y, Deelay RG, Cole SPC.
Multidrug resistance mediated by the multidrug resistance protein (MRP) gene.
Biochem Pharmacol.
1996;52:967[Medline]
[Order article via Infotrieve].
47.
Morrow CS, Smitherman PK, Diah SK, Schneider E, Townsend AJ.
Coordinated action of glutathione S-transferases (GSTs) and multidrug resistance protein 1 (MRP1) in antineoplastic drug detoxification.
J Biol Chem.
1998;273:20,114[Abstract/Free Full Text].
48.
Dirven HA, Megens L, Oudshoorn MJ, et al.
Glutathione conjugation of the cytostatic drug ifosfamide and the role of human glutathione S-transferases.
Chem Res Toxicol.
1995;8:979[Medline]
[Order article via Infotrieve].
49.
Hall AG, Tilby MJ.
Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies.
Blood Rev.
1992;6:163[Medline]
[Order article via Infotrieve].
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Abstract
Introduction