Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contact Us Login 
An Official Publication of the Indian Association of Oral and Maxillofacial Pathologists

  Table of Contents    
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
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jomfp.jomfp_435_21

Rights and Permissions



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

Click here to view
Table 2: Summary of studies on GSTT1 null genotype in oral cancer

Click here to view

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.


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

Click here to view

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

Click here to view

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.


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

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A,Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA CANCER J CLIN 2021;71:209-49.  Back to cited text no. 1
Gupta S, Gupta R, Sinha DN, Mehrotra R. Relationship between type of smokeless tobacco and risk of cancer: a systematic review. Indian J Med Res. 2018;148:56-76.  Back to cited text no. 2
Bagnardi V, Rota M, Botteri E, et al. Alcohol consumption and site-specific cancer risk: a comprehensive dose-response meta-analysis. Br J Cancer. 2015;112:580-93.  Back to cited text no. 3
Han AY, Kuan EC, Mallen-St Clair J, Alonso JE, Arshi A, St John MA. Epidemiology of squamous cell carcinoma of the lip in the United States: a population-based cohort analysis. JAMA Otolaryngol Head Neck Surg. 2016;142:1216-23.  Back to cited text no. 4
Rigel DS. Cutaneous ultraviolet exposure and its relationship to the development of skin cancer. J Am Acad Dermatol. 2008;58(5 suppl 2):S129-S132.  Back to cited text no. 5
Gupta PC, Murti PR, Bhonsle RB, Mehta FS, Pindborg JJ. Effect of cessation of tobacco use on the incidence of oral mucosal lesions in a 10-yr follow-up study of 12,212 users. Oral Dis 1995;1:54-8.  Back to cited text no. 6
Warnakulasuriya KA, Johnson NW, Linklater KM, Bell J. Cancer of mouth, pharynx and nasopharynx in Asian and Chinese immigrants resident in Thames regions. Oral Oncol 1999;35:471-5.  Back to cited text no. 7
Krais A.M., Singh R., Arlt V.M. Carcinogen-DNA adducts. In: Boffetta P., Hainaut P., editors. Encyclopedia of Cancer. 3rd ed. Academic Press; Cambridge, MA, USA: 2018. pp. 282-95.  Back to cited text no. 8
Kumar V, Murthy AK, Suresh KP. Glutathione S-transferase M1 and T1 status and the risk of laryngeal cancer: A meta-analysis. Asian Pac J Cancer Prev 2011;12:2221-6.  Back to cited text no. 9
Evans AJ, Henner WD, Eilers KM, Montalto MA, Wersinger EM, Andersen PE, et al. Polymorphisms of GSTT1 and related genes in head and neck cancer risk. Head Neck 2004;26:63-70.  Back to cited text no. 10
Sato M, Sato T, Izumo T, Amagasa T. Genetic polymorphism of drug-metabolizing enzymes and susceptibility to oral cancer. Carcinogenesis 1999;20:1927-31.  Back to cited text no. 11
Sikdar N, Paul RR, Roy B. Glutathione S-transferase M3 (A/A) genotype as a risk factor for oral cancer and leukoplakia among Indian tobacco smokers. Int J Cancer 2004;109:95-101.  Back to cited text no. 12
Xie H, Hou L, Shields PG, Winn DM, Gridley G, Bravo-Otero E, et al. Metabolic polymorphisms, smoking, and oral cancer in Puerto Rico. Oncol Res 2004;14:315-20.  Back to cited text no. 13
Zhao SF, Yang XD, Lu MX, Sun GW, Wang YX, Zhang YK, et al. GSTM1 null polymorphisms and oral cancer risk: A meta-analysis. Tumour Biol 2014;35:287-93.  Back to cited text no. 14
