0

Cancer Letters 221 (2005) 123–129

www.elsevier.com/locate/canlet

Mini review

Glutathione S-transferase genotypes and cancer risk

Fritz F. Parl*
Department of Pathology and Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Received 1 June 2004; accepted 7 June 2004

Abstract
Over 500 studies have examined the association of genetic variants of glutathione S-transferases with various malignancies
yielding inconsistent results. The genotyping was based on PCR assays that identified the GSTM1 and GSTT1 null (K/K)
genotypes but did not distinguish homozygous wild-type C/C and heterozygous C/K individuals. Complete GSTM1 and
GSTT1 genotyping can be accomplished by recently developed assays [Cancer Res. 64 (2004) 1233–1236; Pharmacogenetics
10 (2000) 557–565] that allow the definition of C/C, C/K, and K/K genotypes by separate identification of the respective
GSTM1 and GSTT1 wild-type and null alleles. Application of the new GSTM1 assay to a breast cancer case-control study
revealed that the relative risk of breast cancer for the C/C genotype compared to the K/K genotype was 2.83 (95% confidence
interval 1.45–5.59; PZ0.002), suggesting a protective effect of the GSTM1 deletion [Cancer Res. 64 (2004) 1233–1236].
Regardless of the explanation for the association between the C/C genotype and increased breast cancer risk, these results
warrant application of true GSTM1 and GSTT1 genotyping to additional or previously analyzed groups with breast cancer or
other malignancies.
q 2004 Elsevier Ireland Ltd. All rights reserved.

Keywords: Genotype; Molecular epidemiology; Cancer; Enzyme conjugation

1. Introduction of the tripeptide glutathione (GSH) to a wide variety

Glutathione S-transferases (GSTs) constitute a
superfamily of ubiquitous, multifunctional enzymes,
which play a key role in cellular detoxification,
protecting macromolecules from attack by reactive
electrophiles [1]. The GSTs catalyze the conjugation
Abbreviations: GSTM1, glutathione S-transferase M1; GSTT1,
glutathione S-transferase T1.
* Address: Department of Pathology, TVC 4918, Vanderbilt
University Medical Center, Nashville, TN 37232, USA.
Tel.: C1-615-343-9117; fax: C1-615-343-9563.
E-mail address: fritz.parl@vanderbilt.edu
0304-3835/$ - see front matter q 2004 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.canlet.2004.06.016
of exogenous and endogenous chemicals with elec-
trophilic functional groups (e.g. products of oxidative
stress, environmental pollutants, and carcinogens),
thereby neutralizing their electrophilic sites, and
rendering the products more water-soluble [2].
Based on sequence homology and immunological
crossreactivity, human cytosolic GSTs have been
grouped into seven families, designated GST Alpha,
Mu, Pi, Sigma, Omega, Theta, and Zeta [3–5]. The
GSTs have presumably arisen from a single common
ancestor and their substrate specificity and diversity
have been reshaped by gene duplication, gene
recombination, and an accumulation of mutations.
124 F.F. Parl / Cancer Letters 221 (2005) 123–129

