Glutathione S-transferase T1 polymorphisms are associated with outcome in colorectal cancer

R. Rajagopal, M. Deakin, A.S. Fawole, J.B. Elder, J. Elder, V. Smith, R.C. Strange and A.A. Fryer *

Human Genomics Research Group, Institute of Science and Technology in Medicine, University of Keele, University Hospital of North Staffordshire, Stoke-on-Trent, Staffordshire, ST4 7PA, UK

* To whom correspondence should be addressed. Tel: +44 0 1782 554669; Fax: +44 0 1782 554646; Email: Anthony.Fryer{at}uhns.nhs.uk


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Colorectal cancer (CRC) remains a significant cause of mortality accounting for ~10% of all deaths from malignancy in the western world. Polymorphism in the glutathione S-transferase GSTT1 gene has been associated with CRC risk in some but not all studies. In this study, we examined associations between GSTT1 genotypes and CRC risk, and prognosis in 361 cases and 881 unrelated controls. GSTT1 null was associated with a small but significant increase in risk (P = 0.0006, odds ratio (OR) = 1.65, 95% confidence interval (CI) = 1.22–2.24). GSTT1 null was also associated with a significantly younger age at diagnosis (mean 65.2 years) compared with GSTT1 A (mean 67.6 years, P = 0.031). There were no significant associations between GSTT1 genotypes and clinical factors (e.g. Dukes stage, differentiation and tumour node metastasis classification) in the total case group. However, following stratification by age (<70 versus ≥70 years at diagnosis), in the patients diagnosed <70 years of age, GSTT1 null was more common in Dukes grade A/B tumours (P = 0.046), stage T1/T2 tumours (P = 0.053) and those with a pushing margin (P = 0.066). We also identified associations between GSTT1 null and increased prevalence of host lymphocyte response, particularly in the younger patients (P = 0.036). Furthermore, GSTT1 null was associated with improved survival in younger patients (P = 0.017, hazards ratio (HR) = 0.52, 95% CI = 0.31–0.89) but poorer survival in older patients (P = 0.017, HR = 1.89, 95% CI = 1.12–3.20). We proposed a model based on the dual functionality of GSTT1 to explain these contrasting results. We suggest that the null genotype is associated with improved immune response in younger patients, but poorer detoxification in older patients. These findings may also provide an explanation for the contrasting finding of other studies on the role of this gene in CRC.

Abbreviations: CI, confidence interval; CRC, colorectal cancer; GST, glutathione S-transferase; HLR, host lymphocyte reaction; HR, hazard ratio; OR, odds ratio; PCR, polymerase chain reaction; SCE, sister chromatid exchange; SD, standard deviation; TNM, tumour node metastasis


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Colorectal cancer (CRC) is the second most common cause of death due to malignancy, accounting for 11% of all malignant neoplastic deaths in England and Wales (~14 300 in 2002), and 10% in the USA (~57 100 deaths in 2003) (1,2). It is estimated that familial CRCs account for 5–15% (3), with the remainder comprising sporadic colorectal carcinoma. Disease risk is determined by an interaction between genetic and environmental factors. In this regard, genetically-determined inter-individual differences in host ability to detoxify diet-derived carcinogens may be important (4,5).

Among various candidate genes implicated in many malignant neoplasms, including colorectal tumours, are the glutathione S-transferases (GSTs). GSTs are a supergene family of phase 2 enzymes whose role has been traditionally viewed as providing protection against chemical carcinogenesis (6,7). There are at least eight classes of cytosolic GSTs. The theta class gene, GSTT1, is located on chromosome 22 (8). It has a common null polymorphism (GSTT1*0 allele) in which the entire gene is deleted (9), with an allele frequency of ~40% in Caucasians (7).

Whilst GSTT1 demonstrates in vitro catalytic activity towards a variety of exogenous and endogenous chemicals (6,7,10), its true in vivo function is unclear. However, whilst the real in vivo functions are unknown, there is ample evidence indicating the importance of GSTT1. Thus, in individuals homozygous for the GSTT1*0 allele, more chromosomal aberrations and sister chromatid exchange (SCE) have been observed after exposure to 1,3-butadiene or various haloalkanes and haloalkenes (11). SCE, in turn, has been shown to have a strong positive correlation with future cancer risk (12).

