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Carcinogenesis, Vol. 22, No. 7, 1053-1060, July 2001
© 2001 Oxford University Press

CANCER BIOLOGY

Glutathione-S-transferase gene polymorphisms in colorectal cancer patients: interaction between GSTM1 and GSTM3 allele variants as a risk-modulating factor

Alexandre Loktionov,2, Mark A. Watson1,, Marc Gunter, William S.L. Stebbings1,, Chris T.M. Speakman1, and Sheila A. Bingham

MRC Dunn Human Nutrition Unit, Cambridge CB2 2XY and
1 Department of General Surgery, Norfolk and Norwich Health Care NHS Trust, Norwich NR1, UK


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
The distribution of polymorphisms in the glutathione S-transferase (GST) family genes has been studied in 355 healthy controls and 206 cancer (59 proximal and 147 distal) patients. All controls were subjected to flexible sigmoidoscopy. Odds ratios (OR) after stratification by age, gender and smoking were slightly higher in the cancer group as a whole for GSTM1-null (*0/*0), GSTT1-null (*0/*0) and GSTM3 *A/*B or *B/*B when compared with the control group, but the differences did not reach statistical significance. GSTP1 variants had no effect. Separate analysis of patients with proximal and distal tumours has shown stronger associations for the distal cancers, the GSTM3*B allele presence being significantly more frequent in these patients [OR = 1.77; 95% confidence interval (CI) = 1.15–2.74]. Taking into account strong linkage between the GSTM1*A and GSTM3*B alleles, a separate analysis of the GSTM1-nulled individuals was undertaken. The combination of GSTM1-null genotype with GSTM3*B allele presence (*A/*B or *B/*B) was significantly overrepresented among patients with proximal and distal tumours taken together (OR = 2.12; 95% CI = 1.24–3.63), and especially in distal cancer patients (OR = 2.75; 95% CI = 1.56–4.84). Male individuals displayed a stronger association between the presence of the GSTM1-null in combination with GSTM3 *A/*B or *B/*B and distal tumours with a higher odds ratio (OR = 3.57; 95% CI = 1.73–7.36). In contrast, the frequency of GSTM1 *B/*0 or *B/*B combined with GSTM3 *A/*A was significantly lower in patients with distal colorectal cancer, especially in males (OR = 0.37; 95% CI = 0.15–0.92). Neither of these combinations was associated with proximal tumours. Our findings suggest that interactions of polymorphic genotypes within the GSTM gene cluster affect individual susceptibility to colorectal carcinogenesis, the GSTM3*B variant presence being a risk factor especially in combination with the GSTM1-null genotype.

Abbreviations: CI, confidence interval; OR, odds ratio; PAH, polycyclic aromatic hydrocarbons; YY1, Yin Yang 1; GST, glutathione S-transferase.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
The glutathione-S-transferases (GSTs) constitute a family of xenobiotic-detoxifying phase II enzymes catalysing the conjugation of glutathione to a variety of electrophilic compounds including polycyclic aromatic hydrocarbons (PAH), which are widely present in the human environment and known to be carcinogenic (1,2). Several GSTs are polymorphic, and some allelic variants causing impaired enzyme activity are suspected to increase susceptibility to malignancies associated with environmental PAH, in particular colorectal (2,3). It was suggested that homozygous deletions of the active alleles of GSTM1 and GSTT1 (`null' or *0/*0 genotypes) may confer elevated colorectal cancer risk; however, case–control studies undertaken in different populations gave controversial results. Higher frequencies of GSTM1 null genotype were found in colorectal cancer patients in several case–control studies (4–6); however, other groups failed to confirm these findings (7–10). GSTT1 null genotype was reported to increase colorectal cancer risk by two groups (7,8), but no effect of this variant was detected in other studies (6,9,10). The unclear relationship between GSTM1 and GSTT1 polymorphisms and colorectal cancer risk has been comprehensively reviewed by Cotton et al. (3).

