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Table of Contents   
ORIGINAL ARTICLE  
Year : 2017  |  Volume : 10  |  Issue : 6  |  Page : 1529-1532
Genetic polymorphism of glutathione S-transferase A1 promoter in patient with colorectal cancer


1 Department of Biochemistry, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
2 Department of Mycology and Parasitology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran

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Date of Web Publication11-Jan-2018
 

   Abstract 


Background: Novel allelic variants have been found in the glutathione S-transferase(GST) A1 gene. The former GSTA1 B allele is associated with low expression. Objective: The aim of this study was to determine the GSTA1 genotype in the Iranian patient with colorectal cancer and determine if there is any populational correlation between genotype and colorectal cancer in Kermanshah-Iran and Tehran-Iran individuals. Material and Methods: Atotal of 186 participants were included in the study, 52 Tehranian and 41 Kermanshahian patients with colorectal cancer, plus 52 Tehranian and 41 Kermanshahian healthy controls. GSTA1 genotype was determined by polymerase chain reaction-restriction fragment length polymorphism. Differences in genotype distributions between the different populational groups were evaluated us in Chi-squared test and a logistic regression was used to investigate the possible association of the genotypes with the disease in both populations. Odds ratio estimates were analyzed for allele frequencies. Results: The GSTA1 B/B genotype prevalence in patients with colorectal cancer(12.2%) was significantly higher than control group in Kermanshah(0.0%), No significant association of GSTA1 B/B genotype with the colorectal cancer was determined in Tehran subjects. No significant association of GSTA1 B/A genotype with the colorectal cancer was determined either population. Conclusion: These findings indicate that the GSTA1 B/B genotype in the Kermanshah population was related to colorectal cancer although there is no significant association between of GSTA1 B/B genotype and colorectal cancer in Tehran population. This study showed different results between populations.

Keywords: Glutathione S-transferase A1 promoter, polymorphism, colorectal, cancer

How to cite this article:
Nomani H, Nazari N. Genetic polymorphism of glutathione S-transferase A1 promoter in patient with colorectal cancer. Ann Trop Med Public Health 2017;10:1529-32

How to cite this URL:
Nomani H, Nazari N. Genetic polymorphism of glutathione S-transferase A1 promoter in patient with colorectal cancer. Ann Trop Med Public Health [serial online] 2017 [cited 2018 Aug 15];10:1529-32. Available from: http://www.atmph.org/text.asp?2017/10/6/1529/222663



   Introduction Top


Colorectal cancer is the fourth most common cancer worldwide; however, the incidence of this disease is much greater in developed countries than in other parts of the world.[1] Recent results from large prospective studies have indicated that exposures to mutagenic heterocycles and oxidative stress in the diet and smoking cigarettes are positively associated with the risk of developing colorectal cancer.[2] The ability to withstand toxic chemicals and oxidative stress is essential for the survival of all organisms. Various mechanisms have evolved to protect cells against foreign compounds and reactive oxygen species. The compounds against which they provide protection can induce a number of genes encoding proteins involved in these processes, thereby enabling cells to survive exposure to harmful xenobiotics as well as oxidants.

Glutathione S-transferase(GSTs) enzymes are involved in the metabolism of xenobiotics that include environmental carcinogens, reactive oxygen species, and chemotherapeutic agents.[3] Due to the detoxifying action, it has been suggested that these enzymes play an important role in cancer susceptibility.[4] Human GSTA1 has been shown to be effective GSTs in detoxifying the reactive mutagenic heterocycles and oxidative stress.[5] It has been described a polymorphism in the promoter region of the hGSTA1 gene that predicts the levels of hepatic expression of hGSTA1 expression.[6] Since hepatic detoxification of reactive metabolites of heterocyclic amines via ester reduction with glutathione could reduce exposure to carcinogenic species in the colorectal tissue.[7] In addition, most studies have identified different effects of biologic and genetic factors on diseases between different populational groups.[8] The genetic polymorphisms in human GSTM1, P1, and T1 have been associated with race, disease risk, and outcome of some cancers.[9]

To determining any populational correlation between genotype and colorectal cancer, we examined the hGSTA1 genotype in patients with colorectal cancer in Kermanshah-Iran and Tehran-Iran individuals.

Objective

The aim of this study was to determine the GSTA1 genotype in the Iranian patient with colorectal cancer and determine if there is any populational correlation between genotype and colorectal cancer in Kermanshah-Iran and Tehran-Iran individuals.


   Materials and Methods Top


Study subjects and data collection

A total of 186 individuals were included in the study, 52 Tehranian and 41 Kermanshahian patients with colorectal cancer, plus 52 Tehranian and 41 Kermanshahian healthy controls. Cases were diagnosed with histological confirmed of colorectal cancer and colorectal subjects per case were selected, matched on race, sex, and age. Blood samples were collected from these individuals and used for genomic DNA isolation. Hospital records were used to verify patient's data, and the study protocol conforms to the ethical guidelines of the 1975Declaration of Helsinki as reflected in the guidelines of the Medical Ethics Committee, Ministry of Health, Iran.

