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 (-/-) genotypes but did not distinguish homozygous wild-type +/+ and heterozygous +/- individuals. Complete GSTM1 and GSTT1 genotyping can be accomplished by recently developed assays (Cancer Res 2004; 64:1233-1236; Pharmacogenetics 2000; 10:557-565) that allow the definition of +/+, +/-, and -/- 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 +/+ genotype compared to the -/- genotype was 2.83 (95% confidence interval 1.45 - 5.59; P = 0.002), suggesting a protective effect of the GSTM1 deletion (Cancer Res 2004; 64:1233-1236). Regardless of the explanation for the association between the +/+ 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.

Abbreviations: GSTM1, glutathione S-transferase M1; GSTT1, glutathione S-transferase T1

Keywords: genotype, molecular epidemiology, cancer, enzyme conjugation

1. Introduction
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 of the tripeptide glutathione (GSH) to a wide variety of exogenous and endogenous chemicals with electrophilic 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. 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 GSTmu, pi, and theta 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. GSTmu
The GSTmu subfamily is encoded by a 100-kb gene cluster at 1p13.3 arranged as 5'-GSTM4-GSTM2-GSTM1-GSTM5-GSTM3-3' [9,10] (Fig. 1). Deletion of the GSTM1 gene, GSTM1*0, frequently affects both alleles, resulting in the so-called -/- genotype, GSTM1-/-. A meta-analysis of 30 studies [11] involving over 10,000 individuals identified the GSTM1 null genotype in 53% Caucasians (with a 42 to 62% range for individual studies). The frequency of the GSTM1-/- genotype was similar in Asians but lower in African-Americans, 27% (16 - 36%). Detailed mapping of the GSTmu 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 recombination 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, espectively), 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 nucleotides [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 three 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].

Figure 1. The GSTM1 gene is part of the Mu-class GST gene cluster at 1p13.3, which is arranged as 5'-GSTM4-GSTM2-GSTM1-GSTM5-GSTM3-3' (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 2,641 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.

3. GSTpi
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' 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 unmethylated in normal breast but hypermethylated in approximately one third of primary breast cancers [23,24]. In these tumors, the hypermethylation was associated with loss of GSTP1 expression as demonstrated 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].

Figure 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' end of the first exon and is 630 bp long, encoding a protein of 209 amino acids with a relative molecular weight M_r 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.

4. GSTtheta
The GSTtheta 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 -/- 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 most likely caused by a homologous recombination event involving the left and right 403-bp repeats. The recombination results in a ~54-kb deletion containing the entire GSTT1 gene (Fig. 3). Determination of GSTT1 enzyme activity in erythrocytes showed a trimodal phenotypic distribution corresponding to the +/+, +/-, and -/- genotypes [31].

Figure 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 exon2/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 2,363 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.

5. GST Genotypes and Cancer Risk
The majority of polymorphisms affecting genes involved in carcinogen metabolism are single nucleotide polymorphisms. Deletions are less common 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 -/- genotypes have attracted so much attention and become the focus of over 500 publications 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 contrast, homozygous deletions of GSTM1 or GSTT1 are expected to have an impaired ability to metabolically eliminate carcinogenic compounds and may therefore place GSTM1 -/- or GSTT1 -/- individuals at increased cancer risk.
Since GSTs have overlapping substrate specificities, deficiency of an individual GST isoenzyme may be compensated by other isoforms. Therefore, simultaneous 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 clarify risk associations but rather led to more contradictory results. For example, Helzlsouer et al. [40] reported significantly increased risk for women with GSTM1 -/- and GSTT1 -/- genotypes together with the GSTP1 (104Val/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 -/-, GSTT1 -/-, and GSTP1 (104Val/Val or Ile/Val) genotypes, whereas Mitrunen et al. [33] noted an increased risk in premenopausal women lacking the GSTM1 and GSTT1 genes and carrying the GSTP1 (104Ile/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 -/- 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 +/+, +/-, and -/- 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 +/+ genotype compared to women with the -/- genotype was 2.82 (95% CI 1.45 - 5.49; P = 0.002) [18]. The association between the GSTM1 +/+ 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]. 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 associated mutagenic lesions. Alternatively, GSTs can convert several classes of compounds, via conjugation with GSH, into cytotoxic, genotoxic, or mutagenic metabolites [44]. Although conjecture, the GSTM1 and GSTT1 +/+ genotypes may be disadvantageous under certain circumstances, explaining the high frequency of the GSTM1 and GSTT1 -/- 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 -/- genotypes has not been consistently observed in over 500 epidemiological studies. However, the genotyping was based on PCR assays that did not distinguish homozygous wild-type +/+ and heterozygous +/- individuals. Complete GSTM1 and GSTT1 genotyping can be accomplished by recently developed assays [18,31] that allow the definition of +/+, +/-, and -/- 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 showed a significantly increased risk of breast cancer for the +/+ genotype compared to the -/- genotype, suggesting a protective effect of the GSTM1 deletion [18]. Regardless of the explanation underlying the association between the +/+ 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.

Acknowledgement
Supported in part by NIH grant 1R01CA/ES83752

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