In addition to its detoxifying activity, there is also increasing evidence implicating GSTT1 in immune processes, such as those seen during inflammation, suggesting a novel role for this protein. For example, Kerb et al. (13) showed that individuals with the GSTT1 null genotype demonstrated increased T-cell mediated inflammatory response following UV exposure. Unpublished data from our laboratory have also shown that, in renal transplant recipients, the GSTT1 null genotype is associated with two immune-related endpoints: (i) higher risk of T-lymphocyte mediated acute rejection and (ii) reduced numbers of cutaneous squamous cell carcinoma (SCC) in those on low dose immunosuppressant (14). We have also shown that, in patients with rheumatoid arthritis, GSTT1 null individuals demonstrated increased levels of inflammatory markers, such as erythrocyte sedimentation rate and platelet levels (data not shown). These data suggest a possible role for GSTT1 in both T-lymphocyte mediated processes and antitumour activity. Furthermore, functional studies have shown that lipid hydroperoxides, which promote arachidonic mobilization and subsequent eicosanoid synthesis, are substrates for GSTT1 (15). Given that previous studies have shown that host lymphocyte reaction (infiltration of T cells into the tumour) is an important determinant of survival in CRC patients (16), GSTT1 null genotype may be associated with both reduced (via increased antitumour activity and T-cell infiltration) and increased (via increased rates of DNA damage) risk of CRC. The overall effect will therefore depend on the balance of these two activities in individual patients.

A number of studies have shown the GSTT1 null genotype to be associated with increased susceptibility to both CRC (721) and non-CRCs (6,7). However, other studies have failed to replicate this association (2225). Indeed, work based on a southern Italian population actually suggested a possible protective effect of the null genotype (26). Some studies have shown a specific association with risk in younger patients, particularly in those with presentation under the age of 60 (20) or 70 years (21). Though an increase in GSTT1 null frequency in distal tumours has also been shown (21), other groups have not identified an association between GSTT1 null and tumour site (17,18). The GSTT1 null frequency has also been shown to be significantly greater in poorly differentiated tumours (18). There has been one study observing the effect of GSTT1 on survival in CRC patients. This was based on 5-fluorouracil/oxaliplatin chemotherapy in patients with advanced CRC, and the GSTT1 genotypes were not associated with survival or clinical response (27).

The discrepancy in these studies may be due to racial and ethnic differences in GSTT1 null frequency (28) or heterogeneity within the case group. The latter is particularly important since there are multiple relevant variables that may confound case–control studies. Furthermore, GSTT1 may be associated with subgroups within the colorectal case group, as evident from other cancers such as basal cell carcinoma (29). Even though there is evidence to implicate GSTT1 null in the pathogenesis of colorectal carcinoma, the mechanism remains unknown and is potentially complicated by the potential multiple, contrasting functions of GSTT1. Furthermore, some studies are small and none has examined the clinical characteristics of the case group in detail.

We hypothesize that the GSTT1 null genotype is an important mediator of CRC susceptibility and outcome. In this study, we have focused on the relationship between GSTT1 genotype and clinical parameters with three principal aims: (i) to confirm (or otherwise) the previously identified associations between GSTT1 genotype and age at diagnosis, tumour location and degree of differentiation, (ii) to assess associations between the GSTT1 genotype and additional clinical parameters (Dukes' stage, survival, tumour margin morphology and host lymphocyte response) and (iii) to propose a mechanism for the observed differences between studies on the role of GSTT1 in CRC.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients
Northern European Caucasian patients with operative and histological confirmation of adenocarcinoma of the colon and rectum (n = 361, mean age ± SD 66.9 ± 11.0 years; 54.0% male) were recruited from the University Hospital of North Staffordshire and followed-up for 2–15 years. Patients were recruited in three phases: (i) 1990–1994 [n = 160, including 143 from our previous study (17)]; (ii) 1996–1998 (n = 78) and (iii) 1998–2000 (n = 123). All case notes were reviewed during the final phase. Age at operation, gender and median survival were similar between the three cohorts. Only patients with sporadic CRC undergoing potentially curative surgery were included. Blood was obtained in the pre-operative period, to reduce possibility of contamination from any subsequent blood transfusion. Unrelated controls (n = 881), with non-malignant, non-inflammatory conditions, were also recruited from the same hospital (mean age 53.9 ± 16.5 years; 40.1% male). All patients and controls were recruited with Ethical Committee approval and written informed consent.