Laboratory methods

Genomic DNA for the present study was isolated and processed from lymphocytes using the salting-out protocol modified from Miller et al. and the base change C-69T in the hGSTA1*B allele was detected by polymerase chain reaction(PCR) and restriction fragment length polymorphism as described by Coles et al.[6] Briefly, PCR amplification was performed using Taq DNA polymerase(Roche Diagnostics Ltd., Penzberg, Germany). The resulting product was exposed to the restriction endonuclease Ear I(New England Biolabs, Beverly, MA, USA) and the digested fragments were resolved using 1.5% agarose gel electrophoresis.

Statistical analysis

To calculate the odds ratios(ORs) and 95% confidence intervals(CIs), theSPSS for Windows(version16, IBM Corporation, Armonk, New York, US) statistical package was used for all statistical comparisons. Differences in genotype distributions between the different populational groups were evaluated using Chi-square test, and logistic regression was used to investigate the possible association of the genotypes with the disease in both populations. The data obtained were analyzed. P=0.05 was considered statistically significant.


   Results Top


The distribution of demographic variables for cases and controls is summarized[Table1]. The patient group and control group were not significantly different with respect to age and sex distribution. Among Tehran patients, 48.1%(25) were homozygous GSTA1A/A, 51.9%(27) were heterozygous GSTA1 A/B, and 0%(0) were homozygous GSTA1 B/B compared to 51.92%(27) were homozygous GSTA1A/A, 46.15%(24) were heterozygous GSTA1 A/B OR(95% CI: 0.89–1.03) and 1.92%(1) were homozygous among Tehran control group.
Table 1: Demographics of the study population

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Among Kermanshah patients, there were 39.02%(16) homozygous GSTA1 A/B compared to 46.78%(20) heterozygous GSTA1 A/B in the control groupOR(95% CI: 0.89-1.04) and 12.19%(5) homozygous GSTA1 B/B compared to 0%(0) homozygous GSTA1 B/B in the control group.

Among the genetic polymorphisms tested, we found that homozygous GSTA1 B/B polymorphisms were significantly associated with the colorectal cancer in Kermanshah patients.


   Discussion Top


There are populational differences in the incidence and characteristics of colorectal cancer.[10],[11] Our objectives were to compare the frequency of the GSTA1 B/B genotype in colorectal cancer patients to that in healthy controls from two different races. The distribution of the GSTA1 B/B genotype[Table2] was significantly more frequent among Kermanshahian patients with colorectal cancer(5/41) than among Tehranian patients with colorectal cancer(0/52). In the Kermanshah subjects, GSTA1 B/B genotype has significantly associated with colorectal cancer, but in the Tehran subjects, there is no association between GSTA1 B/B genotype and colorectal cancer. The frequency of GSTA1 A/B genotype has not any association in each of these groups.
Table 2: Metabolic variations in relation to colorectal cancer

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It has demonstrated that individuals who are homozygous GSTA1 B/B, and who would be predicted to have the lowest levels of hGSTA1 expression in their livers,[6] appear to be at risk of developing colorectal cancer,[12] possibly as a result of inefficient hepatic detoxification of N-acetoxy-2-amino-1-methyl-6-phenylimidazo(4,5-b) pyridine,[7] a selective GSTA1-1 substrate. Since heterocyclic aromatic amines derived from cooked meats are thought to be etiological factors in colon carcinogenesis the hGSTA1 B allele might contribute to individual risk of colon cancer.[12] Similarly, the chemotherapeutic agents thiotepa and cyclophosphamide mustard are substrates for GSTA1. Thus, chemotherapeutic outcome may also be sensitive to hGSTA1 genotype.[13]

Many studies have shown that diet and environmental condition is factors most consistently associated with the development of this disease.[14],[15],[16] Recent results from large prospective studies have indicated that both exposures to nitrosamines in the diet and smoking cigarettes are positively associated with the risk of developing colorectal cancer[14],[17],[18]and GSTA1 is involved in the metabolic activation of nitrosamines from both of these sources.[12] Our finding before, suggest that GSTs measurement may be useful as a marker in colorectal cancer and biopsies obtained at colonoscopy can be used to measure tumor markers.[19] GSTP1 is increased in rectal adenocarcinoma compared with adjacent normal mucosa.[20] GSTp1 promoter methylation can be detected in tumor tissues, and it may serve as a new molecular diagnosis tool to aid in colorectal cancer detection and treatment in future.[21]

We have presented here the genotype distribution of one susceptibility genes of the GST family observed in samples from the Kermanshah and Tehran population in Iran. There were no statistically different distributions between control groups from Kermanshah and Tehran, but results showed significantly difference between colorectal cancer patients from Kermanshah and Tehran.

A better understanding of polymorphic chemical metabolizing genes can contribute, in the future, to preventive actions or risk assessment of humans exposed to environmental carcinogens. For this purpose, further studies are needed to obtain a more conclusive result. It is important to take into account the different characteristics and cultural contexts of each population.


   Conclusion Top


GSTA1 B/B genotype may be associated with colorectal cancer risk, a better understanding of chemical metabolizing gene distribution can contribute to risk assessment of humans exposed to environmental carcinogens in a different race.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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Correspondence Address:
Naser Nazari
Department of Mycology and Parasitology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ATMPH.ATMPH_494_17

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