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ORIGINAL ARTICLE
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Implications and relative importance of GSTP1, GSTM1, and GSTT1 Polymorphisms in the prevalence and severity of prostate cancer in an Eastern Indian Population


1 Department of Biochemistry, Calcutta National Medical College and Hospital, Kolkata, West Bengal, India
2 Department of Community Medicine, Medical College and Hospital, Kolkata, West Bengal, India
3 Department of Urology, Calcutta National Medical College and Hospital, Kolkata, West Bengal, India

Date of Submission29-Mar-2021
Date of Decision25-Jul-2021
Date of Acceptance14-Aug-2021

Correspondence Address:
Anindya Dasgupta,
Department of Biochemistry, Calcutta National Medical College and Hospital, 32, Gorachand Road, Kolkata - 700 014, West Bengal
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mjdrdypu.mjdrdypu_230_21

  Abstract 


Background: Several mutations including the single nucleotide polymorphisms (SNPs) in the GSTP1 and deletional mutations of GSTM1 and GSTT1 isoforms of the glutathione S transferase gene are of significant importance in the etiology and severity of prostate cancer (Pca) with varying degrees of association in different population groups. We investigated the association of these mutations with the prevalence and severity of the Pca in an urban population of Eastern India. Materials and Methods: In the present case–control study, deletional mutations of the GSTM1 and GSTT1 were detected by their presence or absence in the gel electrophoresis after the polymerase chain reaction (PCR). The A to G SNP of the GSTP1 gene resulting in Ile105Val was detected using Restriction Fragment Length Polymorphism after PCR. Severity of Pca was assessed by International Society of Urological Pathology (ISUP) grading. Polymorphic variations obtained were correlated to the prevalence and severity of Pca. Results: The Chi-square tests showed a significantly greater prevalence of all three mutations in the case group. However, the post hoc ANOVA and multiple logistic regression analysis revealed that only the A to G SNP of the GSP1 gene among the three mutations showed significant association with the severity of the Pca as indicated by the ISUP gradings. Conclusion: The results indicated that although the A to G transitional SNP of the GSTP1 and the deletional SNPs of GSTM1 and GSTT1 acted all as important factors for increasing the prevalence of Pca, the A to G SNP of the GSTP1 gene resulting in Ile105Val only contributed to the severity and spread of the disease in our study population.

Keywords: Deletional mutation, International Society of Urological Pathology Grading, prostate cancer, single nucleotide polymorphisms of glutathione S transferase



How to cite this URL:
Roy S, Dasgupta A, Mondal T, Mandal N S, Karmakar D. Implications and relative importance of GSTP1, GSTM1, and GSTT1 Polymorphisms in the prevalence and severity of prostate cancer in an Eastern Indian Population. Med J DY Patil Vidyapeeth [Epub ahead of print] [cited 2022 Dec 7]. Available from: https://www.mjdrdypv.org/preprintarticle.asp?id=343493




  Introduction Top


Prostate cancer (Pca) is the second most commonly diagnosed cancer worldwide and the fifth most common leading cause of death among men population throughout the world.[1] However, the incidence and death from it vary significantly among different regions and ethnicities that is vividly reflected by its wide variation in the incidence of 4.4 and 118.2/100,000 population in India and the USA, respectively.[2],[3] A particular note of interest is that prevalence of the infiltrative variety of Pca is reported to differ more significantly among different races than the noninfiltrative one.[4] The trend of Pca has been recently found to be increasing in the Asian countries including India probably due to the change in lifestyle and adopting of Westernized dietary habits.[5],[6]