Other polymorphic genes of the GST family, in particular GSTM3 (2,11,12) and GSTP1 (2,13–18) have also been shown to be related to cancer risk modulation; however, no effect of GSTP1 on colorectal cancer risk has been found (10,16,17). Possible influence of GSTM3 genotype has not been studied in relation to colorectal cancer so far, but several recent studies indicate that GSTM1 effects may be modulated by the GSTM3 genotype. Two alleles of this gene, GSTM3*A and GSTM3*B, are identified. The GSTM3*B variant, which has a three base deletion in intron 6 creating a recognition sequence for Yin Yang 1 (YY1) transcription factor (19), is linked with the GSTM1*A allele (11). The presence of this GSTM3 allele has been associated with both increased risk for basal cell skin (12) and laryngeal (18,20) cancers, and a protective effect for lung (21) and oral (22) cancers. It is also possible that cancer risk may be affected by other combinations of particular genetic variants of the polymorphic GST enzymes; however, interactions between different members of the GST family in terms of affecting pathogenesis of tumours are still poorly understood.

In the present study we compared the presence of polymorphic variants of GSTM1, GSTM3, GSTT1 and GSTP1 in healthy individuals and colorectal cancer patients from Norfolk region of the UK. An important feature of the study was that all participants assigned to the control group had a negative screening flexible sigmoidoscopy, confirming the absence of distal colon neoplasia.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Subjects
561 people, all Caucasians from the East Anglia region of the UK (predominantly from Norfolk), participated in the study. 206 patients with histopathologically confirmed diagnosis of colorectal cancer (123 males and 83 females) were assigned to the cancer group. The patients were treated during 1997–1999 at the Department of Surgery, Norwich and Norfolk Health Care NHS Trust. There were 59 proximal and 146 distal cancer cases in this group, splenic flexure being taken as the dividing level. No patients with a family history of early onset colorectal cancer or multiple cancer cases were included into the study. The subjects constituting the control group (233 males and 112 females) were participants of the on-going UK Flexible Sigmoidoscopy Screening Trial (23,24). All these people (age range 55–66 years) were subjected to flexible sigmoidoscopy at the same department. Only individuals with a normal flexible sigmoidoscopy were assigned to the control group. All subjects responded to a questionnaire, which provided information on demographic characteristics, occupation, smoking habits and personal medical history. All subjects gave informed consent to the study protocol. Ethical permission for the study was obtained from the Norwich District Ethics Committee.

Blood samples were taken from all participants of the study. Genomic DNA was extracted from blood using Qiagen Blood DNA Extraction kits. GSTM1 genotyping was performed using a three primer PCR designed to co-amplify homologic 122 bp fragments of intron 6–exon 7 of GSTM1 (if present) and GSTM4 (always present) (25) together with a GSTM1-specific 149 bp fragment detectable only in individuals with undeleted GSTM1 present. The anti-sense primer for this reaction (AL56) was modified to introduce an additional diagnostic BsrSI restriction site into the GSTM1*B variant. The primer sequences were as follows: GSTM1-specific sense (AL59), 3'-GAG- ATCTGTTTTGCTTCACGTGTTATG-5'; GSTM1 and GSTM4 sense (AL54), 3'-GAGGTTCCAGCCCACACATTCTTG-5'; GSTM1 and GSTM4 antisense (AL56), 3'-CAGATTTGGGAAGGCGTCCAACCA-5'. Thirty-seven amplification cycles with 60 s denaturation at 94°C and 50 s annealing/extension at 60°C were applied. After assessment of the amplification results by electrophoresis in 8% polyacrylamide gel, GSTM1-positive samples were digested with 2 U BsrSI (Promega) at 65°C for 2 h. Restriction results were then visualized by electrophoresis (Figure 1A and BGo).