Lopes AK, Tacca AL, Nogueira NA, Sodario JA, Vilanova-Costa CA, Saddi VA, et al. Evidence of association of glutathione-S transferase GSTT1 and GSTM1 null genotypes with susceptibility to oral cancer based on meta-analysis. Genet Mol Res 2020;19:Gmr18712.  Back to cited text no. 15
Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539-58.  Back to cited text no. 16
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60.  Back to cited text no. 17
Cooper HM, Hedges LV. The Handbook of Research Synthesis. Vol. 236. New York: Russell Sage Foundation; 1994.  Back to cited text no. 18
Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088-101.  Back to cited text no. 19
Park JY, Muscat JE, Kaur T, Schantz SP, Stern JC, John P. Richie JP and Lazarus P. Comparison of GSTM polymorphisms and risk for oral cancer between African-Americans and Caucasians. Pharmacogenetics 2000,10:123-31.  Back to cited text no. 20
Hayes JD, Flanagan JU, Jowsey IR. Glutathione transferases. Annu Rev Pharmacol Toxicol 2005;45:51-88.  Back to cited text no. 21
Zimniak P, Singh SP. Families of glutathione transferases. In: Taylor Awasthi YC, editors. Toxicology of Glutathione Transferases. Boca Raton, Fl, USA: Francis CRC Press; 2006;11-26.  Back to cited text no. 22
Ladner JE, Parsons JF, Rife CL, Gilliland GL, Armstrong RN. Parallel evolutionary pathways for glutathione transferases: Structure and mechanism of the mitochondrial class kappa enzyme rGSTK1-1. Biochemistry 2004;43:352-61.  Back to cited text no. 23
Allocati N, Federici L, Masulli M, Di Ilio C. Glutathione transferases in bacteria. FEBS J 2009;276:58-75.  Back to cited text no. 24
Varela-Lema L, Taioli E, Ruano-Ravina A, Barros-Dios JM, Anantharaman D, Benhamou S, et al. Meta-analysis and pooled analysis of GSTM1 and CYP1A1 polymorphisms and oral and pharyngeal cancers: A HuGE-GSEC review. Genet Med 2008;10:369-84.  Back to cited text no. 25
Parl FF. Glutathione S-transferase genotypes and cancer risk. Cancer Lett 2005;221:123-9.  Back to cited text no. 26
Norppa H. Cytogenetic biomarkers. IARC Sci Publ 2004;157:179-205.  Back to cited text no. 27
Wiencke JK, Pemble S, Ketterer B, Kelsey KT. Gene deletion of glutathione S-transferase theta: Correlation with induced genetic damage and potential role in endogenous mutagenesis. Cancer Epidemiol Biomarkers Prev 1995;4:253-9.  Back to cited text no. 28
Chen YK, Lin LM. Evaluation of glutathione S-transferase activity in human buccal epithelial dysplasias and squamous cell carcinomas. Int J Oral Maxillofac Surg 1997;26:205-9.  Back to cited text no. 29
Patel BP, Rawal UM, Shah PM, Prajapati JA, Rawal RM, Dave TK, et al. Study of tobacco habits and alterations in enzymatic antioxidant system in oral cancer. Oncology 2005;68:511-9.  Back to cited text no. 30
Hashibe M, Brennan P, Strange RC, Bhisey R, Cascorbi I, Lazarus P, et al. Meta- and pooled analyses of GSTM1, GSTT1, GSTP1, and CYP1A1 genotypes and risk of head and neck cancer. Cancer Epidemiol Biomarkers Prev 2003;12:1509-17.  Back to cited text no. 31
Tripathy CB, Roy N. Meta-analysis of glutathione S-transferase M1 genotype and risk toward head and neck cancer. Head Neck 2006;28:217-24.  Back to cited text no. 32
Ye Z, Song H. Glutathione s-transferase polymorphisms (GSTM1, GSTP1 and GSTT1) and the risk of acute leukaemia: A systematic review and meta-analysis. Eur J Cancer 2005;41:980-9.  Back to cited text no. 33
White DL, Li D, Nurgalieva Z, El-Serag HB. Genetic variants of glutathione S-transferase as possible risk factors for hepatocellular carcinoma: A HuGE systematic review and meta-analysis. Am JEpidemiol 2008;167:377-89.  Back to cited text no. 34
La Torre G, Boccia S, Ricciardi G. Glutathione S-transferase M1 status and gastric cancer risk: A meta-analysis. Cancer Lett 2005;217:53-60.  Back to cited text no. 35