Along with several environmental risk factors such as diet, metabolic states, for example, the metabolic syndrome, sexual behavior, infections, obesity, lifestyle, etc.; family history and genetic alterations such as multiple mutations and single nucleotide polymorphisms (SNPs) have been found to be important causative factors for conferring significant variations in the incidence and prevalence of Pca among different racial and ethnic population groups.[7],[8] Some meta-analytical studies have indicated predictive values of SNPs of glutathione S transferase (GST) in Pca.[9] In fact, SNPs of several isoenzymes of GST have been reported to be closely associated with different types of cancers. GSTT1 and GSTM1 exhibit inherited homozygotic deletional polymorphis (null variants), while the GSTP1 shows a transition of A to G at the 313th position of its gene that leads to substitution of the amino acid isoleucine (Ile) by valine (Val) at the 105th position of the protein. All these changes lead to decreased catalytic activities resulting in decreased clearance of carcinogens by Phase II conjugation system that may potentiate the risk of cancer development significantly.[10] The linkage between GSTM1 null variant with malignant colorectal cancer,[11] association of GSTM1 and GSTT1 null variants with lung cancer,[12] linkage of GSTP1 Ile 105 Val SNP with small cell cancer of the lung,[13] association of GSTM1 null variant with squamous cell cancer,[14] and linkage of null variants of GSTT1, GSTM1, and Ile105val SNP of GSTP1 with acute myeloid leukemia[15] are some important instances. However, the clarity of their relationships with different cancers remains controversial till now in the context of racial and ethnic variations.

Under-expression of the GST genes is one of the five common genetic under-expressions found in Pca.[16] Meta-analytic studies have indicated linkage of Pca with GSTM1 and GSTT1 null variants.[17],[18] On the other hand, Kote-Jarai et al. reported an associated risk of GSTP1 Ile105val SNP with early onset Pca without any significant risk association with the GSTM1 and GSTT1 null variants.[19] Studies have reported inconsistent relationship with GSTP1 polymorphism with biochemical recurrence (BCR), i.e. a prostate-specific antigen (PSA) concentration in serum of >0.2 ng/ml on one or more occasions after a previously undetectable level of l PSA after radical prostatectomy.[20],[21],[22],[23] Cotignola et al. indicated a 2.05 fold risk of BCR with GSTT1 null variants while others failed to find it.[20] Similarly, a positive relationship of BCR between the GSTM1 null variant was reported by Agalliu et al. while other studies did not find such association.[22] On the other hand, Srivastava et al. reported the null variants of GSTM1 and GSTT1 and the Ile105val SNP of GSTP1 as strong predisposing factors for Pca among the North Indian population.[18] Thus, although many studies have already reported risks of Pca with these mutations, their results have been inconsistent and conflicting depending on the racial and ethnic variations.[24]

Based on these lacunae, we hypothesized that the combination of the three common GST mutations, i.e. GSTM1+/-, GSTT1+/- and the Ile 105 Val SNP of GSTP1 gene might confer a higher risk of Pca along with a greater degree of tissue invasion among our study population in an eastern part of India. Accordingly, the current study was planned and performed in an urban population of a metropolitan city of Eastern India.


  Materials and Methods Top


Study design

It was a case–control observational study conducted in the biochemistry department and urology department of a tertiary medical college and hospital in Kolkata for a period of 1 year from 2019 to 2020 March.

Selection of the study population

As the patients were selected from the tertiary care hospital, method of convenience was used for the case selection in the present study. Patients suffering from adenocarcinoma of the prostate gland as diagnosed by the clinical investigations and confirmatory histopathological diagnosis and grading were selected following the inclusion and exclusion criteria. Histopathological grading was done using Gleason's score and International Society of Urological Pathologists (ISUP) grading system. Patients with any other malignancies, metabolic disorder, smoking and alcohol addiction, or any other drug addiction were excluded. Controls were selected from age-matched healthy males in whom any prostate disorder was ruled out by the clinical examination and PSA levels. Both case and control population were selected from the same geographical area with similar nutritional and socioeconomic status.

Ethical consideration

The study was conducted following the guidelines and criteria for human studies as laid on by Helsinki declaration 1975 revised in 2000 and International Committee of Medical Journal Editors. Informed consents were obtained in the local language from all the study participants in consent forms. The study was initiated after obtaining the written permission from the Institutional Ethical Committee vide memo number 4, dated October 26, 2016.

Study technique

3 ml of venous blood was collected in aseptic way from the participants and was stored in EDTA vial for DNA separation. The EDTA blood was stored at −20°C. DNA isolation was done within a maximum period of 7 days. Tissue samples from the prostate gland were collected during surgery and sent for the histopathological analysis including grading.

DNA isolation

DNA was isolated from the EDTA blood by phenol chloroform extraction method as described by Stafford and Blin.[25] The quality and integrity of isolated DNA were checked by gel electrophoresis in 0.7% agarose gel and spectrophotometric quantification at 260 an d 280nm. The GSTP1, GSTT1, and GSTM1 polymorphisms were assessed by gene amplification by the polymerase chain reaction (PCR) followed by Restriction Fragment Length Polymorphism (RFLP) with respective restriction digestion technique for the GSTP1. For the other two, i.e. GSTT1 and GSTM1, null variants were detected by the absence of any bands in the gel.