In view of the importance of GSTs in cellular
detoxification of carcinogens, genetic variants of
GSTs have attracted the attention of epidemiologists
with respect to cancer risk. A search of the literature
up to April 2004 listed more than 500 studies of GST
genotypes in relation to breast, lung, colon, brain, and
various other types of cancer [6–8]. Since GSTM1,
GSTP1, and GSTT1 have been the most commonly
examined genes I will briefly review the GSTm, p, and
q families. I will also review the genotyping of GST
variants, which has been definitive for single-
nucleotide polymorphisms of the GSTP1 gene, but
inadequate for GSTM1 and GSTT1 variants.
2. GSTm
The GSTm subfamily is encoded by a 100-kb gene
cluster at 1p13.3 arranged as 5 0 -GSTM4-GSTM2-
GSTM1-GSTM5-GSTM3-3 0 [9,10] (Fig. 1). Deletion
of the GSTM1 gene, GSTM1*0, frequently affects
both alleles, resulting in the so-called K/K genotype,
GSTM1K/K. A meta-analysis of 30 studies [11]
involving over 10,000 individuals identified the
GSTM1 null genotype in 53% Caucasians (with a
42–62% range for individual studies). The frequency
of the GSTM1 K/K genotype was similar in Asians
but lower in African–Americans, 27% (16–36%).
Detailed mapping of the GSTm gene cluster revealed
that the GSTM1 gene is flanked by two almost
identical 4.2-kb regions (Fig. 1). The GSTM1*0
deletion is caused by a homologous recombination
involving the left and right 4.2-kb repeats [10].
Analysis of 20 GSTM1*0 alleles from 13 unrelated
individuals showed the same recombination pattern,
which results in a 16-kb deletion containing the entire
GSTM1 gene. The GSTM1 gene is excised relatively
precisely leaving the adjacent GSTM2 and GSTM5
genes intact. Therefore, one can rule out recombina-
tion with neighboring GSTM genes as a possible
mechanism for the GSTM1*0 deletion, despite
extensive homologies in certain regions. A missense
single nucleotide polymorphism also occurs in the
GSTM1 gene, i.e. nucleotide 534 G/C (172 Lys/
Asn, corresponding to GSTM1*A and GSTM1*B,
respectively), which does not appear to affect the
enzyme function [12]. Analysis of the other GSTM
isoforms shows extensive homologies. For example,
exon 8 of the GSTM2 gene and exon 8 of the GSTM1
gene are more than 99% identical over 583 nucleo-
tides [13]. The GSTM3 gene is considerably shorter
than the other GSTM isoforms and oriented tail-to-tail
in the cluster [14] (Fig. 1). In the GSTM3 gene, the
GSTM3*A wild type and GSTM3*B variant alleles
differ from each other by a deletion of 3 bp in intron 6,
resulting in the generation of a recognition sequence
for the YY1 transcription factor in the latter [15].
A linkage disequilibrium has been noted between the
GSTM1*A and GSTM3*B alleles [15]. GSTM4
shares amino acid sequence identity with GSTM1
(87%), GSTM2 (83%) and GSTM3 (70%) [16].
Numerous studies have analyzed the GSTM1
genotype using a PCR-based assay designed
to identify the wild-type allele of GSTM1 [17].

Fig. 1. The GSTM1 gene is part of the Mu-class GST gene cluster at 1p13.3, which is arranged as 5 0 -GSTM4-GSTM2-GSTM1-GSTM5-
GSTM3-3 0 (top of diagram). The GSTM1 gene (black box) consists of 8 exons, which range in size from 36 to 112 bp, while the introns vary
from 87 to 2641 bp. GSTM1 is embedded in a region with extensive homologies and flanked by two almost identical 4.2-kb regions (gray
boxes). The GSTM1 null allele arises by homologous recombination of the left and right 4.2-kb repeats, which results in a 16-kb deletion
containing the entire GSTM1 gene (bottom of diagram). The point of deletion cannot be precisely localized because of the high sequence
identity between the repeats.
 F.F. Parl / Cancer Letters 221 (2005) 123–129
In this assay, the absence of a PCR product (273 bp)
indicates the GSTM1 K/K genotype and study
participants were categorized as either wild-type or
null ‘genotypes’. This analytical approach has one
basic flaw in that it does not positively identify the
null allele and, therefore, cannot distinguish homo-
zygous wild-type C/C from heterozygous C/K
individuals. We analyzed the GSTM gene cluster and
recently developed a long-range PCR assay (14 kb
product) to allow positive identification of the null
allele. In combination with the identification of the
wild-type allele, we could perform true GSTM1
genotyping and define the C/C, C/K, and K/K
genotypes. Thus, we could determine the frequency of
the GSTM1 wild-type and null alleles in the
Caucasian and African–American populations. We
found that the GSTM1 wild-type allele is nearly twice
as common in African–American (0.407) than in
Caucasian (0.225) women [18].
3. GSTp
The single GSTP1 gene at 11q13 is 2.8 kb long and
contains seven exons [19–21] (Fig. 2). The open
reading frame starts at the 3 0 end of the first exon and
is 630 bp long, encoding a protein of 209 amino acids
(most authors exclude the initiator methionine).
GSTP1 is expressed in many tissues including breast
where it is the predominant GST [22]. A CpG island
in the GSTP1 promoter was shown to be unmethy-
lated in normal breast but hypermethylated in
Fig. 2. Overview of GSTP1 gene, mRNA, and protein. The GSTP1 gene at 11q13 is about 2.8 kb long and contains seven exons. The open
reading frame starts at the 3 0 end of the first exon and is 630 bp long, encoding a protein of 209 amino acids with a relative molecular weight Mr
23,224. The arrows indicate polymorphic sites. Two of the polymorphisms result in amino acid substitutions in codons 104 (Ile/Val) and 113
(Ala/Val) in exons 5 and 6, respectively.
125
approximately one third of primary breast cancers
[23,24]. In these tumors, the hypermethylation was
associated with loss of GSTP1 expression as demon-
strated by immunohistochemistry. Several single
nucleotide polymorphisms have been described in
the GSTP1 gene. Two of the polymorphisms result in
amino acid substitutions in codons 104 (Ile/Val)
and 113 (Ala/Val) in exons 5 and 6, respectively
[25] (Fig. 2). Both amino acids 104 and 113 affect
substrate specificity to the point of distinguishing
between planar and nonplanar substrates [26,27].
4. GSTq
The GSTq subfamily consists of two genes, GSTT1
and GSTT2, which are located at 22q11.2 and
separated by about 50 kb [8,28,29] (Fig. 3). Both
genes have five exons with identical intron/exon
boundaries but share only 55% amino acid identity.
About 20% of Caucasians are homozygous for a
GSTT1 null allele, GSTT1*0. The GSTT1 K/K
genotype is more common in Asians, with frequencies
ranging from 47 to 64% [11,30]. The deletion of the
GSTT1 gene does not include GSTT2 [28]. Analysis
of a 119-kb section containing the GSTT1 and GSTT2
genes revealed extensive homologies, e.g. two 18 kb
regions, HA3 and HA5, with >90% homology
flanking GSTT1. HA3 and HA5 contained two
identical 403-bp repeats, which were identified as
deletion/junction regions of the GSTT1 null allele
[31]. Similar to GSTM1*0, the GSTT1*0 deletion is
126 F.F. Parl / Cancer Letters 221 (2005) 123–129

