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Proc Natl Acad Sci U S A. 2001 September 25; 98(20): 11592–11597. Published online 2001 September 11. doi: 10.1073/pnas.191211198. | PMCID: PMC58774 |
Copyright © 2001, The National Academy of Sciences Medical Sciences Polymorphism in glutathione S-transferase P1 is
associated with susceptibility to chemotherapy-induced leukemia James M. Allan,*† Christopher P. Wild,* Sara Rollinson,‡ Eleanor V. Willett,§ Anthony V. Moorman,§ Gareth J. Dovey,§ Philippa L. Roddam,‡ Eve Roman,§ Raymond A. Cartwright,§ and Gareth J. Morgan‡ *Molecular Epidemiology Unit and §Leukaemia Research Fund Centre for Clinical Epidemiology, Academic Unit of Epidemiology and Health Services Research, School of Medicine, and ‡Academic Unit of Hematology and Oncology, Institute of Pathology, University of Leeds, Leeds LS2 9JT, United Kingdom Received April 30, 2001. Glutathione S-transferases (GSTs) detoxify
potentially mutagenic and toxic DNA-reactive electrophiles, including
metabolites of several chemotherapeutic agents, some of which are
suspected human carcinogens. Functional polymorphisms exist in at least
three genes that encode GSTs, including GSTM1,
GSTT1, and GSTP1. We hypothesize,
therefore, that polymorphisms in genes that encode GSTs alter
susceptibility to chemotherapy-induced carcinogenesis, specifically to
therapy-related acute myeloid leukemia (t-AML), a devastating
complication of long-term cancer survival. Elucidation of genetic
determinants may help to identify individuals at increased risk of
developing t-AML. To this end, we have examined 89 cases of t-AML, 420
cases of de novo AML, and 1,022 controls for
polymorphisms in GSTM1, GSTT1, and
GSTP1. Gene deletion of GSTM1 or
GSTT1 was not specifically associated with
susceptibility to t-AML. Individuals with at least one
GSTP1 codon 105 Val allele were significantly
over-represented in t-AML cases compared with de novo
AML cases [odds ratio (OR), 1.81; 95% confidence interval (CI),
1.11–2.94]. Moreover, relative to de novo AML, the
GSTP1 codon 105 Val allele occurred more often among
t-AML patients with prior exposure to chemotherapy (OR, 2.66; 95% CI,
1.39–5.09), particularly among those with prior exposure to known
GSTP1 substrates (OR, 4.34; 95% CI, 1.43–13.20), and not among those
t-AML patients with prior exposure to radiotherapy alone (OR,1.01; 95%
CI, 0.50–2.07). These data suggest that inheritance of at least one
Val allele at GSTP1 codon 105 confers a significantly
increased risk of developing t-AML after cytotoxic chemotherapy, but
not after radiotherapy. Extensive use of combination
chemotherapy and radiation therapy has resulted in increased long-term
survival of cancer patients. A life-threatening complication of
improved long-term cancer survival is an increased risk of developing a
second therapy-related cancer, of which acute myeloid leukemia (AML) is
the most common ( 1– 6). The cumulative risk of therapy-related AML
(t-AML) at 10 years after treatment for breast cancer, non-Hodgkin's
lymphoma, ovarian cancer, or Hodgkin's disease has been estimated at
1.5%, 7.9%, 8.5%, and 3.8%, respectively ( 7– 10). The cytogenetic and clinical presentation of t-AML differs according to
the nature of the primary therapy, suggesting the existence of multiple
genetic mechanisms by which t-AML may develop ( 11). Recent efforts have
concentrated on elucidating genetic factors that modulate
susceptibility to t-AML. Indeed, germ-line mutations in the tumor
suppressor gene p53 have been associated with increased
susceptibility to t-AML ( 12, 13), as has polymorphic variation in the
NAD(P)H:quinone oxidoreductase gene ( 14, 15) and the cytochrome P450
3A4 gene ( 16). Polymorphisms of functional significance have also been reported in
genes that encode phase II metabolizing enzymes, including glutathione
S-transferases (GSTs). GSTs detoxify potentially mutagenic
and cytotoxic DNA-reactive metabolites by conjugation to glutathione.