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  		Fig. 1. GSTM1, GSTM3 and GSTT1 genotype determination. (A) First step of the GSTM1 analysis. Identification of GSTM1-nulled and GSTM1-positive individuals (see Materials and methods for details). The presence of at least one functional GSTM1 allele is manifested by successful amplification of a 149 bp fragment. A 122 bp fragment reflects co-amplification of GSTM4, which is never deleted (a perfectly homologic GSTM1 fragment of identical size is also co-amplified in GSTM1-positive samples). The absence of the 122 bp fragment indicates PCR failure. Lane 1, 100 bp ladder (MW marker); lanes 2, 5, 9, 10, 12 and 14, GSTM1-positive samples; lanes 3, 4, 6, 8, 11, 13 and 15, GSTM1-nulled samples; lane 7, amplification failed. (B) Second step of the GSTM1 analysis applied only to GSTM1-positive individuals. Discrimination between GSTM1*A and GSTM1*B after BsrSI digestion (see Materials and methods for details). The presence of unrestricted 149 and 122 bp fragments is diagnostic for GSTM1*A. A 127 bp fragment is characteristic of GSTM1*B. Lanes 1, 7, 9 and 12, *A/*A or *A/0; lanes 2, 3, 4, 6, 8, 10 and 11, *B/*B or *B/0; lane 5, *A/*B. (C) Simultaneous determination of GSTM3 and GSTT1 variants by multiplex PCR (see Materials and methods for details). Lanes 2, 4, 6, 9, 10 and 12, GSTM3 *A/*A, GSTT1-positive; lane 5, GSTM3 *A/*A, GSTT1-null; lanes 1, 3 and 11, GSTM3 *A/*B, GSTT1-positive; lane 7, GSTM3 *A/*B, GSTT1-null; lane 8, GSTM3 *B/*B, GSTT1-positive. Note: all GSTM3 heterozygotes consistently displayed two `shadow' fragments of lower intensity migrating slightly slower in polyacrylamide gels. This pattern could be generated by heterodimer formation due to the abundance of highly homologic fragments of unequal size corresponding to the two gene alleles at the end of amplification.

 
Assessment of the GSTM3 and GSTT1 polymorphisms was performed using a four primer multiplex PCR. Combination of primers AL57 and AL58 provided amplification of an intron 6 fragment of GSTM3, which is always present, being either 79 (GSTM3*A allele) or 76 bp (GSTM3*B allele). The presence of GSTT1 was determined by amplification of a 70 bp fragment of this gene. The following primers were used in these reactions: GSTM3-specific sense (AL57), 3'-GGGGAAAAGGTAGGAAGAAGGGAA-5'; GSTM3-specific antisense (AL58), 3'-GATGCTTAGGTCTGAGGAGTAGTA-5'; GSTT1-specific sense (AL43), 3'-TCCAGGAGGCCCATGAGGTCA-5'; GSTT1-specific antisense (AL44), 3'-TTCTGCTTTATGGTGGGGTCT-5'. Thirty-seven amplification cycles with 45 s denaturation at 94°C and 45 s annealing/extension at 61°C were applied. Amplified fragments were separated by electrophoresis in 10% polyacrylamide gel (Figure 1CGo). The GSTP1 nucleotide 313 (or Ile/Val105) polymorphism analysis was performed by amplification of a 176 bp fragment using primers described by Harries et al. (13) using the same two-step amplification protocol as for GSTM3 and GSTT1. The PCR product was digested with 3 U BsmAI (New England Biolabs, Hitchin, UK) at 55°C for 2 h. The resulting fragments were visualized on precast 4% agarose gels (Invitrogen, Groningen, The Netherlands), and the presence of variants GSTP1*a (Ile105) and GSTP1*b (Val105) (6) was assessed.