Lai R, Crevier L, Thabane L. Genetic polymorphisms of glutathione S-transferases and the risk of adult brain tumors: A meta-analysis. Cancer Epidemiol Biomarkers Prev 2005;14:1784-90.  Back to cited text no. 36
Yang CX, Matsuo K, Wang ZM, Tajima K. Phase I/II enzyme gene polymorphisms and esophageal cancer risk: A meta-analysis of the literature. World J Gastroenterol 2005;11:2531-8.  Back to cited text no. 37
Ntais C, Polycarpou A, Ioannidis JP. Association of GSTM1, GSTT1,and GSTP1 gene polymorphisms with the risk of prostate cancer: A meta-analysis. Cancer Epidemiol Biomarkers Prev 2005;14:176-81.  Back to cited text no. 38
Tanwar R, Iyengar AR, Nagesh KS, Patil S, Subhash BV. Prevalence of glutathione S-transferase M1 null polymorphism in tobacco users, oral leukoplakia and oral squamous cell carcinoma patients in south Indian population: A polymerase chain reaction study. Contemp Clin Dent 2015;6:S59-64.  Back to cited text no. 39
Maurya SS, Katiyar T, Dhawan A, Singh S, Jain SK, Pant MC, et al. Gene-environment interactions in determining differences in genetic susceptibility to cancer in subsites of the head and neck. Environ Mol Mutagen 2015;56:313-21.  Back to cited text no. 40
Zakiullah, Khisroon AM, Saeed M, Khan A, Khuda F, Ali S,Javed N,Ovais M, Masood N, Khalil NK, Ismail M . Genetic susceptibility to oral cancer due to combined effects of GSTT1, GSTM1and CYP1A1 gene variants in tobacco addicted patients of Pashtun ethnicity of Khyber Pakhtunkhwa province of Pakistan. Asian Pac J Cancer Prev 2015;16:1145-50.  Back to cited text no. 41
Dong TT, Wang LJ, Liu LZ, Ma SN. Susceptibility to oral squamous cell carcinoma: Correlation with variants of CYP1A1-MspI, GSTT1, GSTM1, ALDH2, EC-SOD and Lifestyle factors. Balkan J Med Genet 2016;19:61-70.  Back to cited text no. 42
Rao AK, Parameswar P, Majumdar S, Uppala D, Kotina S, Vennamaneni NH. Evaluation of genetic polymorphisms in glutathione S-transferase theta1, glutathione S-transferase Mu1, and glutathione S-transferase Mu3 in oral leukoplakia and oral squamous cell carcinoma with deleterious habits using polymerase chain reaction. Int J Appl Basic Med Res 2017;7:181-5.  Back to cited text no. 43
Saravani S, Miri-Moghaddam M, Bazi A, Miri-Moghaddam E. Association of glutathione-S-transferases M1 and T1 deletional variants with development of oral squamous cell carcinoma: A study in the South-East of Iran. Asian Pac J Cancer Prev 2019;20:1921-6.  Back to cited text no. 44
Kraemer HC, Gardner C, Brooks JO 3rd, Yesavage JA. Advantages of excluding underpowered studies in meta-analysis: Inclusionist versus exclusionist viewpoints. Psychol Methods 1998;3:23-31.  Back to cited text no. 45
Deakin M, Elder J, Hendrickse C, Peckham D, Baldwin D, Pantin C, et al. Glutathione S-transferase GSTT1 genotypes and susceptibility to cancer: Studies of interactions with GSTM1 in lung, oral, gastric and colorectal cancers. Carcinogenesis 1996;17:881-4.  Back to cited text no. 46
Hung HC, Chuang J, Chien YC, Chern HD, Chiang CP, Kuo YS, et al. Genetic polymorphisms of CYP2E1, GSTM1, and GSTT1; environmental factors and risk of oral cancer. Cancer Epidemiol Biomarkers Prev 1997;6:901-5.  Back to cited text no. 47
Park JY, Muscat JE, Ren Q, Schantz SP, Harwick RD, Stern JC, et al. CYP1A1 and GSTM1 polymorphisms and oral cancer risk. Cancer Epidemiol Biomarkers Prev 1997;6:791-7.  Back to cited text no. 48
Matthias C, Bockmühl U, Jahnke V, Jones PW, Hayes JD, Alldersea J, et al. Polymorphism in cytochrome P450 CYP2D6, CYP1A1, CYP2E1 and glutathione S-transferase, GSTM1, GSTM3, GSTT1 and susceptibility to tobacco-related cancers: Studies in upper aerodigestive tract cancers.Pharmacogenetics 1998;8:91-100.  Back to cited text no. 49
