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ORIGINAL ARTICLE
Year : 2019  |  Volume : 56  |  Issue : 3  |  Page : 248-253
 

Promoter methylation and Ile105val polymorphism of GSTP1 gene in the modulation of colorectal cancer risk in ethnic Kashmiri population


1 Departments of Biochemistry and Clinical Biochemistry, University of Kashmir; Department of Immunology and Molecular Medicine, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir, India
2 Department of Immunology and Molecular Medicine, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir, India; 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, Soura, Srinagar, Jammu and Kashmir, India
4 Department of Surgery, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir, India
5 Department of Clinical Biochemistry, University of Kashmir, Soura, Srinagar, Jammu and Kashmir, India

Date of Web Publication19-Jul-2019

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


DOI: 10.4103/ijc.IJC_11_18

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 » Abstract 


BACKGROUND: Glutathione-S-transferases (GSTs) are the most important phase II enzymes of the xenobiotic pathway responsible for the detoxification of carcinogens. GSTP1 gene polymorphisms are mostly associated with a lack or an alteration of enzymatic activity toward several substrates thus resulting in increased cancer susceptibility. GSTP1 promoter methylation is also frequently associated with tumor development or poor prognosis in a wide range of tumors.
AIM: In this study, we examined the role of genetic polymorphism and promoter methylation of GSTP1 gene in the context of modulation of risk of colorectal cancer (CRC) in Kashmiri population.
METHODS: This study used tissue tumor samples (114) and blood samples from (160) patients with CRC and 200 blood samples from healthy donors. GSTP1 polymorphism was studied using polymerase chain reaction (PCR)-restriction fragment length polymorphism and methylation using methylation-specific PCR.
RESULTS: There was no significant association between GSTP1 I105V genotypes and the CRC (P>0.05). However, we found a significant association of the Val/Val variant genotype with the dwelling and smoking status (P-value < 0.05). Overall, the homozygous variant Val/Val genotype was associated with a modestly elevated risk for CRC (OR = 1.57; 95% CI = 0.67–3.57). Methyl-specific-PCR analysis revealed 25.4% methylation of the GSTP1 promoter in CRC cases and was not found to be statistically significantly associated with clinicopathological parameters of the CRC cases (P>0.05). Also, no significant associations of any of the three genotypes with promoter hypermethylation were observed.
CONCLUSION: We conclude that promoter hypermethylation in homozygous GSTP1 mutants did not elevate the risk of CRC in Kashmiri population.


Keywords: Colorectal cancer, GSTP1, Kashmir, MS-PCR, methylation, polymorphism


How to cite this article:
Nissar S, Sameer AS, Rasool R, Chowdri NA, Rashid F. Promoter methylation and Ile105val polymorphism of GSTP1 gene in the modulation of colorectal cancer risk in ethnic Kashmiri population. Indian J Cancer 2019;56:248-53

How to cite this URL:
Nissar S, Sameer AS, Rasool R, Chowdri NA, Rashid F. Promoter methylation and Ile105val polymorphism of GSTP1 gene in the modulation of colorectal cancer risk in ethnic Kashmiri population. Indian J Cancer [serial online] 2019 [cited 2019 Dec 15];56:248-53. Available from: http://www.indianjcancer.com/text.asp?2019/56/3/248/263024





 » Introduction Top


Colorectal cancer (CRC) is a complex disease which usually arises due to the aggregation of various genetic and epigenetic alterations in various numbers of oncogene, tumor suppressor gene, mismatch repair gene, and cell cycle gene in colorectal mucosa cells.[1],[2] All these genetic alterations accumulate to drive the pivotal pathways of CRC initiation and progression along with the multistep tumorigenesis process, known as the adenoma–carcinoma sequence. It represents the third most common cancer in the world and second leading cause of cancer-related deaths in many countries of the western world.[3] In the Kashmir valley, CRC represents the third most common gastrointestinal tract cancer after esophageal and gastric cancer.[4],[5],[6]

Glutathione S-transferases (GSTs) are the most important phase II enzymes of the xenobiotic pathway. These enzymes are responsible for the conjugation of potentially mutagenic electrophilic compounds with nucleophilic glutathione, yielding less toxic and more water-soluble compounds which are readily excreted through urine or bile.[7] GST gene polymorphisms are mostly associated with a lack or an alteration of enzymatic activity toward several substrates,[8],[9] thus resulting in increased CRC susceptibility.[10],[11],[12] GSTP1 is the most extensively studied class of GSTs encoded by a single gene located on chromosome 11q13 and has nine exons. GSTP1 is the common polymorphic enzyme with two common functional variants based on substitutions in amino acid 105 (isoleucine–valine) in exon 5 and amino acid 114 (alanine–valine) in exon 6. Individuals with 105Val allele GSTP1 show significantly lower enzyme activity.[13]