There are four cytosolic families of GSTs, including GST α, GST μ,
GST θ, and GST π ( 17). 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 ( 18,
19). Independent gene deletions exist at both GSTM1 and
GSTT1 loci, resulting in a lack of active protein in ≈50%
and 20% of Caucasians, respectively ( 20, 21). GST π or GSTP1,
encoded by a single locus ( GSTP1) on chromosome 11, is also
subject to polymorphic variation ( 22). Codon 105 residue forms part of
the GSTP1 active site for binding of hydrophobic electrophiles ( 23),
and the Ile–Val substitution affects substrate-specific catalytic
activity and thermal stability of the encoded protein ( 24– 27). Polymorphisms within genes that encode GSTs have been associated with
susceptibility to nonmalignant ( 28) and malignant human diseases ( 29,
30), including AML ( 31). 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. GSTs, particularly GSTP1,
also conjugate and protect against the cytotoxic effects of some
chemotherapeutic agents. Reactive metabolites of ifosfamide, busulfan,
and chlorambucil are substrates for GSTP1-mediated glutathione
conjugation in vitro ( 27, 32, 33). Furthermore, transfection
of GSTP1 gene or antisense expression vectors demonstrates a
role in cellular resistance to platinum derivatives, etoposide,
cyclophosphamide, melphalan, and adriamycin ( 34– 40). Several chemotherapeutic agents, including cyclophosphamide, melphalan,
adriamycin, and chlorambucil, are suspected human leukemogens.
Furthermore, CD34 + bone marrow stem cells, the
target cell population for leukemic transformation, can be protected
against the cytotoxic effects of these suspected leukemogens by
GSTP1-gene transduction ( 37– 39). These observations led us
to question whether GSTs may also protect bone marrow stem cells
against chemotherapy-induced mutagenesis and leukemogenesis. Thus, we
hypothesize that polymorphic variation in genes encoding GSTs may alter
susceptibility to t-AML. To begin to test this hypothesis, we
established a rare-case series of individuals with AML whose leukemia
developed subsequent to cytotoxic therapy for a previous condition, and
we examined this population for the distribution of polymorphisms in
GSTM1, GSTT1, and GSTP1. Subjects. Polymorphisms of three groups of subjects were compared; there were 89
cases of t-AML, 420 cases of de novo AML, and 1,022
unaffected controls. For this study, t-AML is defined as AML following
chemotherapy and/or radiotherapy diagnosed at least 2 months after
the start of the initial cytotoxic therapy. All samples from the
de novo AML and control groups, and 24 of those with t-AML,
were routinely obtained as part of a large, population-based,
case-control study of acute leukemia that has been fully described
elsewhere ( 31, 41– 44). Briefly, all subjects were between 16 and 69
years of age and were diagnosed with AML between April 1991 and
December 1996 while resident in parts of the north and southwest of
England. All diagnoses were pathologically confirmed. Individuals were
considered ineligible if, before a diagnosis of acute leukemia, they
had been diagnosed with chronic myeloid leukemia or myelodysplastic
syndrome within the previous 6 months, or with any malignancy within
the previous 2 years. Two controls per patient, individually matched by
sex, age, and ethnic origin, were randomly selected from the general
practice where the case was registered. Additional DNA samples were obtained from 65 subjects with t-AML