Jourenkova-Mironova N, Voho A, Bouchardy C, Wikman H, Dayer P, Benhamou S, et al. Glutathione S-transferase GSTM1, GSTM3, GSTP1 and GSTT1 genotypes and the risk of smoking-related oral and pharyngeal cancers. Int J Cancer 1999;81:44-8.  Back to cited text no. 50
Katoh T, Kaneko S, Kohshi K, Munaka M, Kitagawa K, Kunugita N, et al. Genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and oral cavity cancer. Int J Cancer 1999;83:606-9.  Back to cited text no. 51
Tanimoto K, Hayashi S, Yoshiga K, Ichikawa T. Polymorphisms of the CYP1A1 and GSTM1 gene involved in oral squamous cell carcinoma in association with a cigarette dose. Oral Oncol 1999;35:191-6.  Back to cited text no. 52
Nomura T, Noma H, Shibahara T, Yokoyama A, Muramatusu T, Ohmori T. Aldehyde dehydrogenase 2 and glutathione S-transferase M 1 polymorphisms in relation to the risk for oral cancer in Japanese drinkers. Oral Oncol 2000;36:42-6.  Back to cited text no. 53
Sreelekha TT, Ramadas K, Pandey M, Thomas G, Nalinakumari KR, Pillai MR. Genetic polymorphism of CYP1A1, GSTM1 and GSTT1 genes in Indian oral cancer. Oral Oncol 2001;37:593-8.  Back to cited text no. 54
Kietthubthew S, Sriplung H, Au WW. Genetic and environmental interactions on oral cancer in Southern Thailand. Environ Mol Mutagen 2001;37:111-6.  Back to cited text no. 55
Hahn M, Hagedorn G, Kuhlisch E, Schackert HK, Eckelt U. Genetic polymorphisms of drug-metabolizing enzymes and susceptibility to oral cavity cancer. Oral Oncol 2002;38:486-90.  Back to cited text no. 56
Buch SC, Notani PN, Bhisey RA. Polymorphism at GSTM1, GSTM3 and GSTT1 gene loci and susceptibility to oral cancer in an Indian population. Carcinogenesis 2002;23:803-7.  Back to cited text no. 57
Gronau S, Koenig-Greger D, Jerg M, Riechelmann H. GSTM1 enzyme concentration and enzyme activity in correlation to the genotype of detoxification enzymes in squamous cell carcinoma of the oral cavity. Oral Dis 2003;9:62-7.  Back to cited text no. 58
Drummond SN, De Marco L, Noronha JC, Gomez RS. GSTM1 polymorphism and oral squamous cell carcinoma. Oral Oncol 2004;40:52-5.  Back to cited text no. 59
Majumder M, Sikdar N, Paul RR, Roy B. Increased risk of oral leukoplakia and cancer among mixed tobacco users carrying XRCC1 variant haplotypes and cancer among smokers carrying two risk genotypes: One on each of two loci, GSTM3 and XRCC1 (Codon 280). Cancer Epidemiol Biomarkers Prev 2005;14:2106-12.  Back to cited text no. 60
Liu CJ, Chang CS, Lui MT, Dang CW, Shih YH, Chang KW. Association of GST genotypes with age of onset and lymph node metastasis in oral squamous cell carcinoma. J Oral Pathol Med 2005;34:473-7.  Back to cited text no. 61
Hosgood HD 3rd, Berndt SI, Lan Q. GST genotypes and lung cancer susceptibility in Asian populations with indoor air pollution exposures: A meta-analysis. Mutat Res 2007;636:134-43.  Back to cited text no. 62
Chen K, Jiang QT, He HQ. Relationship between metabolic enzyme polymorphism and colorectal cancer. World J Gastroenterol 2005;11:331-5.  Back to cited text no. 63
Saadat M. Genetic polymorphisms of glutathione S-transferase T1 (GSTT1) and susceptibility to gastric cancer: A meta-analysis. Cancer Sci 2006;97:505-9.  Back to cited text no. 64
Guo L, Zhang C, Shi S, Guo X. Correlation between smoking and the polymorphisms of cytochrome P450 1A1-Msp I and glutathione S-transferase T1 genes and oral cancer. Hua Xi Kou Qiang Yi Xue Za Zhi 2012;30:187-91.  Back to cited text no. 65
Drummond SN, Gomez RS, Motta Noronha JC, Pordeus IA, Barbosa AA, De Marco L. Association between GSTT-1 gene deletion and the susceptibility to oral squamous cell carcinoma in cigarette-smoking subjects. Oral Oncol 2005;41:515-9.  Back to cited text no. 66