DNA methylation, which is one of the pivotal epigenetic mechanisms, is the most avidly studied process in colorectal carcinogenesis.[14] Among GST family of gene, GSTP1 has been found to be a target of hypermethylation and hence gene silencing. The 5′ region of GSTP1 is rich in CpG islands and its methylation causes changes in expression levels in neoplastic cells. A large number of published studies have reported numerous different types of malignancies to harbor hypermethylation of the GSTP1 gene promoter together with the loss of expression.[15],[16],[17],[18],[19],[20],[21],[22]

GSTP1 promoter methylation is also frequently associated with tumor development or poor prognosis in a wide range of tumors such as neuroblastoma,[23] hepatocellular cancer,[24] endometrial,[25] breast,[26] and prostate cancers.[27]

In this study, we examined the role of genetic polymorphism and promoter methylation of GSTP1 gene in the context of modulation of risk of CRC in Kashmiri population. Furthermore, we investigated whether there is a link between the clinicopathological variables and the GSTP1 genotype and hypermethylated phenotypes.


 » Materials and Methods Top


Sample collection and storage

Patients attending the Department of General Surgery at Sher-i-Kashmir Institute of Medical Sciences (SKIMS) for CRC management were screened for the disease. Two milliliters of blood samples was taken in ethylenediaminetetraacetic acid vial from 160 patients and 200 controls. A total of 114 tissues samples collected from patients were snap frozen at −80°C until further analysis. A pretested, semi-structured questionnaire was used to collect information on clinicopathological parameters such as age, gender, dwelling, tumor location, node status, smoking status, and bleeding per rectum of CRC patients.

DNA extraction and genotype analysis

DNA extraction was performed using the ammonium acetate method. One microliter of DNA was used as the template for each polymerase chain reaction (PCR). Genotype analysis of the GSTP1 gene was carried out by PCR restriction fragment length polymorphism (RFLP) using primers (F: 5′-ACC CCA GGG CTC TAT GGG AA-3′; R: 5′-TGA GGG CAC AAG AAG CCC CT-3′) generating a fragment of 176 bp as previously described.[28] Briefly, PCR was carried out in a final volume of 25 μL containing 50 ng genomic DNA template, 1× PCR buffer with 2 mM MgCl2, 0.5 μM of each primer, 50 μM deoxy nucleotide triphosphates (dNTPs), and 0.5 U DNA polymerase. For PCR amplification, the standard program was used as follows: one initial denaturation step at 94°C for 7 min, followed by 35 denaturation cycles of 30 s at 94°C, 30 s of annealing at 55°C, and 30 s of extension at 72°C, followed by a final elongation cycle at 72°C for 7 min. PCR product of 176 bp was digested by 2U Alw261 (Fermentas, MD, USA) at 37°C. The Val allele was cut into 91 and 85 bp fragments (Ile allele is not digested). The bands corresponding to different alleles were detected by horizontal ethidium bromide 3% agarose gel electrophoresis, along with a 100-bp DNA ladder.

Bisulfite modification and methyl-specific PCR of GSTP1 gene promoter

Isolated genomic DNA (up to 2 μg) was subjected to bisulfite modification using EZ DNA-Methylation Kit (Zymo Research Corp, USA), according to the manufacturer's protocol, which converted the unmethylated cytosines into uracil, whereas the methylated cytosines remained unchanged. Bisulfite converted DNA was subjected to methyl-specific (MS) PCR, using previously described primers targeted for the promoter region of the GSTP1 gene. The DNA was amplified using thermal cycler (Bio-Rad iCycler, USA) in a 50-μl total volume reaction mixture containing 10 ng of modified genomic DNA, 100 μM of each dNTP, 100 ng of each of the primers (UF: 5′-GA TGT TTG GGG TGT AGT GGT TGT T-3′and UR: 5′-CC ACC CCA ATA CTA AAT CAC AAC A-3′ in the case of unmethylation detection; MF: 5′-TT CGG GGT GTA GCG GTC GTC-3′ and MR: 5′-GC CCC AAT ACT AAA TCA CGA CG-3′ in the case of methylation detection), 1.5 mM MgCl2, 5% dimethyl sulfoxide, 10× Taq buffer, and 2 units of Taq DNA polymerase (Fermentas). The conditions of PCR were as follows: initial denaturation at 95°C for 10 min, 45 cycles of denaturation at 95°C for 30 s, annealing at 65°C for methylated allele and at 62°C for unmethylated allele for 40 s, extension at 72°C for 40 s, and final extension at 72°C for 10 min. For positive control, Universal Methylated Human DNA (Zymo Research) was used, whereas for unmethylated alleles DNA of normal lymphocytes was used as internal control for each reaction. Water was used as a negative PCR control in both reactions.