Distributions of genotype frequencies were calculated for each gene for the two main study groups and for those with proximal and distal cancers separately. These calculations were also done separately for men and women. Genotype frequency distributions for the GSTT, GSTM3 and GSTP1 genes were calculated separately for all GSTM1-nulled participants of the study. Genotype frequency distributions were also calculated in the case group according to the Dukes' stages of tumours. Odds ratios (OR) and 95% confidence intervals (CI) for the effects of individual genotypes and genotype combinations were calculated by unconditional logistic regression using the SPSS statistical package, version 6.1 for the Macintosh (SPSS, Chicago, USA). Odds ratios were adjusted for age (<60 and >60), gender and smoking status. Only those who reported active smoking within 10 years before participation in the present study or colorectal cancer diagnosis were classified as smokers.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
The characteristics of the study groups are given in Table IGo. There were more male subjects among both cases and controls. Mean age in the cancer group was higher; however, in many cancer cases large tumours (over 10 cm in diameter) were diagnosed apparently after at least several years of undetected growth. Relatively few study participants were smokers with the highest percentage of smokers among male cancer patients. Prevalence of smoking among the participants of this study was in good accordance with previously published data obtained for similar age groups in the same region of the UK (26). No statistically significant effect of smoking on colorectal cancer risk was revealed (data not shown).


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  		Table I. Characteristics of the study groups including clinical and pathological characteristics of colorectal tumours
 
Analysis of distribution of cancers of different locations in the case group showed that most of them were found within the distal segment of the large bowel, rectosigmoid region being site of 66.5% of all tumours. This distribution pattern of colon tumours is known to be typical for developed countries (27). Assessment of the Dukes' stages showed that in most cases, B or C stages were present. Nevertheless in 18% of cases a prognostically favourable A stage was revealed. It should be noted that 10 Dukes' A cancer cases included in this series were detected by flexible sigmoidoscopy among the participants of the Flexible Sigmoidoscopy Screening Trial that provided all controls. Negative results of the flexible sigmoidoscopy in all control subjects allowed us to completely rule out any asymptomatic tumours distal to the splenic flexure among the controls, whereas a possibility of silent tumours located in the proximal colon could not be excluded.

The genotype frequencies observed in all groups of the study are presented in Table IIGo. GSTM1 analysis has shown that the majority of the study participants displayed the homozygous deletion of the gene (58.6% in the control group and 64.6% among cancer patients). The proportion of individuals with GSTT1-null genotype was much lower, but it was slightly higher in the cancer group as well (Table IIGo). Individuals with the GSTM3*B allele present were found more frequently among cancer patients; however, an obvious difference existed between proximal and distal cases. GSTM3 allele distribution in the proximal cancer group was very similar to the controls, whereas distal cancer patients showed a visibly higher frequency of the GSTM3*A/*B heterozygotes (Table IIGo). Numbers of GSTM3*B/*B homozygotes were low in all study groups. Distributions of the GSTP1 alleles in the cases and controls were very similar (Table IIGo).


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  		Table II. Distribution of the GST genotypes among healthy controls and colorectal cancer patients
 
As expected, we were able to observe a strong linkage between GSTM1*A and GSTM3*B alleles, which has previously been described (2,11,12). Table IIIGo shows that in both study groups over 50% of subjects with *A/*A or *A/*0 GSTM1 genotype had at least one GSTM3*B allele present. In contrast, among subjects with both GSTM1-null and GSTM1*B/*B or *B/*0 variants the proportion of GSTM3B-positive subjects varied between 12.2 and 32%, with much lower percentages among healthy controls and proximal cancer patients compared with the distal cancer group. No individuals with a combination of GSTM1-null and GSTM3 *B/*B were found among controls and proximal cancer patients, whereas this variant was detected in two male patients with distal tumours.


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  		Table III. Distribution of the GSTM3 genotypes among healthy controls and colorectal cancer patients with different GSTM1 variants
 
Table IVGo demonstrates OR estimates for the presence of the particular GST genotypes and genotype combinations in colorectal cancer patients compared with healthy controls. It is evident from the results that proximal and distal tumours appear to be differently associated with the GST gene family polymorphisms. The GSTM1-null genotype was associated with a non-significant OR increase in the distal cancer group, but no association was revealed in the proximal cancer group. Slightly increased OR values were observed for the GSTT1-null variant in patients with both proximal and distal cancers, but these differences did not reach statistical significance either. GSTP1 codon 105 polymorphism also did not affect risk of colorectal tumour development. Analysis of the presence of the GSTP1*b variant associated with the low activity of the corresponding enzyme (13) showed no significant difference between cases and controls (Table IVGo).