enrolled in the Medical Research Council (MRC) of the United Kingdom's
AML trials 10, 11, or 12 (45). To treat these 65 individuals in a
similar manner to those enrolled in the case-control study, each person
was individually matched by sex and age (±3 years, or the nearest age
for MRC trial patients over 70 years old) to one of the unused pool of
unaffected controls recruited in the main case-control study. However,
an unmatched statistical analysis was used in all instances (see
below). DNA Extraction. DNA was extracted either from whole frozen blood (case-control study)
or from archived bone marrow smears (MRC cases). Genomic DNA was
extracted from whole frozen blood, as previously described ( 31), and
from bone marrow smears by using the Qiamp DNA-extraction minikit
(Qiagen, Hilden, Germany) according to the manufacturer's
recommendations for archived bone marrow. GST Genotyping. GSTM1 and GSTT1 genotyping was performed by using
a multiplex PCR assay as previously described ( 28). Briefly, the
presence of 215-bp and 480-bp amplicons corresponds to individuals with
at least one intact GSTM1 and GSTT1 allele,
respectively. The absence of either of these amplicons corresponds to
individuals homozygous for the null allele. The presence of a 268-bp
amplicon from the ubiquitous β-globin gene acts as an internal
control, confirming successful PCR amplification. GSTP1 codon 105 genotyping was performed by using a
PCR-restriction fragment length polymorphism assay as previously
described ( 28). Briefly, digestion of a 177-bp amplicon with
BsmA1 that results in either retention of the 177-bp
amplicon or in complete digestion to 93-bp and 84-bp fragments
corresponds to individuals homozygous for the Ile or Val alleles,
respectively. The presence of all three fragments after digestion
corresponds to individuals heterozygous at codon 105. Statistical Analysis. Odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age
and sex, were estimated by using unconditional logistic regression
( 46). GSTP1 was analyzed as a trichotamous (Ile/Ile,
Ile/Val, Val/Val) or dichotomous (Ile/Ile, Ile/Val + Val/Val)
variable. Chemotherapy was given precedence over radiotherapy;
individuals who received both were grouped with those who received
chemotherapy alone. Confirmed GSTP1 substrates include the following
chemotherapeutic agents wherein GSTP1-catalyzed in vitro
glutathione conjugation has been demonstrated or where sense or
antisense gene expression confers resistance or sensitivity,
respectively: chlorambucil ( 27); busulfan ( 33); ifosfamide ( 32);
adriamycin ( 35– 38, 40); etoposide ( 36, 38, 40); cyclophosphamide ( 37,
39); melphalan ( 36, 38); and cisplatin derivatives ( 34, 36, 38). All
analyses were conducted by using STATA 1999 (Stata,
College Station, TX). Descriptive Results. Table 1 describes the distribution
of the t-AML case series, the de novo AML cases, and the
controls by sex, age, French–American–British (FAB) acute leukemia
classification type, cytogenetic analysis, chromosomal abnormalities,
and prior therapy as appropriate. The series of 89 t-AML cases
comprised 12 individuals (14%) with a documented history of
myelodysplastic syndrome. The remaining 77 individuals presented
without a preceding dysplastic phase. The type of chromosomal
abnormality and prevalence of aberrations observed differed in t-AML
from de novo AML; abnormalities involving 11q23 or the loss
of 5q or 7q were more prevalent among t-AML patients, as was the
occurrence of three or more aberrations (Table 1).