Fig. 3. The GSTT1 gene is part of the Theta-class GST gene cluster at 22q11.2 (top of diagram). GSTT1 and GSTT2 are separated by
approximately 50 kb. GSTT2 lies head-to-head with a gene encoding the D-dopachrome tautomerase (DDCT). The GSTT2 and DDCT genes
have been duplicated in an inverted repeat. The duplicated GSTT2 is a pseudogene (named GSTT2P) because an abnormal exon 2/intron 2 splice
site causes a premature translation stop. The GSTT1 gene (black box) consists of five exons, which range in size from 88 to 195 bp, while the
introns vary from 205 to 2363 bp. The GSTT1 gene is embedded in a region with extensive homologies and flanked by two 18 kb regions, HA3
and HA5 (gray boxes), which are more than 90% homologous. In their central portions HA3 and HA5 share a 403-bp sequence with 100%
identity. The GSTT1 null allele arises by homologous recombination of the left and right 403-bp repeats, which results in a 54-kb deletion
containing the entire GSTT1 gene (bottom of diagram). The point of deletion cannot be precisely localized because of the sequence identity
between the 403-bp repeats.

most likely caused by a homologous recombination
event involving the left and right 403-bp repeats. The
recombination results in a w54-kb deletion contain-
ing the entire GSTT1 gene (Fig. 3). Determination of
GSTT1 enzyme activity in erythrocytes showed a
trimodal phenotypic distribution corresponding to the
C/C, C/K, and K/K genotypes [31].
Similar to GSTM1, numerous studies of the
GSTT1 genotype employed a PCR-based assay that
identified the wild-type allele [32]. The absence of a
PCR product signified the GSTT1 K/K genotype.
However, this assay did not positively identify the
null allele and therefore could not distinguish
homozygous C/C from heterozygous C/K individ-
uals. Sprenger et al. [31] performed an analysis of the
GSTT gene cluster and designed a PCR assay for the
positive identification of the null allele. They further
developed a multiplex PCR for the coamplification of
both wild-type and null alleles, permitting GSTT1
genotyping in a single assay. In Caucasian men the
frequencies of the wild-type and null alleles were 0.57
and 0.43, respectively.
5. GST genotypes and cancer risk
The majority of polymorphisms affecting genes
involved in carcinogen metabolism are single
nucleotide polymorphisms. Deletions are less com-
mon and the complete absence of a gene in form of a
null allele is rare. It is for this reason that the GSTM1
and GSTT1 K/K genotypes have attracted so much
attention and become the focus of over 500 publi-
cations in molecular epidemiology. The underlying
hypothesis of these studies is that normal or increased
GST enzyme activity may protect susceptible tissues
from somatic DNA mutations by facilitating the
detoxification of electrophilic carcinogens. In con-
trast, homozygous deletions of GSTM1 or GSTT1 are
expected to have an impaired ability to metabolically
eliminate carcinogenic compounds and may therefore
place GSTM1 K/K or GSTT1 K/K individuals at
increased cancer risk.
Since GSTs have overlapping substrate specifici-
ties, deficiency of an individual GST isoenzyme may
be compensated by other isoforms. Therefore, simul-
taneous determination of all GST genotypes appears
to be a prerequisite for reliable interpretation of the
role of the GST family in cancer development.
Several molecular epidemiological studies have
examined the relation between breast cancer
risk and genotypes of one, two, or three GST subtypes
[7,33]. Overall, no clear pattern has emerged.
Individual studies of one or two GSTs observed
associations that were not confirmed by other studies
[34–39]. Simultaneous analysis of three GSTs did not
 F.F. Parl / Cancer Letters 221 (2005) 123–129
clarify risk associations but rather led to more
contradictory results. For example, Helzlsouer et al.
[40] reported significantly increased risk for women
with GSTM1 K/K and GSTT1 K/K genotypes
together with the GSTP1 (104 Val/Val) genotype,
whereas Mitrunen et al. [33] did not observe any
association with this genotype combination. Millikan
