|Year : 2019 | Volume
| Issue : 3 | Page : 248-253
Promoter methylation and Ile105val polymorphism of GSTP1 gene in the modulation of colorectal cancer risk in ethnic Kashmiri population
Saniya Nissar1, Aga Syed Sameer2, Roohi Rasool3, Nissar A Chowdri4, Fouzia Rashid5
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 Publication||19-Jul-2019|
Department of Clinical Biochemistry, University of Kashmir, Soura, Srinagar, Jammu and Kashmir
Source of Support: None, Conflict of Interest: None
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 Oct 14];56:248-53. Available from: http://www.indianjcancer.com/text.asp?2019/56/3/248/263024
| » Introduction|| |
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., 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. In the Kashmir valley, CRC represents the third most common gastrointestinal tract cancer after esophageal and gastric cancer.,,
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. GST gene polymorphisms are mostly associated with a lack or an alteration of enzymatic activity toward several substrates,, thus resulting in increased CRC susceptibility.,, 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.
DNA methylation, which is one of the pivotal epigenetic mechanisms, is the most avidly studied process in colorectal carcinogenesis. 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.,,,,,,,
GSTP1 promoter methylation is also frequently associated with tumor development or poor prognosis in a wide range of tumors such as neuroblastoma, hepatocellular cancer, endometrial, breast, and prostate cancers.
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|| |
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. 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 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|| |
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|
Click here to view
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|
Click here to view
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|
Click here to view
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|
Click here to view
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|
Click here to view
| » Discussion|| |
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. 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 ,,, except on the study carried out on a Taiwanese population by Yeh et al. 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. (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. with 370 normal healthy unrelated individuals (age range: 30–85 years) and another from South India (Chennai) by Vettriselvi et al. 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., GST enzyme is directly involved in the detoxification and removal of heterocyclic amines in colorectal tissue. Harries et al., 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, the query of whether hypermethylation of GST genes plays any role in the genetic susceptibility to CRC comparable to that of the genetic mutations  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., 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., 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. 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.
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.
| » Conclusion|| |
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.
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
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Migliore L, Migheli F, Spisni R, Coppedè F. Genetics, cytogenetics, and epigenetics of colorectal cancer. J Biomed Biotechnol 2011;2011:792362.
Grady WM, Ulrich CM. DNA alkylation and DNA methylation: Cooperating mechanisms driving the formation of colorectal adenomas and adenocarcinomas? Gut 2007;56:318-20.
Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer incidence and mortality rates and trends – An update. Cancer Epidemiol Biomarkers Prev 2016;25:16-27.
Rasool MT, Lone MM, Wani ML, Afroz F, Zaffar S, Mohib-ul Haq M, et al.
Cancer in Kashmir, India: Burden and pattern of disease. J Cancer Res Ther 2012;8:243-6.
Sameer AS. Colorectal cancer: A researcher's perspective of the molecular angel's gone eccentric in the vale of Kashmir. Tumour Biol 2013;34:1301-15.
Sameer AS. Colorectal cancer: Molecular mutations and polymorphisms. Front Oncol 2013;3:114.
Ketterer B. Glutathione S-transferases and prevention of cellular free radical damage. Free Radic Res 1998;28:647-58.
Hayes JD, Flanagan JU, Jowsey IR. Glutathione transferases. Annu Rev Pharmacol Toxicol 2005;45:51-88.
Whyatt RM, Perera FP, Jedrychowski W, Santella RM, Garte S, Bell DA, et al.
Association between polycyclic aromatic hydrocarbon-DNA adduct levels in maternal and newborn white blood cells and glutathione S-transferase P1 and CYP1A1 polymorphisms. Cancer Epidemiol Biomarkers Prev 2000;9:207-12.
McIlwain CC, Townsend DM, Tew KD. Glutathione S-transferase polymorphisms: Cancer incidence and therapy. Oncogene 2006;25:1639-48.
Sachse C, Smith G, Wilkie MJ, Barrett JH, Waxman R, Sullivan F, et al.
A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer. Carcinogenesis 2002;23:1839-49.
de Jong MM, Nolte IM, te Meerman GJ, van der Graaf WT, de Vries EG, Sijmons RH, et al.
Low-penetrance genes and their involvement in colorectal cancer susceptibility. Cancer Epidemiol Biomarkers Prev 2002;11:1332-52.