| Table 1Description of t-AML cases, de novo AML cases,
and controls |
Information on the nature of the primary condition was available for 57
of 89 t-AML cases. Cytotoxic therapy was given for primary malignancies
in 50 of these 57 cases. Primary malignancies included breast cancer
(n = 15), Hodgkin's disease (n = 11),
non-Hodgkin's lymphoma (n = 4), carcinoma of the
endometrium (n = 3), acute lymphocytic leukemia
(n = 3), malignant histiocytoma (n =
2), prostate cancer (n = 2), cervical cancer
(n = 2), osteosarcoma (n = 1), bladder
cancer (n = 1), testicular cancer (n =
1), rectal cancer (n = 1), chronic lymphocytic leukemia
(n = 1), basal cell carcinoma (n = 1),
and lung cancer (n = 1). Before diagnosis of t-AML, one
individual received cytotoxic therapy for carcinoma of the endometrium
9 years before and non-Hodgkin's lymphoma 5 years before. The
remaining 7 t-AML patients were treated with cytotoxic therapy for
nonmalignant conditions that included vasculitis (n =
2), thrombocytosis (n = 2), tuberculosis
(n = 1), goiter (n = 1), and rheumatoid
arthritis (n = 1). Among the 38 t-AML patients with previous exposure to
radiotherapy only (Table 1), the median latency period from initial
radiotherapy to diagnosis of AML was 72 months (based on 23 cases with
data available). Fifty-one t-AML patients had previous exposure to
chemotherapy and 19 of these had previous exposure to both chemotherapy
and radiotherapy; the median latency period from initial chemotherapy
to onset of AML was 62.5 months (based on 38 cases with data
available). Among the 35 individuals for whom the usage of specific
chemotherapeutic agents was documented, the majority ( n
= 30) had prior exposure to combination chemotherapy, for which
alkylating agents were the most common components used (Table 1). GST Genotype and Risk of t-AML. Although the frequencies of GSTM1 and GSTT1 null
polymorphisms are elevated in the t-AML patient series relative to the
population controls, the risks for both polymorphisms are equally
raised among de novo AML patients (Table
2), suggesting an increased risk of
developing acute myeloid leukemia per se ( 31). In contrast,
individuals with at least one GSTP1 Val allele (Ile/Val or
Val/Val) at codon 105 are significantly overrepresented among t-AML
patients (63%) but not among de novo AML patients (51%)
compared with population controls (51%), suggesting an increased risk
of developing t-AML specifically (OR 1.58, 95% CI 1.01–2.49) (Table
2). Thus, individuals with at least one GSTP1 codon 105 Val
allele are significantly overrepresented in the t-AML patient series
compared with de novo AML patients (OR 1.81, 95% CI
1.11–2.94) (Table 3).
| Table 2GST genotype and the risk of developing t-AML or de
novoAML |
| Table 3GST genotype and the risk of developing t-AML by type of
previoustherapy |
GST Genotype and Risk of t-AML by Type of Therapy. No association with t-AML and either GSTM1 or
GSTT1 by therapy type was evident (Table 3). In contrast,
the GSTP1 codon 105 Val allele appears to confer a
significantly increased risk of t-AML after chemotherapy (OR 2.66, 95%
CI 1.39–5.09), but not after radiotherapy, compared with de
novo AML (OR 1.01, 95% CI 0.50–2.07) (Table 3). Twenty-one of
the 51 t-AML patients who had prior chemotherapy were exposed to at
least one confirmed GSTP1 substrate, which is associated with an excess
risk of t-AML with presence of at least one Val allele at
GSTP1 codon 105, compared with de novo AML
patients (OR 4.34, 95% CI 1.43–13.20) (Table
4). However, a nonsignificant 2-fold
increased risk of t-AML was still present in persons previously treated
with other or unknown chemotherapeutic agents (OR 2.00, 95% CI
0.91–4.40) (Table 4).
| Table 4Comparison of t-AML cases previously treated with
chemotherapy and de novo AML cases, by exposure to
confirmed GSTP1 substrates or other chemotherapeutic agents and by
genotype forGSTP1 |
Our findings suggest that t-AML, but not de novo AML,
is associated with a polymorphism in the gene that encodes GSTP1.
Specifically, these data suggest that individuals either heterozygous
(Ile/Val) or homozygous for Val at codon 105 of GSTP1 were
twice as likely as Ile homozygotes to develop t-AML after chemotherapy
(OR 2.66, 95% CI 1.39–5.09), and greater than 4 times more likely if
they had been exposed to a known GSTP1 substrate (OR 4.34, 95% CI
1.43–13.20). A statistically nonsignificant 2-fold increased risk of
t-AML was still observed when individuals were not exposed to a known
GSTP1 substrate, suggesting that there are other chemotherapeutic
agents yet to be confirmed as substrates. Unlike GSTP1, the
risks associated with GSTT1 and GSTM1
gene-deletion polymorphisms appear no different for t-AML and de
novo AML, consistent with previous reports ( 15, 31, 47, 48). The more frequent occurrence of abnormalities involving 11q23 or the
loss of 5q or 7q among t-AML patients is consistent with prior exposure
to DNA topoisomerase II inhibitors and alkylating agents, respectively
( 11, 49). Other than the relatively high percentage of patients with a
t(15;17), the cytogenetic profile of these t-AML patients is similar to
those reported in previous studies ( 11, 49, 50). Five subjects had genetic alterations (assessed by cytogenetic
analysis) affecting the chromosomal sites of GSTM1,
GSTT1, or GSTP1. PCR was performed with genomic
DNA extracted from leukemic bone marrow in these five individuals.
