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  Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 53  |  Issue : 4  |  Page : 524-528
 

Evaluation of deletion polymorphisms of glutathione S-transferase genes and colorectal cancer risk in ethnic Kashmiri population: A case–control study


1 Department of Biochemistry, University of Kashmir; Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences; Department of Clinical Biochemistry, University of Kashmir, Srinagar, Jammu and Kashmir, India
2 Department of Basic Medical Sciences, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Jeddah, KSA
3 Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India
4 Department of Surgery, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India
5 Department of Clinical Biochemistry, University of Kashmir, Srinagar, Jammu and Kashmir, India

Date of Web Publication21-Apr-2017

Correspondence Address:
F Rashid
Department of Clinical Biochemistry, University of Kashmir, Srinagar, Jammu and Kashmir
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_17_17

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 » Abstract 

AIM: Glutathione S.transferases. (GSTs) are known to play a pivotal role in the detoxification of potential carcinogens, and their gene variation may alter susceptibility to colorectal cancer. (CRC). The aim of the study was to evaluate the genetic association of GSTM1 and GSTT1 gene deletion/null polymorphism with disease susceptibility and risk development in CRC patients of ethnic Kashmiri population. MATERIALS AND METHODS: Genotype frequencies of GSTM1 and GSTT1 gene deletion/null polymorphism were compared between 160 CRC patients and 200 healthy controls using polymerase chain reaction multiplex. RESULTS: The frequency of GSTM1-null was found to be 76.2% in cases and 81.5% in controls and odds ratio. (OR) = 1.37 (95% confidence interval. [CI]: 0.82–2.28). Likewise, the GSTT1-null genotype was found in 75.5% of cases and 77.5% of controls and the OR = 1.14 (95% CI: 0.76–1.8). The overall association between the GSTM1-null and GSTT1-null polymorphism and the CRC cases was found to be insignificant (P < 0.05). However, individuals with double-null genotype (GSTM1-/GSTT1-) were found to have 3.5-fold increased risk for the development of CRC. Further, the risk genotype (null) of GSTT1 was found to be associated with tumor grade (P = 0.001) and GSTM1 (null) genotype was significantly associated with smoking status (P = 0.004), when compared to the (present) genotype in CRC cases. CONCLUSION: Our results suggest that GSTM1 and GSTT1 gene deletion/null gene polymorphisms are not a key modulators of the risk of developing CRC in Kashmiri population.


Keywords: Colorectal cancer, GSTM1, GSTT1, Kashmir, polymerase chain reaction multiplex, polymorphism


How to cite this article:
Nissar S, Sameer A, Rasool R, Chowdri N, Rashid F. Evaluation of deletion polymorphisms of glutathione S-transferase genes and colorectal cancer risk in ethnic Kashmiri population: A case–control study. Indian J Cancer 2016;53:524-8

How to cite this URL:
Nissar S, Sameer A, Rasool R, Chowdri N, Rashid F. Evaluation of deletion polymorphisms of glutathione S-transferase genes and colorectal cancer risk in ethnic Kashmiri population: A case–control study. Indian J Cancer [serial online] 2016 [cited 2019 Aug 22];53:524-8. Available from: http://www.indianjcancer.com/text.asp?2016/53/4/524/204754



 » Introduction Top


Colorectal cancer (CRC) represents the third most common malignancy worldwide and the second leading cause of cancer-related death in many parts of the Western world.[1] It is the third most common cancer in men and the second most common cancer in women worldwide.[2] In Kashmir valley, CRC has been reported to be the third most common gastrointestinal cancer [3],[4],[5],[6] after esophageal and gastric cancer.

Glutathione S-transferases (GSTs) are the important multigenic family of Phase II drug-metabolizing enzymes which catalyze the conjugation of an electrophilic species of a large variety of endogenous and exogenous compounds, including carcinogens and xenobiotic as well as their metabolites with reduced glutathione leading to the elimination of toxic compounds.[7]

Human GSTs are divided into three main families: Cytosolic, mitochondrial, and membrane-bound microsomal. The cytosolic and mitochondrial GSTs are soluble enzymes with three-dimensional fold structural similarity, whereas microsomal GSTs designated as “membrane-associated proteins in eicosanoid and glutathione metabolism” are structurally distinct from cytosolic GSTs but are functionally similar in the ability to catalyze the conjugation of glutathione to electrophilic compounds.[7] There are at least seven distinct classes of cytosolic GSTs, namely, alpha (A), mu (M), pi (P), sigma (S), zeta (Z), omega (O), and theta (T), based on differences in amino acid sequence, and each gene is mapped on different chromosomes.[7],[8]

