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An Official Publication of the Indian Association of Oral and Maxillofacial Pathologists


 
  Table of Contents    
ORIGINAL ARTICLE  
Year : 2022  |  Volume : 26  |  Issue : 4  |  Page : 592
 

Null genotypes of Glutathione S-transferase M1 and T1 and risk of oral cancer: A meta-analysis


1 Professor and HOD Department of Oral Pathology, ESIC Dental College, Kalaburagi, Karnataka, India
2 Associate Professor, Department of Periodontics, ESIC Dental College, Kalaburagi, Karnataka, India
3 Dean, Professor and HOD, Department of OMFS, ESIC Dental College, Kalaburagi, Karnataka, India
4 Associate Professor, Department of Oral Pathology and Oral Medicine, Faculty of Dentistry, Mahsa University, Selangor, Malaysia

Date of Submission09-Dec-2021
Date of Decision25-Dec-2021
Date of Acceptance27-Dec-2021
Date of Web Publication22-Dec-2022

Correspondence Address:
K Vinod Kumar
Professor and HOD Department of Oral Pathology, ESIC Dental College, Kalaburagi, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jomfp.jomfp_435_21

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   Abstract 


Background: Glutathione S-transferase M1 (GSTM1) and Glutathione S-transferase T1 (GSTT1) null genotypes have been considered risk factors for many cancers. Numerous studies have been conducted to evaluate the association of null genotype of GSTM1 and GSTT1 with increased susceptibility to oral cancers, and these have produced inconsistent and inconclusive results. In the present study, the possible association of oral cancer(OC) with GSTM1 and GSTT1 null genotypes was explored by a meta analysis.
Materials and Methods: A meta-analysis was conducted on published original studies retrieved from the literature using a bibliographic search from two electronic databases: MEDLINE (National library of medicine, USA) and EMBASE. The pooled odds ratio and presence of publication bias in those studies were evaluated.
Results: A total of 49 studies concerning oral cancer (OC) were identified for GSTM1 null genotype. Similarly, 36 studies were identified for GSTT1 null genotype. The pooled OR was 1.551(95% confidence interval [CI]: 1.355–1.774) for the GSTM1 null genotype, while for GSTT1 null genotype, the pooled OR was 1.377 (95% CI: 1.155–1.642). No evidence of publication bias was detected among the included studies.
Conclusion: The results suggest that the Glutathione S-transferase M1 and Glutathione S-transferase T1 null genotypes significantly enhances the risk of developing oral cancer by a substantial percentage.


Keywords: GSTM1 null genotype, GSTT1 null genotype, head-and-neck neoplasm, meta-analysis, oral cancers, oral cavity polymorphisms


How to cite this article:
Kumar K V, Goturi A, Nagaraj M, Sekhar Goud E V. Null genotypes of Glutathione S-transferase M1 and T1 and risk of oral cancer: A meta-analysis. J Oral Maxillofac Pathol 2022;26:592

How to cite this URL:
Kumar K V, Goturi A, Nagaraj M, Sekhar Goud E V. Null genotypes of Glutathione S-transferase M1 and T1 and risk of oral cancer: A meta-analysis. J Oral Maxillofac Pathol [serial online] 2022 [cited 2023 Jan 27];26:592. Available from: https://www.jomfp.in/text.asp?2022/26/4/592/364813





   Introduction Top


Oral cancer (OC) is the most common cancer in the world, accounting for 2.0% of all cancers. In India, oral cancer is the leading cause of cancer death amongst men.[1] Eastern and Western Europe and Australia/New Zealand also show high incidence rates, and the etiology of oral cancer has been linked to tobacco smoking, HPV infection, and ultraviolet radiation.[2],[3],[4],[5],[6] However, oral cancer, is confined only to a fraction of individuals who are subjected to these etiological factors, demonstrating that cancer susceptibility varies from individual to individual. Therefore, variations in genetic host factors that contribute to carcinogenic pathways may have a role in the development of oral cancer susceptibility. The implication is that a genetic deficit in the enzymes that metabolise tobacco carcinogens is likely to have a role in a person's susceptibility to oral cancer.[6] Further more, animal studies that relate the association of carcinogens produced due to tobacco smoking with OCs, have bestowed the precise mechanism of oral carcinogenesis on abilities of metabolites formed as a resultant of tobacco smoking, to bind onto DNA forming DNA adducts.[7] Failure to repair such DNA adducts prior to DNA replication may induce mutation in oncogenes or tumor suppressor genes that can lead to malignant transformation of the cell and thereby initiating carcinogenesis.[8]