Thus, it is possible that genotyping may be inaccurate because of loss
of genetic material. However, three of these subjects showed only gains
of genetic material at the involved sites, which is unlikely to affect
genotyping. Deletions affecting 11q13 (GSTP1) were found in
the remaining two individuals, both of whom were genotyped as Ile
homozygotes at codon 105. The statistical significance of the results
is not affected by assuming loss of a Val allele during leukemogenesis
in these subjects and therefore considering them to be Ile/Val
heterozygotes at the GSTP1 codon 105 locus (data not shown).
We also acknowledge the hypothetical possibility that point mutation at
the GSTP1 codon 105 locus during leukemic initiation and the
subsequent selection of mutated clones during disease development may
give rise to inaccurate genotyping if leukemic bone marrow is used as a
source of DNA, as it is for some t-AML patients in this study. However,
we feel it is unlikely that GSTP1 mutations would be
selected during tumor initiation or progression because this gene is
neither a tumor suppressor nor a protooncogene. As such, we feel that
inaccurate genotyping does not represent a significant problem in this
study. Forty-two of the 51 t-AML individuals with prior chemotherapy exposure
were confirmed as United Kingdom Caucasians. The results of statistical
analysis remained significant when individuals of unknown ethnic origin
were excluded (OR 3.47, 95% CI 1.60–7.50). Twenty of the 21 t-AML
patients with prior exposure to a known GSTP1 substrate were confirmed
as United Kingdom Caucasians. The results of statistical analysis
remained significant when the individual of unknown ethnic origin was
excluded (OR 4.09, 95% CI 1.34–12.54). Our data support the hypothesis that the GSTP1 codon 105
polymorphism modulates the leukemogenic effect of certain
chemotherapeutic agents; this is consistent with prior observations
showing that this polymorphism alters protein function. Biochemical
studies have demonstrated a lower thermal stability of GSTP1 Val-105
compared with GSTP1 Ile-105 ( 24, 25) and also lower conjugating
activity in Val homozygotes compared with Ile homozygotes, with
heterozygotes displaying intermediate activity ( 51). In contrast, the
data reported in this study are not consistent with an allele dosage
effect. When GSTP1 was analyzed as a trichotamous variable,
heterozygotes and Val homozygotes appeared to have a similarly
increased risk of t-AML following chemotherapy (Ile/Val, OR 2.87,
95% CI 1.45–5.67; Val/Val, OR 2.17, 95% CI 0.89–5.29), which
suggests a threshold effect rather than a dosage effect for t-AML
susceptibility. However, the small number of Val homozygotes limits the
interpretation of these data in this respect. Individuals with at least one Val allele at codon 105 of
GSTP1 may have an underlying predisposition to cancers when
exposure to environmentally derived or endogenously formed
GSTP1 substrates is a risk factor ( 29). However, acute leukemia appears
not to be one of these cancers because GSTP1 codon 105
status is not a risk factor for de novo AML ( 31) (Table 2),
providing evidence that the increased susceptibility to t-AML suggested
in our study is specific to prior therapeutic exposure. It remains possible that the population at risk of t-AML may be
genetically biased because of a role for the GSTP1 codon 105
polymorphism in modulating either susceptibility to primary cancer or
survival after therapy. Indeed, the GSTP1 codon 105 Val
allele has been reported to be associated with a significantly
increased risk of bladder and testicular cancer ( 29), and with a
nonsignificantly increased risk of breast cancer ( 52). However, a
similar distribution in GSTP1 codon 105 genotype in healthy
controls and t-AML patients with prior exposure to radiotherapy
suggests that predisposition to primary cancer does not result in