Polymerase chain reaction technique of GSTP1/GSTM1/GSTT1 gene

All PCR reactions were performed using the 12.5 μL of 2 × PCR master-mix obtained from the Thermofisher, USA. The PCR reactions were carried out in the veriflex PCR Thermocycler (ProflexTM) obtained from the Applied Biosystems, Thermofischer Scientific, USA.

GSTP1 gene

The forward and reverse primers selected were 5´- GTCTCTCATCCTTCCACGCA-3´ and 5´- CTGCACCCT

GACCCAAGAA-3´ respectively. We used 10 pmol of each primer and 1 μL of the DNA sample in the final PCR mixture of 25 μl. The PCR protocol included the initial preheating at 95°C for 2 min, followed by 30 cycles of denaturation at 95°C for 30 s, annealing at 60°C for 30 s, and extension at 72°C for 1 min. The final extension step was done at 72°C for 5 min. PCR products obtained were run in 1.2% agarose gel against 100 bp DNA ladder (Genie, Bangalore, India). The products were identified as 365 bp using the Gel Doc system obtained from Applied Biosystem, Thermofischer Scientific, USA.

GSTM1 gene

10 pmol each of forward (5'-GAACTCCCTGAAAA

GCTAAAGC-3') and reverse primer (5'-GTTGGGCTC

AAATATACGGTGG-3') and 1 μl of DNA sample were taken and were made to a final volume of 25 μL with nuclease free water. The PCR protocol included an initial preheating at 95°C for 2 min, followed by 30 cycles of denaturation at 95°C for 30 s, annealing at 58°C for 30 s, and extension at 72°C for 1 min. After the completion of 30 cycles, the final extension was programmed at 72°C for 5 min. PCR product obtained were run in 1.2% agarose gel against 100 bp DNA ladder and was identified as 215 bp length product using the Gel Doc system. The presence of PCR band at 215 bp was detected as no deletion, and absence of the PCR product was taken as deletion null variant of the Gene.

GSTT1 gene

10 pmol of forward (5'-TTCCTTACTGGTCCTCAC

ATCT-3') and reverse primer (5'-TCACCGGATCATG

GCCAGCA-3') each and 1 μl of DNA sample were made to a final volume of 25 μL with nuclease free water. PCR was run using the following protocol: The initial preheating was done at 95°Cfor 2 min, followed by 30 cycles of denaturation at 95°C for 30 s, annealing at 58°C for 30 s, and extension at 72°C for 1 min. After completion of 30 cycles, the final extension was programmed at 72°C for 5 min. PCR products obtained were run in 1.2% agarose gel against 100 bp DNA ladder and was identified as 473 bp length product in Gel Doc system. The presence of PCR band at 473 bp was detected as no deletion, and absence of PCR product was taken as deletion, i.e. the null variant of the gene.

PCR of the beta globin gene having a PCR product of 268 bp was obtained as the positive control for all PCRs.

Restriction digestion

PCR products of GSTP1 obtained were digested using the restriction enzyme Alw261 obtained from Thermofischer USA. When digested by the restriction enzyme the 365 bp PCR product produced two fragments of 222 bp and 143 bp due to replacement of the A allele by the G allele (SNP rs 1695). Restriction digestion products were identified on 4% agarose gel against 100 bp DNA ladder using the Gel Doc system. The sequence having homozygous AA allele showed no cut by RFLP and showed a single band at 365 bp. Those with homozygous GG allele were cut at both chromosomes and showed two bands at 222bp and 143bp cut whereas, those with heterozygous AG allele showed three bands at 365, 222, and 143 bp regions [Figure 1], [Figure 2], [Figure 3].
Figure 1: Electrophoretic pattern of A to G single nucleotide polymorphisms of GSTP1 genotypes (rs 1695). The figure shows wild uncut AA homozygotes with a single band at 365 bp region at lane numbers 1, 6, 8, 9, and 11–15. Homozygotes for cut mutant GG alleles are represented by two bands at 222 bp and 143 bp regions at lane no 3. Heterozygotes for AG alleles are shown with three bands at 365 bp (uncut wild) and 222 bp and 143 bp (cut mutant) regions at lane numbers 2, 4, 5, 10, and 16. Lane 7 shows 100 bp DNA ladder