The PCR products of each reaction were electrophoresed on 2.5% agarose gels and visualized under ultraviolet radiation after staining with ethidium bromide.

Statistical analysis

Statistical analysis was performed using SPSS Software (IBM). Observed frequencies of genotypes in patients with cancer were compared with controls using chi-squared or Fisher's exact test when expected frequencies were small. The chi-squared test was used to verify whether genotype distributions were in Hardy–Weinberg equilibrium. Odds ratio (OR) was used to determine the association of the presence of mutations with various clinicoepidemiological characteristics. Statistical significance was considered when P ≤0.05.


 » Results Top


GSTP1 gene polymorphism

A total of 160 cases with prior consent were recruited for the study. All of them presented with constipation and bleeding PR as their chief complaint. Furthermore, of 160 confirmed cases of CRC, 64 cases were females and 96 males, 88 rural, and 72 urban; 70 cases had carcinoma in the colon and 90 in the rectum, and 73 were smokers and 87 non-smokers [Table 1]. The mean age of patients having confirmed CRC was 55 years. Among control subjects, 102 consisted of males and 98 females. 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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For GSTP1 gene, two bands of 91 and 85 bp were seen for homozygous Val allele, while three bands of 176, 91, and 85 bp were seen for heterozygous variant allele, and Ile allele was not digested.

In our study, we found a difference in the genotype frequency of GSTP1 I105V between CRC cases and the matched controls. The incidence of the GSTP1 Val/ Val genotype was slightly higher in CRC cases when compared with healthy controls [Table 2]. The frequency of Ile/Val genotype in CRC cases was 16.25% and that of Val/Val was 8.1%, compared with healthy controls, where it was 21% and 5.0%, respectively.
Table 2: Genotype frequencies of GSTP1 gene polymorphism in CRC cases and controls

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The overall hazard ratio of the GSTP1 Val allele in patients with CRC was 0.91 [95% confidence interval (CI) 0.56–1.4]. Overall, the homozygous variant Val/Val genotype was associated with a modestly elevated risk for CRC (OR 1.57, 95% CI 0.67–3.57). The correlation of GSTP1 I105V polymorphic status with clinicopathological characteristics was analyzed. There was no significant association between GSTP1 I105V genotypes and the CRC (P > 0.05). However, we found a significant association of the Val/Val variant genotype with dwelling and smoking status (P < 0.05) [Table 3].
Table 3: Association of GSTP1 genotypes with various clincopathological variables in patients with CRC

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GSTP1 promoter methylation

A total of 114 CRC cases were included in the study. The patients comprised 67 males and 47 females (male/female ratio of 1.42). The demographic and clinical characteristics of the CRC cases are shown in [Table 1] and [Table 4].
Table 4: Clinicoepidemiological variables of the colorectal carcinoma patients versus 29 hypermethylated phenotypes of GSTP1 gene

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MS-PCR analysis revealed a less methylation status of the GSTP1 promoter in CRC cases. Twenty-nine (25.4%) of the tumors were found to be hypermethylated at the promoter region, and the remaining 85 (74.5%) of the tumors were not methylated at all [Table 4].

Statistical analysis between the GSTP1 hypermethylation status and clinicopathological parameters of the CRC cases did not reveal any significant association (P > 0.05).

Furthermore, the role of the GSTP1 polymorphism in promoter hypermethylation was tested. However, no significant associations of any of the three genotypes with promoter hypermethylation were observed [Table 5]. Therefore, it was concluded that promoter hypermethylation in homozygous mutants with reduced enzymatic activity due to the substitution mutation did not elevate the risk of CRC.
Table 5: Distribution of methylated status among various genotypes of GSTP1 in CRC cases

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 » Discussion Top


GSTP1 gene is located on human chromosome 11q13 and encodes a GST π family enzyme. Polymorphism in exon 5 (A105G) of GSTP1 gene results in variation in the amino acid sequence in the enzyme which affects its substrate specificity and activity.[29] A number of different environmental factors play a critical role in cancer development in the majority of cases; the role of GSTP1 polymorphism in CRC appears to be very important. In this study, we were not able to find any evidence of an association between GSTP1 single-nucleotide polymorphism (SNP) and the risk of CRC. In our Kashmiri population, we observed that the genotype frequency of three SNPs of GSTP1 Ile/Ile, Ile/Val, and Val/Val was 75.6%, 16.3%, and 8.1% among CRC cases and 74%, 21%, and 5.0% among the control subjects, respectively. Furthermore, the genotype distribution frequency in our CRC cases and controls did not match with the genotype frequencies reported in the previously published literature [30],[31],[32],[33] except on the study carried out on a Taiwanese population by Yeh et al.[28] Our results also demonstrated that having the Val/Val genotype increased risk among the CRC cases (OR 1.57, 95% CI 0.67–3.75), and the findings were matching with the study by Yeh et al.[28] (OR 1.91, 95% CI 1.21–3.02).

