Browse Subject Areas

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Association between GSTM1 and GSTT1 Allelic Variants and Head and Neck Squamous Cell Cancinoma

Association between GSTM1 and GSTT1 Allelic Variants and Head and Neck Squamous Cell Cancinoma

  • Yang Zhang, 
  • Yuanyuan Ni, 
  • Hao Zhang, 
  • Yongchu Pan, 
  • Junqing Ma, 
  • Lin Wang



GSTM1 and GSTT1 are involved in the detoxification of carcinogens such as smoking by-products, and polymorphisms in these two genes with a result of loss of enzyme activity may increase risk of carcinogenesis. Although many epidemiological studies have investigated the association between GSTM1 or GSTT1 null genotype and head and neck squamous cell carcinoma (HNSCC), the results remain conflicting. To elucidate the overall association of GSTM1, GSTT1 and HNSCC, we included all available studies and performed this meta-analysis.

Methodology/Principal Findings

A dataset including 42 articles for GSTM1, 32 articles for GSTT1, and 15 articles for GSTM1 and GSTT1 in combination were identified by a search in PubMed. Associations beween HNSCC and polymorphisms of GSTM1 and GSTT1 alone and in combination were analysed by software RevMan 5.1. Stratification analysis on ethnicity and smoking status, sensitivity analysis, heterogeneity among studies and their publication bias were also tested. Association was found in overall analysis between HNSCC and GSTM1 and GSTT1 null genotype. Stratified by ethnicity, we found increased risks of HNSCC in carriers with GSTM1 null genotype in Asian, GSTT1 null genotype in South American, and dual null genotype in European and Asian. When stratified by smoking, a more significant association of GSTM1 null genotype with HNSCC risk was observed in smokers.


This meta-analysis presented additional evidence of the association between GSTM1 and GSTT1 polymorphisms and HNSCC risk.


Head and neck neoplasms are the sixth leading cause of death by cancer [1]. The most common histological type is the squamous cell carcinoma, accounting for about 90% of all cases [2], [3]. Being a multifactorial disease, the etiology of head and neck squamous cell carcinoma (HNSCC) is still a much debated question. Smoking of cigarettes, consumption of alcohol and genetic causes are some of the foci of former etiological studies.

Enzymes of the glutathione S-transferase (GST) family are present in eukaryotes and in prokaryotes, which are composed of many cytosolic, mitochondrial, and microsomal proteins. They catalyze various reactions and participate in the phase II biotransformation of xenobiotics. GSTs contribute to the detoxification of by-products of smoking and alcohol and other exogenous chemical carcinogens which may induce HNSCC, so they have been considered as potential candidates for HNSCC susceptibility. Classesι and μ of the GST superfamily have been paid lots of attention, which are encoded by GSTT1 and GSTM1 genes. The GSTM1 and GSTT1 gene have been localized to chromosome 1p13.3 and 22q11.2. Both of the genes are polymorphic and frequent homozygous deletions of the genes presenting null genotype are associated with loss of the corresponding enzyme activity. Therefore, carriers with null genotype will increase the risk of the development of HNSCC due to the decreased ability to detoxify carcinogens theoretically.

In 2003, a meta-analysis conducted by Hashibe et al. indicated modest associations of GSTM1 and GSTT1 genotypes with head and neck cancer risk [4]. However, more than twenty independent studies from various populations have further examined the relationships between these two genes and HNSCC risk, and still reported conflicting results. Some studies in HNSCC have indicated that the null genotype of GSTM1 or GSTT1 is a risk factor of HNSCC development [5][7]. However, such an association was not observed in some other groups [8][10]. Therefore, it is necessary to reevaluate the association of GSTM1 or GSTT1 null genotype with the risk of HNSCC by pooling the new published studies using meta-analysis. The present study included all eligible published case-control studies to establish a relatively comprehensive picture of the relationship between these two genes and HNSCC.