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Figure 2: Electrophoretic pattern of GSTM1 null and wild variants. The figure shows wild nondeletional genotypes with polymerase chain reaction products at 215 bp regions at lane numbers 2, 4, 5, 6, and 7. Lane no. 3 shows the betaglobin PCR product as the positive control and deletional null variant at lane no. 8 with no band. Lane 1 shows 100 bp DNA ladder

Click here to view
Figure 3: Electrophoretic pattern of GSTT1 null and wild variants. The figure shows wild nondeletional genotypes with polymerase chain reaction (PCR) products at 473 bp regions at lane numbers 1, 4, 7, and 9; and the deletional null variants with no PCR product at lane numbers 2, 3 5, 6, 8, and 10-15. Lane 16 shows 100 bp DNA ladder

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Sequencing for the SNP rs 1695 of GSTP1 gene

As a cross checking and quality control for the RFLP process, we performed DNA sequencing of 20% of the total samples [Figure 4] and [Figure 5]. The sequencing was performed using the Big dye V3.1 sequencing terminator kit and 5 × sequencing buffer in ABI 3730 Sanger's sequencer from the Applied Biosystem.
Figure 4: Chromatograph of the sequencing for the rs1695 A to G single nucleotide polymorphisms of the GSTP1 gene. Heterozygote variant is observed by the presence of both A and G alleles at 143 position

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Figure 5: Chromatograph of the sequencing for the rs1695 A to G single nucleotide polymorphisms of the GSTP1 gene. Homozygote variant is observed by for the presence of only A allele at 143 position

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ISUP grading

The grading system proposed by the ISUP is more improved and specific form of the overall Gleason grading system.[20] Accordingly, the prostate cancer patients in our study were divided into five distinct ISUP grades; Grade 1: Gleason's score ≤6, Grade 2: Gleason's score 3 + 4 = 7, Grade 3: Gleason's score 4 + 3 = 7, Grade 4: Gleason's score 4 + 4 = 8, and Grade 5: Gleason's score 9 and 10.

Statistical analysis

After obtaining the data, they were analyzed for the significance of distribution of the allelic variations among the case and controls using the Chi-square tests, odd ratio, and ANOVA. The relationship between the ISUP grading and allelic variations in the case group was assessed by the multivariate logistic regression analysis. The status of equilibrium of the target SNPs in the study population was analyzed using the Hardy and Weinberg's principle. For all statistical tests, P value was considered statistically significant at P ≤ 0.05 at 95% confidence interval. For all studies, power of statistical interpretation was supposed to be 80% with an alpha value of 0.05 and a confidence interval of 95%. The authors confirm the availability of, and access to, all original data reported in this study.


  Results Top


The case and control participants in our study population were matched for their age (mean ± SD for case and control group in years were 69.3 ± 1.9 and 70.2 ± 5.2, respectively, P = 0.06, data not shown in Tables). The genotypic distribution of all three genes under study followed the Hardy–Weinberg's equilibrium state with a P > 0.05.

A Chi-square value of 7.25 with a P = 0.027 signified a considerable higher distribution of the GG allele in the case group in comparison to the protective AA allele [Table 1]. A further assessment of the overall distribution of the G and A alleles in this Table clearly showed a significantly higher distribution of the mutant G allele among the case group with a Chi-square value of 6.35 and a P = 0.011. The odd's ratio interval of more than one for both lower and upper level of 95% confidence interval also strengthened the mutant G allele with PCa patients.
Table 1: Chi-square and odds ratio tests to show the distribution of the mutant and wild genotypes of the GSTP1, GSTM1, and GSTT1 single nucleotide polymorphisms between the case and control groups

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Regarding the distribution of the mutant null and wild genotypes of the GSTM1 and GSTT1 alleles, it was evident from the Chi-square values and odd's ratio that the presence of the deletional alleles in the case group was significantly higher as risk factors.

For assessing the association of the severity of Pca with different genotypes, simple one-way ANOVA followed by post hoc ANOVA with Bonferroni correction was done [Table 2]a and [Table 2]b.