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  		Table IV. Odds ratios for the presence of different GST genotypes and genotype combinations in colorectal cancer patients in comparison with healthy controls (95% confidence intervals are given in brackets)
 
The most interesting results were obtained with the GSTM3. Even initial separate analysis of the intron 6 polymorphism of this gene revealed significantly elevated OR values among patients with distal cancers (OR = 1.77; 95% CI 1.15–2.74). It was suggested that the effect could be partially masked by the linkage between GSTM1*A and GSTM3*B (Table IIGo). For this reason we decided to repeat our analysis regarding the combination of GSTM1-null with GSTM3*B as a distinct genetic variant. Statistically significant associations were revealed between the presence of this allele combination and distal cancers, whereas proximal cancers did not seem to be related to the polymorphisms at all. When the combination of GSTM1-null with GSTM3*B was analysed as a distinct genetic variant, 23.6% of male patients with distal cancers were shown to have it, whereas it was found in only 8.0% of control males. The OR of 3.57 (95% CI 1.73–7.36) reflected this phenomenon. The odds ratios for female patients were lower, and they did not reach statistical significance (Table IVGo). In contrast, the combination of active GSTM1*B (*B/*0 or *B/*B genotype) with GSTM3 *A/*A variant appeared to be underrepresented in distal cancer patients. Again, the difference was more pronounced in males with only 5.7% of male distal cancer patients displaying this combination, its frequency among controls being 18.1% (OR = 0.37; 95% CI 0.15–0.92). No difference between the groups was found when combined presence of the GSTM1*A (*A/*0 or *A/*A genotype) and GSTM3 *A/*A was assessed. Similar results were obtained in logistic regression analyses including and excluding smoking as a covariate.

We also analysed the relationship between GST allele distributions and the Dukes' stage of tumours, but failed to reveal any statistically significant associations (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
The present study was undertaken to assess the possible effects of both individual gene polymorphisms and polymorphism combinations within the GST family on colorectal cancer risk. The subjects of the study represented a well-characterized, ethnically-homogenous Caucasian population, which has recently been used to establish a cohort of 25 000 men and women aged 45–74 for the European Prospective Investigation of Cancer (EPIC) project (26).

The analysis of the GST gene family allele distribution patterns in the control group showed that they were within the range characteristic of Caucasian populations repeatedly reported elsewhere (1–5,7–16,18,21,22). These distributions appeared to be slightly shifted in the cancer group for all GTSs with the exception of GSTP1. We observed weak trends showing non-significantly increased ORs for GSTM1 and GSTT1 null-genotypes in association with the presence of both proximal and distal colon cancers. No information on the role of GSTM3 in colorectal cancer is currently available. Our initial analysis has shown that the GSTM3*B allele presence was associated with distal tumours, whereas no detectable effect on proximal cancers was observed. It was evident that these results could be affected by the linkage between GSTM1*A and GSTM3*B (2,11,12,21), which was clearly observed among the subjects of the present study (Table IIIGo). To eliminate any bias caused by interference between the active alleles of the two genes we performed a separate analysis of the 341 GSTM1-nulled subjects constituting the majority among the study participants (208 controls and 133 colorectal cancer patients). The effect of the presence of the GSTM3*B allele in the GSTM1-nulled individuals was stronger, and again it was detected only for the distal cancers (Table IVGo). Proximal tumours did not show any association with the polymorphism. Unfortunately we were unable to assess the role of GSTM3 *B/*B homozygosity combined with the GSTM1-null variant due to very low number of individuals with this combination. It should be noted, however, that subjects with this genotype were detected only among distal cancer patients (Table IIIGo).