Further, these chemical carcinogens are eliminated by the action of xenobiotic metabolizing enzymes, that have molecular and cellular mechanisms for detoxifying and excreting harmful substances, and are distinguished into phase I and phase II enzymes. Phase I xenobiotic enzymes are involved in oxidation, reduction and hydroxylation, rendering hydrophobic substances into more hydrophilic in nature, which can easily be excretable,[9] examples of these enzymes include cytochrome P450s (CYPs), cyclooxygenases and aldo keto-reductases. Phase II xenobiotic enzymes are involved in introduction of polar groups moieties and thereby assisting in excretion.[9] Examples of phase II enzymes include uridine diphosphate glucuronosyltransferases, N, O-acetyltransferases, sulfotransferases and glutathione S-transferases (GSTs).

Glutathione-S-transferases (GSTs) a phase II enzymes, are known to protect cells from oxidative stress. Polymorphism of GSTM1 and GSTT1 has been extensively explored in various malignancies. It is hypothesized that any deleted variants of the GSTM1 and GSTT1 genes result in loss of functional activity, often reported as a factor influencing the individual susceptibility to cancer encouraging the concept of gene–environment interactions to Oral cancer risk.[10],[11],[12] However, this concept has been addressed by focal studies, but the results have been inconsistent and obscure.[10],[11],[12],[13] Further, a previous meta-analysis has rested GSTM1 null genotype and risk of OC to be associated with only in Asian population,[14] yet another recent study has a related association of GSTM1 null polymorphisms with increased risk of OC.[15] In addition to this, a recent meta-analysis on association of null genotype GSTT1[15] with OC suggests an increased risk of development of OC. However, this comes with limited literature due to criteria for selection of studies. Therefore, whether null genotypes of GSTM1 or GSTT1 is a risk factor for OC remains obscured. Hence, in the present study, an evidence-based quantitative meta-analysis was conducted to address this controversy.


   Materials and Methods Top


Selection of studies

Two investigators independently searched two electronic databases, MEDLINE (National Library of Medicine, USA) and EMBASE, for studies pertaining to the deficiency of enzymes GSTM1 and GSTT1 and the risk of oral cancer, covering all papers published up to October 2021. The search was conducted using the combination of the following search GSTM1, GSTT1, oral cancers, mouth neoplasm, glutathione, null genotype. Additional articles were also manually retrieved via the references cited in these publications and review articles.

The following criteria were used for the selection of articles for the meta-analysis: (1) Only studies which explicitly describe the association of oral squamous cell carcinoma with GSTM1/GSTT1 null genotypes; (2) The sources of cases and controls, as well as the histopathological diagnosis of oral squamous cell carcinoma, should be mentioned; (3) Individuals should have been genotyped solely through the use of polymerase chain reaction technique; (4) The sample size, odds ratios (ORs), and 95% CIs, as well as any other information that can be used to deduce the results should have been stated. Accordingly, the exclusion criteria used were: (1) design and the definition of the experiments were obviously different from those of the selected papers; (2) the sample size, source of cases and controls and other essential information was not presented and (3) reviews and literature that is repeated.

Extraction of data

Data from the selected articles were extracted and entered into MedCalc, version 20.018. The extraction was performed by two investigators independently. For conflicting evaluations, an agreement was reached following a discussion. For each study, the author, year of publication, country where the study was carried out, number, race and gender of patients and controls, control source (hospital based or population based) and matching of cases and controls were rigorously tabulated.

Statistical analysis

The OR of GSTM1 and GSTT1 polymorphisms in OCs for each study was recalculated and their corresponding 95% CIs were recorded. Presumption was made that all the studies considered are estimating different effect sizes (alternative hypothesis [HA]), and therefore, null hypothesis (H0) was that all studies are estimating the same effect size. To determine whether study heterogeneity exists or not, Q statistics was used, and the I2 statistic was used to quantify the percentage of variation across studies that is attributable to heterogeneity rather than chance.[16],[17] If, P value was ≤ 0.05, indicated evidence against the null hypothesis and null hypothesis was rejected and HA was accepted and ORs were pooled according to the random effect model by DerSimonian and Laird method,[18] otherwise fixed-effect model by inverse variance method was used.[9] To identify publication bias, Begg rank correlation and Egger regression test were used.[19]