Sharma A, Pandey A, Sharma S, Chatterjee I, Mehrotra R, Sehgal A, et al.
Genetic polymorphism of glutathione S-transferase P1 (GSTP1) in Delhi population and comparison with other global populations. Meta Gene 2014;2:134-42.
Guinney J, Dienstmann R, Wang X, de Reyniès A, Schlicker A, Soneson C, et al.
The consensus molecular subtypes of colorectal cancer. Nat Med 2015;21:1350-6.
Silvestrini R, Veneroni S, Benini E, Daidone MG, Luisi A, Leutner M, et al.
Expression of p53, glutathione S-transferase-Pi, and Bcl-2 proteins and benefit from adjuvant radiotherapy in breast cancer. J Natl Cancer Inst 1997;89:639-45.
Esteller M, Corn PG, Urena JM, Gabrielson E, Baylin SB, Herman JG, et al.
Inactivation of glutathione S-transferase P1 gene by promoter hypermethylation in human neoplasia. Cancer Res 1998;58:4515-8.
Millar DS, Ow KK, Paul CL, Russell PJ, Molloy PL, Clark SJ, et al.
Detailed methylation analysis of the glutathione S-transferase pi (GSTP1) gene in prostate cancer. Oncogene 1999;18:1313-24.
Lee JS. GSTP1 promoter hypermethylation is an early event in breast carcinogenesis. Virchows Arch 2007;450:637-42.
Jerónimo C, Varzim G, Henrique R, Oliveira J, Bento MJ, Silva C, et al.
I105V polymorphism and promoter methylation of the GSTP1 gene in prostate adenocarcinoma. Cancer Epidemiol Biomarkers Prev 2002;11:445-50.
Chan QK, Khoo US, Chan KY, Ngan HY, Li SS, Chiu PM, et al.
Promoter methylation and differential expression of pi-class glutathione S-transferase in endometrial carcinoma. J Mol Diagn 2005;7:8-16.
Zhong S, Tang MW, Yeo W, Liu C, Lo YM, Johnson PJ, et al.
Silencing of GSTP1 gene by CpG Island DNA hypermethylation in HBV-associated hepatocellular carcinomas. Clin Cancer Res 2002;8:1087-92.
Tokumaru Y, Harden SV, Sun DI, Yamashita K, Epstein JI, Sidransky D, et al.
Optimal use of a panel of methylation markers with GSTP1 hypermethylation in the diagnosis of prostate adenocarcinoma. Clin Cancer Res 2004;10:5518-22.
Gumy-Pause F, Pardo B, Khoshbeen-Boudal M, Ansari M, Gayet-Ageron A, Sappino AP, et al.
GSTP1 hypermethylation is associated with reduced protein expression, aggressive disease and prognosis in neuroblastoma. Genes Chromosomes Cancer 2012;51:174-85.
Li QF, Li QY, Gao AR, Shi QF. Correlation between promoter methylation in the GSTP1 gene and hepatocellular carcinoma development: A meta-analysis. Genet Mol Res 2015;14:6762-72.
Fang C, Wei XM, Zeng XT, Wang FB, Weng H, Long X, et al.
Aberrant GSTP1 promoter methylation is associated with increased risk and advanced stage of breast cancer: A meta-analysis of 19 case-control studies. BMC Cancer 2015;15:920.
Fiolka R, Zubor P, Janusicova V, Visnovsky J, Mendelova A, Kajo K, et al.
Promoter hypermethylation of the tumor-suppressor genes RASSF1A, GSTP1 and CDH1 in endometrial cancer. Oncol Rep 2013;30:2878-86.
Goering W, Kloth M, Schulz WA. DNA methylation changes in prostate cancer. Methods Mol Biol 2012;863:47-66.
Yeh CC, Hsieh LL, Tang R, Chang-Chieh CR, Sung FC. Vegetable/fruit, smoking, glutathione S-transferase polymorphisms and risk for colorectal cancer in Taiwan. World J Gastroenterol 2005;11:1473-80.
Kopps S, Angeli-Greaves M, Blaszkewicz M, Prager HM, Roemer HC, Lohlein D, et al.
Glutathione S-transferase P1 ILE105Val polymorphism in occupationally exposed bladder cancer cases. J Toxicol Environ Health A 2008;71:898-901.
van der Logt EM, Bergevoet SM, Roelofs HM, van Hooijdonk Z, te Morsche RH, Wobbes T, et al.