GSTM1 is one of the genes encoded by a 100kb gene cluster located on chromosome 1p13.3, encoding the mu class of enzymes and has three polymorphisms.[9] One polymorphism is a deletion that results in a lack of functional gene product (GSTM1-null). The other two, GSTM1*A and GSTM1*B, differ by a C519G substitution, resulting in asparagine to lysine substitution at amino acid 173.[10]

GSTT class consists of two genes, GSTT1 and GSTT2, located at 22q11.2 and separated by about 50-kb.[11] Similar to GSTM1, the most common genetic variant in GSTT1 consists of a deletion of the whole gene, resulting in the lack of active enzyme.[12] Another less common polymorphism (rs11550605) results in a threonine to proline substitution at amino acid 104.[13]

GST gene polymorphisms are mostly associated with a lack or an alteration of enzymatic activity toward several substrates,[7],[14],[15] thus with increased CRC susceptibility.[16],[17],[18],[19] In the case of GSTT1-null, which occurs at frequencies of 11%–38% in different populations, 50 kb of genomic sequence containing the entire gene is deleted. While for the GSTM1- null, variable frequencies have a range of 20%–70%, involving a 15kb sequence deletion.[8],[20],[21]

In the present case–control study, we determined the genotypic frequency of the GSTM1-null and GSTT1-null polymorphism in CRC patients to substantiate its association with CRC risk in the sample of Kashmiri population.


 » Materials and Methods Top


Subjects

This study included 160 consecutive primary CRC patients. All CRC patients were recruited from the Department of Surgery, Sher-I-Kashmir Institute of Medical Science. Tumor types and stages were determined by two experienced pathologists. Blood samples of 200 age- and sex-matched cases with no signs of any malignancy were collected for controls. The mean age of both patient and control groups was 55 years.

Data on all CRC patients were obtained from personal interviews with patients and/or guardians, medical records, and pathology reports. The data collected included sex, age, dwelling, tumor location, Dukes stage, and lymph node status. All patients and/or guardians were informed about the study and their will to participate in this study was taken on predesigned questionnaire (available on request). The collection and use of tumor and blood samples for this study were previously approved by the appropriate Institutional Ethics Committee.

DNA extraction and genotype analysis

DNA extraction was performed using ammonium acetate method. The extraction product was stored at −20°C. 2.5 μL of DNA was used as the template for each polymerase chain reaction (PCR). Genotype analysis of GSTM1 and GSTT1 gene was performed by the PCR multiplex using previously described primers.[22] Primers: GSTM1 _R 50-GTT GGGCTCAAATATACGGTGG-30; GSTM1 _F 5'-GAACTCCCTGAAAAGCTAAAGC-3' and GSTT1_R 5'-TCACCGGATCATGGCCAGCA-3'; GSTT1_F 5'-TTCCTCACTGGTCCTCACATCTC-3'. The GSTM1 fragment was 215 bp, and the GSTT1 fragment was 480 bp. Each set of reaction included both positive and negative controls. The multiplex PCR method was used to detect the presence or absence of the GSTT1 and GSTM1 genes in the genomic DNA samples, simultaneously in the same tube. Briefly, PCR was carried out in a final volume of 25 μL containing 50 ng genomic DNA template, 1X PCR buffer with 2 mM MgCl2, 0.5 μM of each primer, 50 μM dNTPs, and 0.5 U DNA polymerase. For PCR amplification, the standard program was used as follows: One initial denaturation steps at 94°C for 7 min, followed by 35 denaturation cycles of 1 min at 94°C, 1 min of annealing at 58°C, and 1 min of extension at 72°C, followed by a final elongation cycle at 72°C for 10 min. The PCR products were electrophoresed in 2% agarose gels and visualized by ethidium bromide staining. DNA from samples positive for GSTM1 and GSTT1 genotypes yielded bands of 215 and 480 bp, respectively.

Quality control

The quality control included the assessment of genotyping errors including the false estimates of a particular allele frequency and the evaluation of the reproducibility of the genotyping done. For these assessments, approximately 10% of the patient and control samples selected randomly were re-genotyped. In addition, in each PCR-restriction fragment length polymorphism setup, previously amplified and genotyped samples representing different genotypic scenarios were included as a reference control.

Statistical analysis

The observed frequencies of the above genotypes in patients with CRC were compared with the control using Chi-square or Fisher's exact test when the expected frequencies were small. The Chi-square test was used to verify whether the genotype distributions were in Hardy–Weinberg equilibrium. Statistical significance was set at P< 0.05. Statistical analyses were performed using SPSS version 22 software (Armonk, NY).