Clinical data
Clinical details, including operative and histological data, were obtained retrospectively from case notes and histology reports from a specialist colorectal histopathologist. The following clinical data were collected: tumour site (left, right and rectum), tumour differentiation (well, moderate or poor), Dukes' stage, tumour node metastasis (TNM) classification (depth of local invasion, evidence of positive lymph nodes and their position and the presence or absence of distant metastases) (30), presence of host lymphocyte reaction (HLR), tumour margin morphology (pushing or invasive) and survival. The survival period was defined as the time interval from the date of operation to the date of death or the date last confirmed to be alive. Patients who died within 30 days of surgery were classified as peri-operative deaths, and were excluded from survival analyses.

Polymerase chain reaction
Genotyping was performed using DNA obtained from peripheral blood collected into EDTA. The GSTT1 A and null genotypes were identified using polymerase chain reaction (PCR) with primers to GSTT1 (5'-TTCCTTACTGGTCCTCACATCTC-3' and 5'-TCACCGGATCATGGCCAGCA-3') and ß-globin, which acted as an internal control. The PCR products were resolved in 2% agarose gels stained with ethidium bromide. DNA from subjects with the GSTT1 positive genotype (GSTT1*A homozygotes) produces two PCR products, 480 bp (GSTT1) and 325 bp (ß-globin). GSTT1 null subjects (GSTT1*0 homozygotes) amplified only the 325 bp (ß-globin) band. This assay does not differentiate between the GSTT1*A/GSTT1*A homozygotes and GSTT1*A/GSTT1*0 heterozygotes (9) and cannot therefore identify potential gene dosage effects.

Statistical analysis
All statistical analyses were performed using Stata, version 8.0 (Stata Corporation, Texas). {chi}2-tests were used to test for homogeneity between groups (e.g. cases versus controls and tumour location). The Armitage trend test was used to assess increasing/decreasing genotype frequencies in ordered categories (e.g. Dukes' stage). Since age at operation was not normally distributed, Mann–Whitney U-tests were used for comparisons of ages between groups. Survival analysis was performed using the Cox's regression model and survival curves were constructed using the Kaplan–Meier method.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Case–control analysis
The GSTT1 null genotype was significantly more common in cases (96/361, 26.6%) than controls (158/881, 17.9%; P = 0.0006, odds ratio (OR) = 1.65, 95% confidence interval (CI) = 1.22–2.24). This association was similar for right-sided (27/101, P = 0.032, OR = 1.67, 95% CI = 1.00–2.72), left-sided (21/87, P = 0.155, OR = 1.46, 95% CI = 0.82–2.49) and rectal (46/161, P = 0.0018, OR = 1.83, 95% CI = 1.22–2.72) tumours (Table I).


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Table I. The frequency of GSTT1 genotype according to clinical characteristics, in the total case group and stratified by age

 
Association of the GSTT1 genotype with clinical factors
In the total CRC cases, we found no significant association between the GSTT1 genotype and sex, tumour site (right, left and rectum), tumour differentiation, TNM classification and tumour margin morphology (Table I). A trend for decreasing GSTT1 null frequency with more advanced Dukes' stage was observed, but this did not achieve statistical significance (Armitage trend test; P = 0.14). A significant correlation between GSTT1 null and the presence of HLR (P = 0.013, OR = 2.54, 95% CI = 1.21–5.33) was observed in the 208 patients on whom these data were available (Table I).

When stratified by age, GSTT1 null was more common in female than male patients in the younger (<70 years) group (Table I). In this group, there was a general tendency for GSTT1 null to be associated with better outcome. Thus, GSTT1 null was more common in stage T1 and T2 tumours, grade A and B tumours and those with a pushing margin (Table I). Similar associations were not identified in older patients. Furthermore, the association of GSTT1 null with HLR in the total group was confined to younger patients (Table I).

Effect of age
Table II shows that GSTT1 null patients presented earlier than those with GSTT1 A, with a mean age at operation of 65.2 years versus 67.6 years (P = 0.031). Thus, the GSTT1 null frequency was 31.4% in those cases aged <70 years compared with 21.1% in those aged ≥70 years (P = 0.025, {chi}21 = 5.0). This difference was seen in Dukes A and B cases (63.1 years versus 68.2 years, P = 0.002), but not in those cases with Dukes C or D tumours (Table II).