Genetic polymorphisms in UDP-glucuronosyltransferases and glutathione S-transferases and colorectal cancer risk. Carcinogenesis 2004;25:2407-15.
Sun XF, Ahmadi A, Arbman G, Wallin A, Asklid D, Zhang H, et al.
Polymorphisms in sulfotransferase 1A1 and glutathione S-transferase P1 genes in relation to colorectal cancer risk and patients' survival. World J Gastroenterol 2005;11:6875-9.
Kweekel DM, Koopman M, Antonini NF, Van der Straaten T, Nortier JW, Gelderblom H, et al.
GSTP1 ile105Val polymorphism correlates with progression-free survival in MCRC patients treated with or without irinotecan: A study of the Dutch colorectal cancer group. Br J Cancer 2008;99:1316-21.
Pande M, Amos CI, Osterwisch DR, Chen J, Lynch PM, Broaddus R, et al.
Genetic variation in genes for the xenobiotic-metabolizing enzymes CYP1A1, EPHX1, GSTM1, GSTT1, and GSTP1 and susceptibility to colorectal cancer in Lynch syndrome. Cancer Epidemiol Biomarkers Prev 2008;17:2393-401.
Mishra DK, Kumar A, Srivastava DS, Mittal RD. Allelic variation of GSTT1, GSTM1 and GSTP1 genes in North Indian population. Asian Pac J Cancer Prev 2004;5:362-5.
Vettriselvi V, Vijayalakshmi K, Paul SF, Venkatachalam P. Genetic variation of GSTM1, GSTT1 and GSTP1 genes in a South Indian population. Asian Pac J Cancer Prev 2006;7:325-8.
Nijhoff WA, Grubben MJ, Nagengast FM, Jansen JB, Verhagen H, van Poppel G, et al.
Effects of consumption of Brussels sprouts on intestinal and lymphocytic glutathione S-transferases in humans. Carcinogenesis 1995;16:2125-8.
de Bruin WC, Wagenmans MJ, Board PG, Peters WH. Expression of glutathione S-transferase theta class isoenzymes in human colorectal and gastric cancers. Carcinogenesis 1999;20:1453-7.
Lin D, Meyer DJ, Ketterer B, Lang NP, Kadlubar FF. Effects of human and rat glutathione S-transferases on the covalent DNA binding of the N-acetoxy derivatives of heterocyclic amine carcinogens in vitro
: A possible mechanism of organ specificity in their carcinogenesis. Cancer Res 1994;54:4920-6.
Harries LW, Stubbins MJ, Forman D, Howard GC, Wolf CR. Identification of genetic polymorphisms at the glutathione S-transferase Pi locus and association with susceptibility to bladder, testicular and prostate cancer. Carcinogenesis 1997;18:641-4.
Baylin SB, Belinsky SA, Herman JG. Aberrant methylation of gene promoters in cancer – Concepts, misconcepts, and promise. J Natl Cancer Inst 2000;92:1460-1.
Gazzoli I, Loda M, Garber J, Syngal S, Kolodner RD. A hereditary nonpolyposis colorectal carcinoma case associated with hypermethylation of the MLH1 gene in normal tissue and loss of heterozygosity of the unmethylated allele in the resulting microsatellite instability-high tumor. Cancer Res 2002;62:3925-8.
Baylin SB, Esteller M, Rountree MR, Bachman KE, Schuebel K, Herman JG, et al.
Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet 2001;10:687-92.
Widschwendter M, Jones PA. DNA methylation and breast carcinogenesis. Oncogene 2002;21:5462-82.
Esteller M, Fraga MF, Guo M, Garcia-Foncillas J, Hedenfalk I, Godwin AK, et al.
DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. Hum Mol Genet 2001;10:3001-7.
Nomani H, Jalejo N, Yaghmaei B, Ghobadlu SM, Keshavarz AA, Izadi B. Methylation of the GSTP1 gene promotor in colorectal cancer. Behbood 2009;13:39-45.
Adler V, Yin Z, Fuchs SY, Benezra M, Rosario L, Tew KD, et al.
Regulation of JNK signaling by GSTp. EMBO J 1999;18:1321-34.
Kinzler KW, Vogelstein B. Cancer-susceptibility genes. Gate keepers and caretakers. Nature 1997;386:761-3.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]