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Post hoc ANOVA with Bonferroni correction helped to find out the significance between individual groups separately. Data indicated that in case of GSTP1 polymorphism, the severity of the disease was comparatively higher in the double mutant GG and mutant heterozygote AG genotypes in comparison to the protective AA phenotypes (mean difference 1.38 and 0.85, respectively, P < 0.001). However, independent t test between the two groups of deletional null variants and nondeletional wild variants of the GSTM1 and GSTT1 genotypes in the Pca patients showed no significant difference between their ISUP scores (P value 0.561 and 0.529, respectively. Furthermore, when the relative importance of the mutant null variants of the GSTM1 and GSTT1 was compared with the mutant G allele of the GSTP1 SNP in the context of their corresponding ISUP scores using independent t test, the results did not show a significant higher value of ISUP scores in the deletional mutant variants of GSTM1 and GSTT1 in the patient group compared to the patients having the normal A variant of the GSTP1 gene (P = 0.807). However, the ISUP score was found to be significantly higher in patients having the G variant of GSTP1 gene (P = 0.016) who did not show any deletional mutation in their GSTM1 and GSTT1 gene [Table 3]. These results clearly suggested that higher ISUP grades were associated with the G allele of the GSTP1 gene only.
Table 3: Independent sample t-test to show the difference in International society of urological pathologists scores between the GG/AG phenotype (G+ alleles) and other mutants i.e., GSTM (del ±) and GSTT (del ±) taken together

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These results have been further strengthened by the logistic regression analysis where the dependence of ISUP grading scores was assessed on the GSTP1, GSTM1, and GSTT1 genotypes by considering them as the independent predictive factor [Table 4]. It was found that with a Z value of 3.77 with a P = 0.001, ISUP grading was only significantly dependent on the GSTP1 polymorphism only without showing any significant dependence on the GSTT1 and GSTM1 polymorphisms with Z values of 0.15 and 0.58 and P = 0.52 and 0.55, respectively.
Table 4: Logistic regression analysis showing the dependence of International society of urological pathologists scores on GSTP1, GSTT1, and GSTM1 polymorphisms

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  Discussion Top


The GST gene and its expressed product GST enzyme are in fact a superfamily of several isoforms involved in the detoxification system of our body. Inside the cells, the nucleophilic form of the reduced GST enzymes is most efficiently utilized to neutralize the electrophilic foreign materials such as several drugs including chemotherapeutic agents, environmental pollutants, free radicals, etc., by the process of conjugation with glutathione. The major isoforms of this enzyme, i.e. the GSTP1, GSTM1, and GSTT1 are distributed widely in the epithelial tissues of different parts of the body including intestinal tracts, urinary bladder, lung, skin, prostate, etc., Hence, certain polymorphic variations in these genes are significantly associated with the decreased production of the corresponding enzymes leading to reduced detoxification of the toxic chemicals that is often associated with the development of cancers of different organs.[11],[12],[13],[14],[15]

In the transitional mutation of the GSTP1 gene where the A allele is replaced by the G allele at the 313th nucleotide, isoleucine is substituted by the more hydrophobic and smaller sized amino acid valine (Ile105Val) at the 105th position of the corresponding enzyme. It results in a decrease in both thermal stability and catalytic activity of the enzyme that leads to lesser detoxification of the carcinogenic xenobiotics, particularly the pro-oxidants heterocyclic amine carcinogens, leading to increased DNA damage, increased DNA adduct formation, and ultimately increased prevalence and severity of several cancers including the cancer of prostate.[26] Moreover, the mutant form has been found to inhibit the mitogenic protein c-jun N terminal kinase (c-jun) much less efficiently in comparison to its wild form that promotes the carcinogenic potentiality of the vulnerable cells.[27] Similarly, the deletional polymorphs/null variants of the GSTM1 and GSTT1 genes show impaired ability to detoxify and excrete several electrophile pro-carcinogens leading to increased susceptibility to a wide range of cancers.[24] These findings are reflected in [Table 2] which suggest that in our study population all these three mutations expose the patients to greater risk of carcinogens. Ineffective detoxification by the defective or deficient enzymes due to their genetic mutations has been reported as a plausible explanation for carcinogenesis in other places also in some recent studies.[28]