   Results Top


A total of 51 studies associating GSTM1 null genotype with respect to oral squamous cell carcinoma were identified. After a careful review, two irrelevant studies were excluded based on the inclusion and exclusion criteria. The data Pertaining to one study as that of Park JY20 et al., for computing purpose in this meta-analysis, was divided into two as the study was performed in two different populations (African Americans and Caucasians) with a larger sample size and both the data were published in a single literature, accounting for two different populations. A database was established according to the extracted information from each published literature as indicated in [Table 1]. A total of 36 studies were listed for GSTT1 null genotype after excluding 1 study based on the inclusion and exclusion criteria, as indicated in [Table 2].
Table 1: Summary of studies on GSTM1 null genotype in oral cancer

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Table 2: Summary of studies on GSTT1 null genotype in oral cancer

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Out of 49 studies included in the meta-analysis of GSTM1, 33 studies came from Asian countries, 6 from European countries and 10 from American countries. The source of controls in all the studies of GSTM1 was predominantly hospital based followed by population based and combination of hospital and population based constituting 27 studies, 17 studies and 5 studies, respectively. The controls were matched with case's sex, age, geographical location, ethnicity and race in 22 studies, 20 studies, 7 studies, 9 studies and 4 studies, respectively. Socioeconomic status of cases was matched with controls in 4 studies, and in 1 study, hospital distribution was matched with controls. In 2 studies, control matching with cases was done with habits. In GSTT1 null genotype, there were 26 studies from Asian countries, 3 from European countries and 7 from American countries. Source of controls from 20 studies were hospital based, 13 studies were population based and 3 studies were mixed by hospital and population based. The controls were matched with case's sex, age, geographical location, ethnicity and race in 15 studies, 19 studies, 7 studies, 8 studies and 2 studies, respectively. Socioeconomic status of cases was matched with controls in 3 studies, and in 1 study, hospital distribution was matched with controls. In 4 studies, control matching with cases was done with habits. In 14 studies of GSTM1 and 10 studies of GSTT1, matching concerning case and control was not mentioned.

Population frequencies

A total of 7049 cases and 10,308 controls from 49 included case–control studies for GSTM1 null genotype were analyzed, out of which 3677 cases and 4200 controls showed the null genotype constituting 52.1% among the cases and 40.7% among the controls. Whereas, in GSTT1, 5169 cases and 7307 controls from 36 included case–control studies were analyzed, of which 1759 cases and 1849 controls showed the null genotype accounting for 34.02% among the cases and 25.3% among the controls.

Meta-analysis

Heterogeneity when tested for all the 50 studies of GSTM1 null genotype gave Chi-square-based Q-value of 267.6496 with 50 degrees of freedom (df), I2 of 81.32% and P = 0.0001, indicating heterogeneity across the studies. Therefore, a random-effect model was used and the overall OR for GSTM1 null genotype was 1.551 with 95% CI of 1.355–1.774 as indicated in [Figure 1]. On the basis of these findings, it is likely that GSTM1 null status significantly increases the susceptibility to OC.
Figure 1: Forest Plot of Odds Ratio of GSTM1 Deficiency and Risk of Developing Oral Cancer

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Likewise, heterogeneity test for all the 36 studies of GSTT1 null genotype yielded Chi-square-based Q-value of 183.8086 with 36 degrees of freedom (df), I2 of 80.41% and P = 0.0001, indicating heterogeneity across the studies. Hence, a random-effect model was used for GSTT1 null genotype also, which showed an overall OR of 1.377 with 95% CI of 1.155–1.642 as indicated in [Figure 2]. The data implied that GSTT1 null genotype was significantly associated with OC risk.
Figure 2: Forest Plot of Odds Ratio of GSTT1 Deficiency and Risk of Developing Oral Cancer

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For the diagnosis of publication bias, both Egger's test and Begg's test, when applied, showed no evidence of publication bias as P was 0.2454 and 0.2844 in GSTM1 and GSTT1 null genotype, respectively. Hence, none of the studies were excluded.