et al. [41] found the lowest risk for women
simultaneously carrying the GSTM1 K/K, GSTT1
K/K, and GSTP1 (104 Val/Val or Ile/Val) geno-
types, whereas Mitrunen et al. [33] noted an increased
risk in premenopausal women lacking the GSTM1
and GSTT1 genes and carrying the GSTP1 (104 Ile/
Ile) genotype. Yet another study of 500 breast cancer
patients and 395 controls found no increase in risk
associated with any combination of GSTM1, GSTP1,
and GSTT1 genotypes [42]. The different results of
these studies may be attributed to differences in the
study populations and their exposure to environmental
or dietary factors. On the other hand, none of the
preceding studies truly genotyped GSTM1 and
GSTT1. They only identified K/K homozygosity
and thereby oversimplified the phenotype as all or
none. The positive identification of the wild-type and
null alleles described by Roodi et al. [18] for GSTM1
and by Sprenger et al. [31] for GSTT1 allowed
definition of the C/C, C/K, and K/K genotypes
and unambiguous assignment of high, low, and none
conjugator phenotypes.
Application of true GSTM1 genotyping to a
breast cancer case-control study revealed that the
relative risk of breast cancer for Caucasian women
with the C/C genotype compared to women with
the K/K genotype was 2.82 (95% CI 1.45–5.49;
PZ0.002) [18]. The association between the
GSTM1C/C genotype and elevated breast cancer
risk was unexpected and requires an explanation,
which is speculative at this time, ranging from
linkage of GSTM1 with other genes to the substrate
GSH and population genetics of the null deletion.
With regard to GSH, mammalian cells have evolved
protective mechanisms such as GSH conjugation to
minimize injurious events that result from toxic
chemicals and normal oxidative products of cellular
metabolism. GSH depletion to about 20–30% of
total glutathione levels can impair the conjugation
defense against the toxic actions of such compounds
and become detrimental to cellular processes [43].
127
Thus, the combined conjugation activities of all
GSTs may lead to GSH depletion and thereby
become counterproductive. Instead of protecting, the
GSTs collectively may expose the cell to injurious
effects such as oxidative DNA damage and associ-
ated mutagenic lesions. Alternatively, GSTs can
convert several classes of compounds, via conju-
gation with GSH, into cytotoxic, genotoxic, or
mutagenic metabolites [44]. Although conjecture,
the GSTM1 and GSTT1C/C genotypes may be
disadvantageous under certain circumstances,
explaining the high frequency of the GSTM1 and
GSTT1 K/K genotypes in the general population.
It seems that the deletion of the GSTM1 and GSTT1
genes occurred not only with impunity but
may actually have offered a survival advantage for
the cell.
6. Conclusions
Deletions of the GSTM1 and GSTT1 genes are
common in the general population. The expected
increase in cancer risk associated with the GSTM1
and GSTT1 K/K genotypes has not been consist-
ently observed in over 500 epidemiological studies.
However, the genotyping was based on PCR assays
that did not distinguish homozygous wild-type C/C
and heterozygous C/K individuals. Complete
GSTM1 and GSTT1 genotyping can be accom-
plished by recently developed assays [18,31] that
allow the definition of C/C, C/K, and K/K
genotypes by separate identification of the respect-
ive GSTM1 and GSTT1 wild-type and null alleles.
Application of the new GSTM1 assay to a breast
cancer case-control study showed a significantly
increased risk of breast cancer for the C/C
genotype compared to the K/K genotype,
suggesting a protective effect of the GSTM1
deletion [18]. Regardless of the explanation under-
lying the association between the C/C genotype
and increased breast cancer risk, true GSTM1 and
GSTT1 genotyping of additional or previously
analyzed groups with breast cancer or other
malignancies should improve our understanding of
GSTs in cancer development.
128 F.F. Parl / Cancer Letters 221 (2005) 123–129
Acknowledgements
Supported in part by NIH grant 1R01CA/ES83752.
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