The effective sample size and the statistical power were computed using the “Genetic Power Calculator” developed by Purcell et al. (2003) (http://pngu.mgh.harvard.edu/~purcell/gpc/).[23] The statistical power of 80% is widely used in genetic association studies to avoid Type II errors and to determine a cost-effective sample size under the assumption of 10%–25% variant allele frequency, 1:1 case–control ratio, and 5% Type I error rate (α). We obtained a healthy power score of about 85% for the single nucleotide polymorphism under the study in our case–control study design, with 160 case subjects and 200 control subjects.


 » Results Top


A total of 160 cases and 200 control subjects were included in this study with prior consent. All of the cases presented constipation and bleeding per rectum as their chief complaint. Furthermore, out of 160 confirmed cases of CRC, 96 cases were male and 64 cases were female, 88 were rural and 72 were urban, 70 had carcinoma in colon and 90 in rectum, and 73 were smokers and 87 nonsmokers [Table 1]. The mean age of patients having confirmed CRC was 55 years. Among controls, 102 were male and 98 were female. No significant gender- or age-related differences were observed between the study groups (P > 0.05).
Table 1: Frequency distribution analysis of selected demographic and risk factors in colorectal cancer cases and controls

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Among the 360 subjects (160 cases and 200 controls), the frequency of GSTM1- null was found to be 76.2% in cases and 81.5% in controls and odds ratio (OR) = 1.37 (95% confidence interval [CI]: 0.82–2.28). Likewise, the GSTT1-null genotype was found in 75.5% of cases and 77.5% of controls and OR = 1.14 (95% CI: 0.76–1.8) [Table 2]. The overall association between the GSTM1- and GSTT1-null polymorphism and the CRC cases was found to be insignificant (P < 0.05). GSTM1- and GSTT1-null genotypes were similar for cases and controls.
Table 2: Genotype frequencies of GSTM1 and GSTT1 gene polymorphism in colorectal cancer cases and controls

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The distribution analysis for the both GSTT1 and GSTM1 genotypes showed a low frequency of individuals for both case and control groups (5% and 1.5%, respectively) who had a double-null genotype (GSTM1−/GSTT1−) and a higher prevalence of individuals with a double present genotype (GSTM1+/GSTT1+) for both groups (56.2% and 60.5%, respectively). Furthermore, there was no significant difference in any of the genotype combinations. However, individuals with double-null genotype (GSTM1−/GSTT1−) were found to have increased risk for development of CRC (OR = 3.5, 95% CI: 0.9–13.8) [Table 3].
Table 3: Distribution frequencies of genotype combination between GSTM1 and GSTT1 gene polymorphism in colorectal cancer cases and controls and risk analysis

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Despite the fact that GST deletion polymorphisms did not have any CRC susceptibility, the influence of GSTT1 and GSTM1 deletion on clinicopathological variables was analyzed in the group of patients that were studied by comparing individuals with null and present genotypes. It was found that the risk genotype (null) of GSTT1 is associated with tumor grade (P = 0.001) and GSTM1 (null) genotype was significantly associated with smoking status (P = 0.004), when compared to the (present) genotype in CRC cases [Table 4] and [Table 5].
Table 4: Association of GSTM1 genotypes with various clinicopathological variables in colorectal cancer patients

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Table 5: Association of GSTT1 genotypes with various clincopathological variables in colorectal cancer patients

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 » Discussion Top


The present hospital-based case–control study was conducted to investigate the possible role of GSTM1 and GSTT1 gene deletion/null polymorphisms and their relation with the risk of CRC in ethnic Kashmiri population.

Xenobiotic-metabolizing enzymes, GSTs constitute an important line of defense against a variety of carcinogens. The genetic variants thus can be more or less efficient in metabolizing carcinogen, thereby contributing to individual disease susceptibility depending on the substrate metabolized. Several studies have shown influence of GSTs polymorphism in cancer susceptibility due to their role in modulation of the biological effects of the carcinogens. Furthermore, the relation between genetic polymorphisms of GSTs and cancer risk has been studied thoroughly, demonstrating either positive or negative relation between the GST polymorphisms and CRC.[24]

GST gene polymorphism may exert an effect on the functioning of GST enzymes through the change in both the level of gene expression and activity of the protein itself. In this way, it has an influence on the possibility of detoxification of carcinogens, and consequently, the level of DNA damage; thus, it may have an indirect effect on the risk of development of cancer.[25]