In two important population-specific studies from India on two different sets of population – one from North India (Uttar Pradesh) by Mishra et al.[34] with 370 normal healthy unrelated individuals (age range: 30–85 years) and another from South India (Chennai) by Vettriselvi et al.[35] with 255 random healthy unrelated individuals – it was reported that the prevalence for wild (Ile/Ile), heterozygous (Ile/Val), and mutant (Val/Val) genotypes of GSTP1 in North India was 164/370 (44.3%), 186/370 (50.3%), and 20/370 (5.4%), respectively, while it was 149/255 (58.4%), 98/255 (38.4%), and 8/255 (3.2%), respectively, in South India. These reported genotype frequencies are in striking contrast to the Kashmiri population frequencies. In our study, we found the frequencies for wild (Ile/Ile), heterozygous (Ile/Val), and mutant (Val/Val) genotypes of GSTP1 to be 148/200 (74%), 42/200 (21%), and 10/200 (5.0%), respectively.

Since GSTP1 gene encodes the most predominant of all GST isoenzymes, it plays a prominent role of being a cancer susceptibility candidate.[36],[37] GST enzyme is directly involved in the detoxification and removal of heterocyclic amines in colorectal tissue.[38] Harries et al.,[39] in their study on GSTP1 I105V polymorphism, reported that the CRC cases possessing GSTP1 with a Val allele were at an elevated risk in comparison to those having Ile/Ile genotype (OR 1.77, 95% CI 1.03–3.06).

Since the hypermethylation of the gene does sometimes imitate the mutation pattern,[40] the query of whether hypermethylation of GST genes plays any role in the genetic susceptibility to CRC comparable to that of the genetic mutations [41] was also examined in this study. Of all the classes of GST gene family, promoter hypermethylationof GSTP1 gene has been studied fervently. Several studies have indicated that hypermethylation of the CpG islands located in the GSTP1 promoter region is involved in carcinogenesis.[42],[43] It has been reported that the silencing of GSTP1 gene expression in CRC is induced by CpG island hypermethylation, observed in 4%–62% of CRC cases.[44],[45] GSTP1 has been reported to function as a tumor-suppressor gene as well, facilitating the growth of tumor in its inactivated state; this is mediated through interference of GSTP1 with c-Jun kinase signaling.[46] When inactivated by hypermethylation of the upstream promoter, GSTP1 functions as a caretaker gene leading to additional somatic genetic alterations that eventually promote tumor growth.[47]

In this study, we investigated the frequency of GSTP1 CpG island hypermethylation and found that 25.4% of patients showed CpG island hypermethylation which was not found to be statistically significantly associated with clinicopathological parameters of the CRC cases (P > 0.05).

Previous findings indicated that GSTP1 polymorphism was associated with decreased protein function and that GSTP1 hypermethylation correlated with lack of protein expression. Thus, it was suspected that the polymorphism may be promoted or linked with GSTP1 hypermethylation status. To test the hypothesis whether the somatic epigenetic modification of the gene in the homozygous mutants in combination with decreased enzymatic activity does increase the susceptibility of CRC in the carrier population, we analyzed the role of GSTP1 gene polymorphism on its promoter hypermethylation and vice versa. However, the results of this study showed no association between GSTP1 hypermethylation and GSTP1 polymorphism, agreeing with a previous report on prostate cancer.[19]


 » Conclusion Top


Our study did not find any association between GSTP1 gene polymorphism and CRC risk, thereby suggesting that this does not confer any additional risk for CRC in our population. Also, GSTP1 CpG island hypermethylation with a frequency of 25.4% was also not found to be statistically significantly associated with clinicopathological parameters of the CRC cases (P > 0.05) revealing that the silencing of this gene does not only occur with low frequency in CRCs but also does not affect the colorectal carcinogenesis mechanisms significantly.

Acknowledgment

The authors thank each and every patient with CRC who took part in this study and cooperated during the interview and sample collection. The authors gratefully acknowledge the support provided by Dr. Zafar A Shah, Head, Department of Immunology and Molecular Medicine, SKIMS for conducting this work. Our thanks also go to the Head and Technical Staff of the operation theater of the Department of General Surgery, SKIMS who helped us in tissue procurement. They also thank the pathologists of the Department of Pathology for the histopathological assessment of the tumor 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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