significant population bias. Individuals with Val at GSTP1
codon 105 may respond better to chemotherapy given for their primary
cancer because of lower GSTP1 activity and increased
chemotherapy-induced cytotoxicity in target tumor tissue. Indeed, codon
105 Val homozygotes have a significantly better prognosis than codon
105 Ile homozygotes treated with cyclophosphamide and adriamycin (both
GSTP1 substrates) for breast cancer ( 53). Improved prognosis and
long-term survival after therapy would increase the prevalence of
individuals with Val at codon 105 in the population at risk of t-AML,
although, unfortunately, we are presently unable to determine the
potential effect on our results. Bone marrow is particularly sensitive to the toxic effects of
chemotherapeutic alkylating agents, which include cyclophosphamide,
chlorambucil, busulfan, and ifosfamide, among others ( 54). The reasons
for this remain unclear, although low DNA repair activity and lack of
GST α expression in bone marrow CD34 + cells
have been implicated ( 55, 56). Toxicity manifests clinically as
pancytopenia, and it is dose-limiting for several chemotherapeutic
alkylating agents. One approach to overcome acute toxicity is to
artificially protect the bone marrow by using gene transfer techniques.
Presumably this approach would also protect against mutagenesis and
reduce the risk of t-AML. Use of GSTP1 as the transgene has
proven successful in protecting human bone marrow stem cells and bone
marrow in animal models against the toxic effects of chemotherapeutic
alkylating agents ( 37– 39). Our results highlight the importance of
selecting the appropriate transgene variant to confer maximum
protection and suggest codon 105 as a residue that may be artificially
mutated to potentially generate variants with even higher catalytic
activity. In conclusion, our data suggest that individuals with at least one
GSTP1 codon 105 Val allele are at a significantly increased
risk of developing t-AML, compared with Ile homozygotes, after exposure
to such chemotherapeutics as cyclophosphamide, chlorambucil,
adriamycin, etoposide, and cisplatin derivatives. These agents form the
backbone of chemotherapeutic regimes for the treatment of numerous
malignancies, including lymphatic, bladder, breast, ovarian, lung, and
testicular cancer. If GSTP1 codon 105 status can identify
individuals at high risk of developing a second therapy-related cancer,
then it may be possible to tailor chemotherapy to minimize leukemogenic
potential. Of course, the primary aim of any cancer therapeutic regime
is to cure the patient of the disease. However, with high cure
frequency and long-term survival after treatment for such cancers as
pediatric Hodgkin's disease ( 57) and pediatric acute lymphocytic
leukemia ( 58), the threat of t-AML in later life must be considered.
GSTP1 codon 105 status may also be used to identify patients
who may benefit from more intensive surveillance for t-AML after
chemotherapy. We are grateful to Rachel Clack (Clinical Trial Service Unit,
Radcliffe Infirmary, Oxford) and to the staff at the Leukaemia Research
Fund Centre for Clinical Epidemiology at Leeds University for their
expert assistance. We acknowledge the support of Stephen Langabeer at
the MRC DNA/RNA bank, University College London Hospital, a facility
funded by the Kay Kendall Leukemia Fund of the United Kingdom. This
work was funded by the Kay Kendall Leukaemia Fund of the United Kingdom
(to J.M.A.) and the Leukaemia Research Fund of the United Kingdom (to
G.J.M. and R.A.C.). James M. Allan is a fellow of the Kay Kendall
Leukaemia Fund. | | AML | acute myeloid leukemia | | | t-AML | therapy-related AML | | | GST | glutathione S-transferase | | | MRC | Medical Research
Council | | | OR | odds ratio | | | CI | confidence interval |
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