   Discussion Top


The synthesis, species-specific expression and distribution of GST are considered an evolutionary adaptive mechanism against endogenous and exogenous toxic metabolites.[21],[22] GST consists of three major families of proteins,[23] of which cytosolic GSTs (cGSTs) are extensively explored[9] and constitute a larger class divided into cGST alpha (A, α), mu (M, μ), Pi (pi, π), omega (ω), theta (T, θ), delta (δ), sigma (σ) and zeta (ζ)[21],[22],[24] and the GSTs have a critical role in cell growth, oxidative stress, as well as in disease progression and prevention. GST, demonstrate polymorphisms in humans, which may be a prime cause for interindividual variations in responses to xenobiotic.[21]

Likewise, in most of the cancers, genetic mechanism also influence the initation and progression of oral cancer. Further, OC is also found to be assosciated with environmental factors such as tobacco usage. Hence, it is important to evaluate the gene–environment interactions and also gene–gene interactions. However, only environmental risk factors are well established in the development of oral squamous cell carcinoma, whereas collaborative role of environmental factors and genetic polymorphisms has exhibited diversity with inconsistent results.[15] Considering the fact that the development of cancer is attributed to carcinogenic exposure, then the genetic mechanism governing the mechanics of carcinogen metabolism may be a probable mechanism to elucidate interindividual susceptibility.

However epidemiological studies have indicated the combined role of genetic and environmental factors in individual susceptibility to cancer.[25] Over the years, it has been postulated that a reduced detoxification by phase II enzymes was directly proportional to susceptibility to cancers,[26] which is emphasized by toxicology studies that associates increased sister chromatid exchange (SCE) in GSTM1 null genotype and baseline frequency of SCE in GSTT1 null genotype in tobacco smokers.[27],[28] Further, studies have correlated upregulation of GST with tumor stage and differentiation with GSTs.[28],[29] Hence, it is logical to believe that deprived status of these enzymes can contribute toward tumorigenesis and survival depending on the initiative stage or propagative stage of carcinogenesis respectively.

A large number of studies have contemplated the association of GSTM1 and GSTT1 deficiency and the risk of OC. Studies pertaining to GSTM1 and GSTT1 null genotypes have demonstrated complete abolished enzyme activities of GSTM1 and GSTT1, respectively. This may enhance the exposure of individuals to environmental toxins and carcinogens and may be responsible for an Individuals increased susceptibility to cancer[30]. However, these studies have produced inconsistent conclusions. Previous meta-analyses suggest that GSTM1 deficiency might modestly increase the risk of head-and-neck cancer.[31],[32],[33] In contrast to these, a number of meta-analyses indicated no marked association of GSTM1 null mutations with hepatocellular cancer,[34] gastric cancers,[35] brain tumors,[36] nasopharyngeal cancer[37] and prostate cancer.[38]

In a meta-analysis, pertaining to OC, Zhao et al.[14] have suggested that the effect of GSTM1 null polymorphisms on the risk of OC may differ by ethnicity, and that asian population with tobacco habits are at higher risk of developing OC. A meta-analysis, as that of Zhao et al.,[14] is limited with literature up to 2013 and therefore does not contain the published data of recent years, as that of Tanwar et al.[39] Maurya et al.,[40] Zakiullah et al.,[41] Dong et al.,[42] Rao et al.[43] and Saravani et al.[44] Further, studies as that of Maurya et al.,[40] Zakiullah et al.[41] and Dong et al.[42] consists of larger sample size which are adequately powered studies which can influence[45] the meta-analysis results. Yet, another study, as that of Lopes et al.,[15] indicates the association of GSTM1 null polymorphisms with increased risk of OC but the meta-analytic study of Lopes et al.[15] has left out initial studies as that of Deakin et al.[46] Hung et al.,[47] Park et al.,[48] Matthias et al.,[49] Jourenkova-Mironova et al.,[50] Katoh et al.,[51] Tanimoto et al.,[52] Sato et al.,[11] Park et al.,[20] Nomura et al.,[53] Sreelekha et al.,[54] Kietthubthew et al.,[55] Hahn et al.,[56] Buch et al.[57] Gronau et al.,[58] Sikdar et al.,[12] Xie et al.[13] Drumond et al.,[59] Majumder et al.[60] and Liu et al.[61] towards the association of GSTM1 null genotype with OC.