For GSTM1-null genotype, the frequencies are higher in Caucasians (34%–58.3%), Asians (47.6%–56.2%), and Arabs (44%–56.3%) than in Africans (17%–46.7%) and in native Latin-American populations (0%–43%). GSTT1-null genotype is lower in Caucasians, South American natives (0%–38.2%) and increases significantly in Asian populations (64.4%) and similar frequencies among Arabian and African descendants.[26]

A meta-analysis by Economopoulos and Sergentanis [27] observed that GSTM1-null allele carriers exhibited increased CRC risk in Caucasian populations (pooled OR = 1.150, 95% CI: 1.060–1.248, and random effects), whereas no significant association was detected for Chinese subjects (pooled OR = 1.025, 95% CI: 0.903–1.163, and fixed effects). Similarly, GSTT1-null allele carriers exhibited increased CRC risk in Caucasian populations (pooled OR = 1.312, 95% CI: 1.119–1.538, and random effects) whereas no significant association in Chinese subjects was observed (pooled OR = 1.068, 95% CI: 0.788–1.449, and random effects). GSTM1- and GSTT1-null genotypes confer additional risk for CRC in Caucasian populations.

Wang et al., 2011[28] conducted a study which confirmed that the GSTM1-null genotype is significantly related to an increased risk of rectal cancer and the GSTT1-null genotype to an increased risk of colon cancer. In addition, it was suggested that the concomitance of polymorphism in three genes, GSTM1, GSTT1, and GSTP1, may be an important factor predisposing to the development of CRC in the Hindu population.

In our study, we found the frequency of GSTM1- null to be 76.2% in cases and 81.5% in controls and GSTT1-null genotype to be 75.5% in cases and 77.5% in controls. The overall association between the GSTM1- null and GSTT1-null polymorphism and the CRC cases was found to be insignificant (P < 0.05). Further individuals with double-null genotype (GSTM1−/GSTT1−) were found to have 3.5-fold increased risk for development of CRC.

We did not find any association between GSTM1 polymorphism and CRC risk. Despite some divergence in the literature data, our findings are in accordance with many other studies [17],[18],[29],[30] which also revealed no association. On the contrary, Sachse et al.[16] found a significant association between GSTM1-null genotype carriers and an increased CRC risk. Similarly, Cotterchio et al.[31] confirmed that GSTT1 gene polymorphism significantly modified the relationship between the consumption of red meat and CRC risk, while GSTM1 gene polymorphism did not change this risk. The association between GSTM1-null genotype carriers and a reduced risk of CRC may be related to their role of in the disposition of isothiocyanates, breakdown products of glucosinolates, which are abundant in cruciferous vegetables, and strong inducers of the GSTs and other detoxification enzymes. The GSTM1-null polymorphism, associated with reduced enzyme activity, may result in longer circulating half-lives of inverse transition cycling and potentially greater chemopreventive effects of cruciferous vegetables,[32] thereby contradicting the primary hypothesis whereby the GSTM1-null genotypes are eventually at higher cancer risk due to lower capacity carcinogen disposition.

We found no significant association between the GSTT1-null genotype and CRC risk. The lack of association is in agreement with the results found in many other studies.[18],[29],[30] However, the meta-analysis by de Jong et al., 2002[17] and Butler et al., 2001[33] are reported the opposite findings. Furthermore, the relation between genetic polymorphisms in GSTs and cancer risk has been studied vividly, demonstrating either positive or negative relation between the GST polymorphisms and CRC.[24]

The deviation in results from different studies may be related to the fact that environmental or genetic factors are of fundamental importance in disease risk and may be influenced by ethnic diversity. Further, it is supposed that some populations could be more susceptible to chemical-induced carcinogenesis than others and influence of genetic determinants of cancer may be modulated by other modifying genes, specific environmental factors, other diseases as well as lifestyle which demonstrate a powerful or strong effect.


 » Conclusion Top


Our study did not find any association between GSTM1 and GSTT1 gene polymorphisms and CRC risk, thereby suggesting that these polymorphisms do not confer any additional risk for CRC in Kashmiri population.

Acknowledgments

The authors wish to thank each and every CRC patient who took part in this study and cooperated during the interview and sample collection. The authors also thank Prof. Zafar Amin Shah, Head Department of Immunology and Molecular Medicine, SKIMS, Soura for his professional help and support in carrying out this study. We also thank the head and technical staff of the operating theatre in the Department of General Surgery, Sher-I-Kashmir Institute of Medical Sciences, Kashmir who helped us with tissue procurement, and the anonymous pathologists at the Department of Pathology, Sher-I-Kashmir Institute of Medical Sciences, Kashmir for the histopathological assessment of the tumour tissues.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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