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Table II. GSTT1 genotype and mean age at presentation

 
Association of GSTT1 genotype with survival
We investigated the relationship between being GSTT1 null and survival using Cox proportional hazards regression. GSTT1 null did not affect the overall survival (hazard ratios (HR) = 0.80, 95% CI = 0.55–1.16, P = 0.235). However, in younger patients (<70 years) GSTT1 null was significantly associated with increased survival (HR = 0.52, 95% CI = 0.31–0.89, P = 0.017; Figure 1A). In contrast, in older patients GSTT1 null (≥70 years) was associated with poorer survival (HR = 1.89, 95% CI = 1.12–3.20, P = 0.017; Figure 1B).



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Fig. 1. Kaplan–Meier survival curve for GSTT1 for CRC patients diagnosed (A) <70 years and (B) ≥70 years.

 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In keeping with our previous findings (17), we have shown that GSTT1 has a modest effect on susceptibility to CRC, but we failed to demonstrate any significant associations with a number of clinical parameters in the total case group. However, our data support the observation of Chenevix-Trench et al. (21) by demonstrating that the frequency of GSTT1 null is particularly increased in CRC cases diagnosed before the age of 70 years. This is supported by our finding that GSTT1 null individuals present at an earlier age than those with the GSTT1 A genotype, particularly in patients presenting with Dukes A or B tumours. When patients were stratified by age at presentation, we also demonstrated differential effects of the GSTT1 genotype on Dukes' stage, survival and host lymphocyte response.

The association between GSTT1 and CRC risk has been demonstrated in several previous studies (5,1721), though others have failed to replicate this association (2225). We believe that the data presented here present some insights into the possible reason for these discrepancies.

Age of onset appears to be a key factor in examining the effect of GSTT1 on CRC risk and prognosis. We and Nascimento et al. (20) and Chenevix-Trench et al. (21) have identified an increased GSTT1 null frequency in younger CRC patients, but none of the previous studies have suggested a reason for this finding. Our data show that GSTT1 null individuals with less advanced tumours (Dukes A and B) are more likely to present at an earlier age. We also found that there was a significant trend of decreasing GSTT1 null frequency with increasing Dukes' stage in younger patients and a similar trend with T-stage. This is consistent with Welfare et al. (23) who also showed an association between decreasing GSTT1 null frequency and increasing Dukes' stage. Furthermore, in younger patients, GSTT1 null was associated with improved survival compared with patients with GSTT1 A genotype, while in older patients GSTT1 null was associated with poorer survival.

These data may explain the discrepancies between case–control studies. If GSTT1 null is associated with early grade tumours, which present at a younger age, a higher proportion of patients with these tumours in the case group would appear to give a higher frequency of GSTT1 null in the case group compared with controls. Conversely, a generally older case group with more advanced tumours would fail to show significant differences in GSTT1 null frequency between cases and controls.

The finding of differing effects of GSTT1 null on survival and tumour stage in younger and older patients may also imply that the effect of GSTT1 null in younger CRC patients may be via a different pathogenetic process than older patients. Taken together, these data lead us to suggest the following putative mechanism for the role of GSTT1 null in CRC. We propose that GSTT1 has a dual function, in detoxication of environmental carcinogens and in modulating the immune response to tumour cells. Thus, in tumour initiation, detoxication is the critical function as highlighted by the association between GSTT1 null and susceptibility and earlier onset. In determining prognosis, the balance between the two functions is determined by patient age. In younger patients, relative to GSTT1 A, GSTT1 null is associated with increased levels of lipid hydroperoxides, which potentiate an inflammatory reaction, increase subsequent antitumour activity and result in a protective effect of this genotype. In older patients, as the immune reaction diminishes with age (31), the detoxication activity associated with GSTT1 becomes more important leading to poorer detoxication of carcinogens in GSTT1 null patients, more rapid accumulation of mutations and more rapid conversion to more advanced stage tumours, with poorer prognosis. A schematic diagram showing this putative mechanism is shown in Figure 2.



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Fig. 2. Proposed mechanism for the effect of GSTT1 genotype on CRC survival.