However, in spite of having a higher prevalence, the invasive effect of all these three mutations is not the same in Pca in all regions. Hence, after finding the increased prevalence of these mutations in our study population, we proceeded for determining the individual and combined gene to gene interaction of these mutations on the severity of Pca using its histopathological gradings. Although severity of Pca was assessed using both the Gleason's score and the grading system proposed by the ISUP,[29] we preferred the ISUP grading to Gleason's score due to its more precise histopathological grading system and more accurate gradation of the tissue invasion. Individual comparisons using simple one-way and post hoc ANOVA showed that among the three GSTP1 genotypes, the mutant GG and heterozygore GA alleles had significantly more ISUP scores in comparison to the wild AA allele that indicated increased severity and tissue spread in patients having the G allele of the GSTP1 gene. However, ISUP scores did not show any significant relationship with the null variants of the GSTM1 and GSTT1 genotypes indicating a lack of association of these two mutations with the severity and tissue spread of Pca in spite of their higher prevalence in the case group [Table 2]. For studying the combined effect, i.e. the gene to gene interaction of all genotypes on ISUP grading, we first performed the independent sample t test to compare between the effects of G alleles of GSTP1 SNP only (GG/AG mutants only) and all mutants taken together (G allele, GSTMdel+, and GSTTdel+) on the ISUP score [Table 1]. An insignificant difference of ISUP scores (P = 0.807) between these two groups, indicated no additional effect of the GSTMdel + and GSTTdel + null genotypes on the severity of the disease. This observation was further strengthened by a significant difference (P = 0.016) of the ISUP scores between the group having GG/AG mutants and the group having the mutant GSTM and GSTT variants without any GG/AG genotype [Table 1]. Hence, the results indicated that the disease severity was significantly more with the G allotype of the GSTP1 Ile105Val SNP when it was considered separately from the GSTM1 and GSTT1 null variants. The combinatorial effects of these mutations on the severity of Pca were confirmed by the multivariate logistic regression analysis [Table 4]. It showed a significant dependence of the ISUP scores on the G alleles of the GSTP1 only (z = 3.78, P < 0.001) when all three polymorphisms were considered together for their gene to gene interaction induced collective impact on the ISUP score. No, significant dependence of ISUP score was found on the other two mutations, i.e. the GSTM1 and GSTT1 (Z values of 0.587 and 0.153; and P = 0.55 and 0.52, respectively).

However, these results need to be interpreted in the context of several other studies undertaken throughout the world for assessing the gene to gene interaction and gene to environment interaction in Pca in different regions. Our findings correlate well with a Caucasian study reported by Kote-Jarai et al. where significant association of Ile105Val polymorphism of the GSTP1 gene was found with an early onset Pca with no association with GSTM1 and GSTT1 gene null variants[19] but not with an Iranian study where Safarinejad et al. (2011) reported a significantly increased risk of Pca in the Iranian population having three polymorphic variations of GSTM1 null variant, GSTT1 null variant and the Ile105Val variant of GSTP1 genes taken together.[30] We could not get any report about the effect of these polymorphisms on Pca in the eastern part of our country, and probably, this is the first report that assessed the relative importance of these three common mutants on the incidence and severity of Pca in this region.


  Conclusion Top


Among all three prevalent mutations in our study population, the disease severity and its progression are mainly attributed to the Ile105Val SNP of the GSTP1. As this SNPs was found to have in Hardy–Weinberg's equilibrium, it is supposed to be well equilibrated and established in our population group. Hence, the presence of this SNP is closely linked to the prognosis of Pca in our study region. An early detection of it in Pca patients may provide significant improvement in the overall management process of the disease with reduced mortality. The present research work further suggests an early screening of male persons with family history of Pca for these mutations in so that effective preventive measures and timely monitoring can be undertaken in them.

As a long-term impact, this study reiterates the fact that polymorphic variations linked to different cancers should be explored on the regional basis to find out the relative significance of them in different ethnic population groups.

Acknowledgments

We acknowledge Science and Technology and Biotechnology Department, Government of West Bengal for the financial support and funding vide project no. 81(Sanc)/ST/P/S and T/9G-12/2018.

Financial support and sponsorship

This research project is granted and funded by the Science and Technology and Biotechnology Department, Government of West Bengal, India, for the year 2019–2020.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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