Materials and Methods

Selection criteria and identification of eligible studies

Candidate studies were identified through computer-aided literature searches in PubMed for relevant articles in English and Chinese (1995 to May 2012). To identify all articles that studied the association of GSTT1 and GSTM1 polymorphisms with HNSCC, we conducted the search using the following keywords and subject terms: ‘GSTT1’ or ‘GSTM1’, and ‘squamous’. We also searched the references cited in the articles and included published works. Abstracts, case-only articles, editorials, review articles and repeated literatures were excluded. Of the articles with the overlapping data, we only included the publication with the most extensive information. The inclusion criteria in the current meta-analysis were as follows: (a) they are unrelated studies; (b) identification of squamous cell carcinoma was histologically confirmed; and (c) they have original data of genotype frequency and provided sufficient information to calculate the odds ratio (OR) or P-value.

Data extraction

Two reviewers (Zhang Y and Ni Y) independently examined the studies for inclusion in the meta-analysis and collected data on the genotype of GSTT1 and GSTM1. We extracted the following information from each study: first author, year of publication, country, ethnicity, numbers of case and control, smoking status and genotyping information. Disagreements between two reviewers were discussed and resolved with consensus. When essential information was not found in articles, we made effort to get the data from the authors (Figure 1).

Statistical analysis

The meta-analysis for GSTM1 or GSTT1 null genotype or dual null genotype compared HNSCC vs. controls. Odds ratio (OR) and its 95% confidence interval (CI) were assessed for each study. The Cochran's Q-statistic was used to test heterogeneity, and the heterogeneity was considered statistically significant when P<0.1 [11]. The Mantel-Haenszel method was used to calculate the OR for the included data in a fixed effects model in the absence of between-study heterogeneity, while random effects model was used for those with heterogeneity. P-value<0.05 was considered statistically significant, and 0.05≤P-value<0.10 was indicated suggestive. In addition, we also performed stratification analyses on ethnicity, smoking and combined analyses of GSTM1 and GSTT1 on HNSCC risk. The sensitivity analysis was carried out to test the stability of the pooled effect after excluding individual studies. Begg's funnel plot was used to evaluate publication bias. All above statistical analysis was carried out using the software packages Review Manager (RevMan) 5.1.


Eligible studies and meta-analysis databases

We identified 221 articles through the initial computerized search of published work. After reading titles, abstracts, 55 articles were retained. For the analysis of GSTM1 or GSTT1, after discarding 11 articles [7], [12][21] due to the overlapping data and 1 article [22] due to lack of essential genotype information, 44 case-control studies [5], [6], [8][10], [23][60] finally met our criteria for inclusion. Among them, 42 studies described the association between GSTM1 null genotype and HNSCC, and 32 between GSTT1 null genotype and HNSCC. For the association between dual null genotype and HNSCC, 1 discarded article [13] containing the distribution information of dual null genotype was reincorporated, and 15 studies were included (Table 1). For the analyses stratified by smoking, eight studies [5], [8], [29], [33], [45], [47], [48], [55] for GSTM1, and seven studies [5], [33], [38], [45][48] for GSTT1 were included.

Heterogeneity result

Cochran's Q tests indicated heterogeneity exist in different studies in the analysis except studies of dual genes in South American (P = 0.51, I2 = 0%) and GSTM1 in non-smokers (P = 0.65, I2 = 0%). The random or fixed effect model was selected for comparisons with or without heterogeneity, respectively.

Meta-analysis results

A total of 7584 HNSCC cases and 8576 controls for GSTM1, 6255 cases and 7138 controls for GSTT1, 2657 cases and 3092 controls for dual genes were investigated.

For GSTM1 polymorphism, the overall meta-analysis showed a suggestively increased risk in null genotype as compared to wild genotype (OR = 1.145, 95% CI: 1.00–1.29, P = 0.05) (Figure 2). In sensitivity analysis by temporarily excluding individual studies, no single study substantially affected the pooled OR, indicating that the results of these meta-analyses are stable. Analysis after stratification by ethnicity indicated GSTM1 null genotype tended to be associated with HNSCC in Asian (OR = 1.48, 95% CI: 1.24–1.75, P<0.01), while no significant association was found in European or South American (Table 2).

Figure 2. Forest plot of GSTM1 associated with HNSCC under random-effects model.

Each study is shown by point estimate of OR and 95% CI by a horizontal line. The diamond shows the overall risk and the line represent the 95% CI for each meta-analysis. Events: null genotype.

Table 2. Genotype distribution of GSTM1 and GSTT1 in different Ethnicities.