 
There are several lines of evidence to support this proposed mechanism. It is well established that GSTT1 null is associated with increased DNA damage (e.g. SCE) on exposure to a range of environmental carcinogens (11,12). However, the role of GSTT1 in immune regulation is less well recognized. GSTT1 utilizes the products of oxidative stress as substrates, some of which are potent chemotactic agents for lymphocytes (32). Furthermore, cells with severely damaged DNA also induce an immune response (33). Consequently, GSTT1 null would be associated with an increased recruitment of lymphocytes to the tumour. For example, in our study of SCC risk in transplant recipients, we would hypothesize that in those on low dose immunosuppressant GSTT1 null is associated with an increased antitumour activity (due to either increased SCE and activation of the immune mechanisms, or increased oxidative stress contributing to increased overall T-cell activation) relative to those on high dose prednisolone, leading to reduced likelihood of SCC development compared with GSTT1 expressing genotypes. In this study, we have shown that GSTT1 null is associated with the presence of an antitumour host lymphocyte reaction, particularly in younger patients. HLR is associated with improved survival in our patients (P = 0.001, HR = 0.38, 95% CI = 0.21–0.68), data shown elsewhere (16). In pilot studies on GSTT1 in 183 renal transplant recipients, we have shown that GSTT1 null is associated with increased risk of acute rejection, a lymphocyte-mediated response (data not shown). Furthermore, age is also an important modifier of immune response, with older individuals exhibiting a greater amount of DNA damage and mutations within lymphocytes, leading to failure or decreased rate of proliferation, and consequently to an impaired immune response (31). This effect of age on immune response, also known as immunosenescence, has been extensively studied and has led to the recent launch of a specialist journal, Immunity and Ageing, on the topic. Licastro et al. (34) have recently published a comprehensive review of the field, including its impact on cancer, and describe how T-cell activation and natural killer cell killing decreases with age. Though GSTT1 null will be expected to enhance the immune response even in older patients, this effect may be insufficient to counterbalance the negative effect of this genotype on DNA damage.

The protective effect of GSTT1 null on antitumour immunity is also shown by the finding that KRAS2 mutation frequency, which is present in ~85% of CRCs, is significantly lower in patients with this genotype compared with those with the wild-type genotype (35). KRAS may contribute to immune escape mechanisms of tumours by downregulating the antigen processing machinery, leading to more advanced stage and worse outcome (36).

The dual role of GSTT1 in CRC may account for the discrepancies seen in case–control and outcome studies with respect to the GSTT1 polymorphism. Thus, those showing a significant association between the null genotype and susceptibility may reflect a population similar to that described here, while those with no association may reflect a population of older patients with more advanced tumours where the effect of GSTT1 null is less evident. Stoehlmacher et al. (27) failed to demonstrate an association between GSTT1 genotype and survival in 107 patients with advanced CRC receiving 5-fluorouracil/oxaliplatin combination chemotherapy. This may be due to several factors, the smaller numbers of patients recruited, a wider age distribution than that seen in our study, or the association between GSTT1 null and poorer survival due to the effect of this gene on the response to chemotherapy, as shown by Howells et al. (37) in ovarian cancer patients receiving platinum-based chemotherapy.

Clearly, these speculations require further assessment in large groups of well characterized patients. As we have also used hospital-based controls, there is a possibility that our findings on susceptibility may reflect the control genotype frequencies, rather than those in the cases. However, the main message of this study comes from the examination of the case group, where the number of patients is a more significant limiting factor. Furthermore, the role of GSTT1 null in immune function has not been tested fully. Indeed, the macrophage inhibitory factor, a gene whose protein product has clear immune functions, is located downstream of GSTT1 on the chromosome 22q11.2 (38), and it is possible that the immune-related associations reflect linkage disequilibrium with variants in this gene. However, we believe that there is now sufficient evidence to warrant further examination of both the molecular epidemiology and functional aspects of GSTT1 in this context. If supported, this putative role for GSTT1 in immune function may have implications for several other diseases where GSTT1 has been implicated, particularly those where age is a significant predictor of outcome, such as breast cancer.


    Acknowledgments
 
The authors acknowledge the contribution of John White to patient recruitment. This study was supported by Nuffield Foundation studentships to R.R. and A.S.F.

Conflict of Interest Statement: None declared.


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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received March 31, 2005; revised June 27, 2005; accepted July 22, 2005.





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