Biselli JM, de Angelo Calsaverini Leal RC, Ruiz MT, Goloni-Bertollo EM, Maníglia JV, Rossit AR, et al. GSTT1 and GSTM1 polymorphism in cigarette smokers with head and neck squamous cell carcinoma. Braz J Otorhinolaryngol 2006;72:654-8.  Back to cited text no. 67
Sugimura T, Kumimoto H, Tohnai I, Fukui T, Matsuo K, Tsurusako S, et al. Gene-environment interaction involved in oral carcinogenesis: Molecular epidemiological study for metabolic and DNA repair gene polymorphisms. J Oral Pathol Med 2006;35:11-8.  Back to cited text no. 68
Amtha R, Ching CS, Zain R, Razak IA, Basuki B, Roeslan BO, et al. GSTM1, GSTT1 and CYP1A1 polymorphisms and risk of oral cancer: A case-control study in Jakarta, Indonesia. Asian Pac J Cancer Prev 2009;10:21-6.  Back to cited text no. 69
Yadav DS, Devi TR, Ihsan R, Mishra AK, Kaushal M, Chauhan PS, et al. Polymorphisms of glutathione-S-transferase genes and the risk of aerodigestive tract cancers in the Northeast Indian population. Genet Test Mol Biomarkers 2010;14:715-23.  Back to cited text no. 70
Pacifici GM, Franchi M, Bencini C, Repetti F, Di Lascio N, Muraro GB. Tissue distribution of drug-metabolizing enzymes in humans. Xenobiotica 1988;18:849-56.  Back to cited text no. 71
Moscow JA, Fairchild CR, Madden MJ, Ransom DT, Wieand HS, O'Brien EE, et al. Expression of anionic glutathione-S-transferase and P-glycoprotein genes in human tissues and tumors. Cancer Res 1989;49:1422-8.  Back to cited text no. 72
Howie AF, Forrester LM, Glancey MJ, Schlager JJ, Powis G, Beckett GJ, et al. Glutathione S-transferase and glutathione peroxidase expression in normal and tumour human tissues. Carcinogenesis 1990;11:451-8.  Back to cited text no. 73
Chuang CY, Tung JN, Su MC, Wu BC, Hsin CH, Chen YJ, et al. BPDE-like DNA adduct level in oral tissue may act as a risk biomarker of oral cancer. Arch Oral Biol 2013;58:102-9.  Back to cited text no. 74
Blot WJ, McLaughlin JK, Winn DM, Austin DF, Greenberg RS, Preston-Martin S, et al. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res 1988;48:3282-7.  Back to cited text no. 75
Hecht SS. Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 1999;91:1194-210.  Back to cited text no. 76
Vogl FD, Taioli E, Maugard C, Zheng W, Pinto LF, Ambrosone C, et al. Glutathione S-transferases M1, T1, and P1 and breast cancer: A pooled analysis. Cancer Epidemiol Biomarkers Prev 2004;13:1473-9.  Back to cited text no. 77
Ethnic Group Statistics: A Guide for the Collection and Classification of Ethnicity Data. London : A National Statistics Publication; 2003.  Back to cited text no. 78
Huang P, An Y, Wu C, Meng X. GSTT1, GSTM1 polymorphisms, and oral and maxillofacial cancer. J Pract Oncol (Chin) 2006;21:39-42  Back to cited text no. 79
Sharma A, Mishra A, Das BC, Sardana S, Sharma JK. Genetic polymorphism at GSTM1 and GSTT1 gene loci and susceptibility to oral cancer. Neoplasma 2006;53:309-15.  Back to cited text no. 80
Gattás GJ, de Carvalho MB, Siraque MS, Curioni OA, Kohler P, Eluf-Neto J, et al. Genetic polymorphisms of CYP1A1, CYP2E1, GSTM1, and GSTT1 associated with head and neck cancer. Head Neck 2006;28:819-26.  Back to cited text no. 81
Cha IH, Park JY, Chung WY, Choi MA, Kim HJ, Park KK. Polymorphisms of CYP1A1 and GSTM1 genes and susceptibility to oral cancer. Yonsei Med J 2007;48:233-9.  Back to cited text no. 82
Anantharaman D, Chaubal PM, Kannan S, Bhisey RA, Mahimkar MB. Susceptibility to oral cancer by genetic polymorphisms at CYP1A1, GSTM1 and GSTT1 loci among Indians: Tobacco exposure as a risk modulator. Carcinogenesis 2007;28:1455-62.  Back to cited text no. 83