Although the ORs for female patients were visibly lower than in males, they were always in accordance with the trends found in males. Lack of statistical significance here seems to result primarily from considerably lower numbers of females in the study groups (Table IGo). Differences between males and females may also be related to gender-associated expression patterns of the GST family enzymes (28,29) or the influence of sex hormones, importance of which for GST regulation is well established in rodent models (30–32). Lifestyle factors should also be considered. Among the latter smoking does not appear to be a likely candidate since we did not observe any substantial effect of this factor on the results. Dietary influences may be of great importance, and it is intriguing that more pronounced effect of potentially cancer-protective vegetable diets on GST activity in women compared with men has recently been reported (33).

The combination of GSTM1*B (*B/*0 or *B/*B genotype) with GSTM3 *A/*A variant appeared to be associated with some protective effect in distal cancer patients. While GSTM1*A and GSTM1*B show identical catalytic activity in vitro, there appears to be differences in the protection against colorectal carcinogenesis provided by the two forms, and the basis of this remains unclear (2,34). Moreover, the functional interactions between GSTM1 and GSTM3 are still obscure. Our findings do not allow us to make reliable conclusions on this protective effect due to the low number of patients with this allele combination, and also because of the uncertainty regarding GSTM1 homo- or hemizygosity.

The results show the existence of an interaction between GSTM1 and GSTM3 in terms of influence on colorectal tumor risk, whereas GSTT1 polymorphism was associated with a very weak trend, most probably acting independently, and GSTP1 variants had no effect at all. Unfortunately our analysis did not include positive identification of the hemizygous GSTM1 variants *A/*0 and *B/*0 and GSTT1 hemizygotes. In the course of this study we attempted to assess the presence of *A/*0 and *B/*0 GSTM1 hemizygotes among GSTM1-positive subjects by measuring relative intensities of amplification of the two products of our three primer reaction using the co-amplified GSTM4 fragment as an internal standard. The approach was similar to that recently described by Charrier et al. (35), but we failed to obtain consistent results in some cases and eventually abandoned it. We are planning to resolve the problem by applying recently described approaches of positive identification of GSTM1-null and GSTT1-null alleles by long PCR (36,37).

Our findings indicate that the presence of the GSTM3*B allele can be regarded as another risk factor for the development of distal colorectal cancer, especially in GSTM1-nulled subjects. The mechanism of this effect is unclear, albeit it can be hypothesized that the presence of an additional recognition site for the YY1 multifunctional transcription factor in the GSTM3*B sequence is of importance. It is well known that YY1 can both repress and activate transcription; however, molecular mechanisms controlling its behaviour are complex and still not completely understood (19). The long GSTM1 deletion combined with the GSTM3*B allele possessing the YY1 site may result in serious structural and functional changes both within and around the GSTM locus. Recent observations of lower levels of GSTM3 expression in GSTM1-nulled individuals (34) suggest that interactions between GSTM genes are indeed important. The possible contribution of presently unknown additional genetic factors linked to the GSTM gene variants should also be taken into account. It is obvious that further investigations are needed to clarify these mechanisms.

This is the first report linking the GSTM3 gene polymorphism with colorectal cancer risk. Our initial observations highlight the possibility of important colorectal cancer risk-modulating interactions between different variants of the two closely associated members of the GSTM gene cluster located on chromosome 1. The effect appears to be confined to the distal colon, i.e. rectosigmoid region, which is the most common site of colorectal cancers. Therefore our findings can also reflect etiopathogenetic differences between carcinogenesis of the proximal and distal colon. Although the results look very interesting, the number of individuals in our genotype groups were relatively low, and therefore we have to be cautious with our conclusions. Larger-scale molecular epidemiological studies are required to both confirm associations found in this study and comprehensively investigate genotype interactions within the GST gene family.


   Notes
 
2 To whom correspondence should be addressed Email: asl{at}mrc-dunn.cam.ac.uk Back


   Acknowledgments
 
This study was made possible through an MRC Strategic Trials Grant for the UK Flexible Sigmoidoskopy Screening Trial.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received November 24, 2000; revised March 6, 2001; accepted March 8, 2001.


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