In addition to this, null genotype of GSTT1 has been suggested to increase the risk of numerous cancers such as lung cancer,[62] colorectal cancer,[63] gastric cancer,[64] leukemia,[32] head-and-neck cancer[30] and OC.[65],[66] In contrast, few studies did not find an association of GSTT1 null genotypes with a greater risk of OC.[67],[68],[69],[70] Very recent meta-analyses, as that of Lopes et al.,[15] have suggested that GSTT1 null polymorphisms may increase the risk of development of OC. Meta-analysis of Lopes et al.[15] has left out studies as that of M Deakin et al.,[45] Hung et al.,[46] Jourenkova-Mironova et al.,[50] Katoh et al.,[51] Sreelekha et al.,[54] Kietthubthew et al.,[55] Buch et al.,[57] Gronau et al.,[58] Sikdar et al.,[12] Xie et al.,[13] Drumond et al.,[66] Majumder et al.[60] and Liu et al.[61] Out of these nonincluded studies, three studies are of adequately powered studies, two studies as that of Buch et al.[57] and Majumder et al.[60] negate the association of GSTT1 null genotype with OC and one study as that of Sikdar et al.[12] only relates GSTT1 polymorphism among heavy chewers with OCs. Thus, these studies may influence the meta-analysis results. These ambiguous views created the necessity of meta-analysis to extract an estimate of risk associated with GSTM1 and GSTT1 null status with susceptibility to OC.

The presented meta-analysis from 50 published studies (The data Pertaining Park,[20] divided into two studies) suggests that null genotype of GSTM1 and null genotype of GSTT1 are significantly (P = 0.0001) associated with a modestly increased risk of OC, which may be attributed to expression of GST enzymes in the squamous mucosa of the head and neck[71],[72],[73] and secondly to activation of benzo[a] pyrene-7,8-dihydrodiol-9,10-oxide (benzo[a] pyrene) which later transforms into 7,8-diol-9,10-epoxide in tobacco-associated OC patients.[74],[75] This 7,8-diol-9,10-epoxide is an identifiable substrate for the GSTM1 enzyme. GSTM1 null genotype individuals with adverse habits of tobacco accumulate more DNA adducts through their inefficiency at excreting activated carcinogens such as 7,8-diol-9,10-epoxide.[74],[75] Further, if these DNA adducts, starts accumulating at locus of oncogenes or tumor suppressor genes, leads to somatic mutation and disruption of the cell cycle,which may lead to carcinogenesis.[76] Further, the ORs of null GSTM1 and null GSTT1 varied with geographic location. The prevalence of these genotypes in controls varied widely among and within regions. The data pertaining to GSTT1 null genotype meta-analysis from 36 studies showed that GSTT1 deficiency was associated with OC. This may be attributed to multifactorial role of the GSTT1, both activation and detoxification process, expression of GSTT1 in red blood cells resulting in more generalized detoxification process[9] and expression of GSTT1 in the squamous mucosa of the head and neck.[71],[72],[73] In the present meta-analysis, GSTT1 null genotype was a significant risk factor for OC, in line with meta-analysis of esophageal cancers,[37] prostate cancer,[38] breast cancer[77] and OC.[15]

Within ethnic groups, categorization appears to be subjective and varied. There exists no unanimity on defining an “ethnic group.” In consequence, ethnic groups, regardless how it is defined, will tend to evolve around social and political attitudes or developments.[78] Hence, basing ethnic identification upon an objective and rigid classification is nonreasonable. Down to the ground, in the meta-analysis, most of the studies relied on geographical location for ethnicity and failed to define a criterion for ethnicity-based recruitment of OC subjects and controls for the study. In the present meta-analysis, the pooled ORs for different ethnic groups was not conducted for two reasons: first, the stratification of studies based on ethnicity would have been vague and spurious, and second, due to the number of studies in each stratum defining particular ethnic group other than Asians would be very few or absent.

In the meta-analysis, the evidence of heterogeneity was observed across studies. The reasons for this might be methodological diversity, especially with arbitrary recruitment of cancer subjects and use of hospital based controls.[9] Nevertheless, from sensitivity analysis, it was found that studies that contributed toward heterogeneity did not demonstrate any significant alteration in the estimated overall OR. Since only published studies were utilized in the meta-analysis, the combination of Egger's and Begg's test did not indicate the evidence of publication bias indicating results of the present study to be stable and credible.


   Conclusion Top


In conclusion, the findings of this meta-analysis study suggest a significant role of GSTM1and GSTT1 null genotype in increasing the risk for OC; these findings have to be viewed with caution, as it contained substantial heterogeneity across studies. However, the estimated risk is tainted by heterogeneity across the studies and lack of exhaustive study designs. Further, studies with larger sample size exploring GSTM1and GSTT1 null genotypes among various demographic subgroups with optimum study design are needed to precisely conclude on risk of development of OC in individuals with GSTM1 or GSTT1 null genotype and habits of consumption of tobacco.

Acknowledgement

We thank Mr. Gaurav Srivastav; BA; MPA; ESIC Dental College, Kalaburagi…, for his extensive technical assistance.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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