Hatagima A, Costa EC, Marques CF, Koifman RJ, Boffetta P, Koifman S. Glutathione S-transferase polymorphisms and oral cancer: A case-control study in Rio de Janeiro, Brazil. Oral Oncol 2008;44:200-7.  Back to cited text no. 84
Losi-Guembarovski R, Cólus IM, De Menezes RP, Poliseli F, Chaves VN, Kuasne H, et al. Lack of association among polymorphic xenobiotic-metabolizing enzyme genotypes and the occurrence and progression of oral carcinoma in a Brazilian population. Anticancer Res 2008;28:1023-8.  Back to cited text no. 85
Bathi RJ, Rao R, Mutalik S. GST null genotype and antioxidants: Risk indicators for oral pre-cancer and cancer. Indian J Dent Res 2009;20:298-303.  Back to cited text no. 86
[PUBMED]  [Full text]  
Chen MK, Tsai HT, Chung TT, Chih SS, Kao TY, Tseng HC, et al. Glutathione S transferase P1 and alpha gene variants; role in susceptibility and tumour size development of oral cancer. Head and Neeck 2010;32:1079-87.  Back to cited text no. 87
Sharma R, Ahuja M, Panda NK, Khullar M. Combined effect of smoking and polymorphisms in tobacco carcinogen-metabolizing enzymes CYP1A1 and GSTM1 on the head and neck cancer risk in North Indians. DNA Cell Biol 2010;29:441-8.  Back to cited text no. 88
Cordero K, Espinoza I, Caceres D, Roco A, Miranda C, Squicciarini V, et al. Oral cancer susceptibility associated with the CYP1A1 and GSTM1 genotypes in Chilean individuals. Oncol Lett 2010;1:549-53.  Back to cited text no. 89
Masood N, Kayani MA, Malik FA, Mahjabeen I, Baig RM, Faryal R. Genetic variation in carcinogen metabolizing genes associated with oral cancer in Pakistani population. Asian Pac J Cancer Prev 2011;12:491-5.  Back to cited text no. 90
Lourenço GJ, Silva EF, Rinck-Junior JA, Chone CT, Lima CS. CYP1A1, GSTM1 and GSTT1 polymorphisms, tobacco and alcohol status and risk of head and neck squamous cell carcinoma. Tumour Biol 2011;32:1209-15.  Back to cited text no. 91
Ruwali M, Singh M, Pant MC, Parmar D. Polymorphism in glutathione S-transferases: Susceptibility and treatment outcome for head and neck cancer. Xenobiotica 2011;41:1122-30.  Back to cited text no. 92
Shukla D, Dinesh Kale A, Hallikerimath S, Vivekanandhan S, Venkatakanthaiah Y. Genetic polymorphism of drug metabolizing enzymes (GSTM1 and CYP1A1) as risk factors for oral premalignant lesions and oral cancer. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2012;156:253-9.  Back to cited text no. 93
Zhang C, Guo L, GuoX. Correlation of the polymorphism of EC-SOD and GSTM1 and smoking with oral cancer risk. Wei Sheng Yan Jiu 2012;41:555-61.  Back to cited text no. 94
Mondal R, Ghosh SK, Choudhury JH, Seram A, Sinha K, Hussain M, et al. Mitochondrial DNA copy number and risk of oral cancer: A report from Northeast India. PLoS One 2013;8:e57771.  Back to cited text no. 95
Singh RD, Haridas N, Shah FD, Patel JB, Shukla SN, Patel PS. Gene polymorphisms, tobacco exposure and oral cancer susceptibility: Astudy from Gujarat, West India. Oral Dis 2014;20:84-93.  Back to cited text no. 96
D' Mello S, Bavle RM, Paremala K, Makarla S, Sudhakara M, Bhatt M. The synergy of tobacco and alcohol and glutathione S-transferase θ 1 gene deletion and oral squamous cell carcinoma. J Oral Maxillofac Pathol 2016;20:348-53.  Back to cited text no. 97


  [Figure 1], [Figure 2]

  [Table 1], [Table 2]


Print this article  Email this article


    Similar in PUBMED
    Search Pubmed for
    Search in Google Scholar for
  Related articles
    Article in PDF (1,004 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  

    Materials and Me...
    Article Figures
    Article Tables

 Article Access Statistics
    PDF Downloaded18    
    Comments [Add]    

Recommend this journal

Journal of Oral and Maxillofacial Pathology | Published by Wolters Kluwer - Medknow
Online since 15th Aug, 2007