For GSTT1 polymorphism, null genotype was associated with an increased risk of HNSCC (OR = 1.32, 95% CI: 1.07–1.64, P = 0.01) (Figure 3A). Sensitivity analysis showed that the association still exist even with exclusion of the study of Hamel et al. which was obviously deviating from others (OR = 1.21, 95% CI: 1.01–1.45, P = 0.04) [32] (Figure 3B). Analysis stratified by ethnicity indicated that GSTT1 null genotype increased the HNSCC risk in South American (OR = 1.63, 95% CI: 1.03–2.58, P = 0.04) (Table 2).

Figure 3. Forest plot of GSTT1 associated with HNSCC under random-effects model.

A: Overall analysis. B: Sensitivity analysis with exclusion of the study by Hamel et al. 2000. The diamond shows the overall risk and the line represent the 95% CI for each meta-analysis. Events: null genotype.

Combined analysis of GSTM1 and GSTT1 on HNSCC risk showed that OR of individuals with dual null genotype was elevated (OR = 1.48, 95% CI: 1.12–1.96, P = 0.006) compared to GSTM1 or GSTT1 individual null genotype (Figure 4). After stratification for ethnicity, we observed a significant association for HNSCC in European (OR = 2.01, 95% CI: 1.15–3.53, P = 0.01) and Asian (OR = 1.56, 95% CI: 1.05–2.33, P = 0.03) populations among GSTM1 and GSTT1 dual null individuals (Table 2). The exclusion of individual studies did not change these results qualitatively.

Figure 4. Forest plot of GSTM1 and GSTT1 associated with HNSCC under random-effects models.

The diamond shows the overall risk and the line represent the 95% CI for each meta-analysis. Events: null genotype.

We further performed stratification analysis by smoking status. As shown in Table 3, significant association of GSTM1 deletion with risk of HNSCC was observed in smoking group (OR = 1.51, 95% CI: 1.05–2.17, P = 0.03) but not in non-smoking group (OR = 1.14, 95% CI: 0.90–1.43, P = 0.28). However, we did not found any significant associations for GSTT1 in either smokers (OR = 1.01, 95% CI: 0.64–1.60, P = 0.96) or non-smokers (OR = 1.13, 95% CI: 0.68–1.86, P = 0.64) (Table 3), which may be due to the limited number of study with smoking information.

Table 3. Genotype distribution of GSTM1 and GSTT1 in different smoking status.

Publication bias

Funnel plots were performed to assess the publication bias, and these shapes did not suggest any obvious evidence of asymmetry in the analyses of GSTM1, gene-gene interaction, and GSTT1 analysis stratified by smoking status. When one study [32] for GSTT1 analysis and two studies [46], [49] for GSTM1 analysis stratified by smoking status were omitted, funnel plots illustrated symmetric shape.


Genetic factors play an important role in the etiology of tumors. For HNSCC, genes encoding xenobiotic-metabolizing enzymes (XMEs) are some of the most likely candidates that could affect individual's susceptibility to the disease, due to their involvement of the metabolic activation and detoxification of the environmental carcinogens [61]. Conjugation is one of the most common pathways of xenobiotic metabolism and is considered phase II metabolism which is catalyzed by multiple enzyme superfamilies including Glutathione S-transferases (GSTs). GSTs mediate the reactions of glutathione with electrophiles, resulting in the elimination of potentially carcinogenic chemicals [62]. GSTM1 and GSTT1 genes belonging to GSTs have been studied extensively due to their important detoxification function and high-frequency polymorphisms. GSTM1 and GSTT1 homozygous deletions (null genotype) may lead to deficient enzyme activity [63]. In the present study, the overall frequency of GSTM1 and GSTT1 null genotype in controls were 47.65% and 23.77% respectively in accordance with other studies [64][67]. After stratification for ethnicity, the frequency of GSTM1 and GSTT1 null genotype in controls in European, Asian and South American were 53.14%, 40.06%, 49.29% and 21.86%, 23.67%, 26.34% respectively, which indicated ethnic differences.

The importance of GSTM1 and GSTT1 polymorphisms effects on HNSCC has been a concern in recent years, but the data of existing studies are contradictory. An increase in the risk of HNSCCC was observed in cases with null genotypes of GSTM1 or GSTT1 in some studies [5][8]. However the risk was not found in other studies. For example, Boccia [9] and Biselli [10] did not find the association between GSTM1 or GSTT1 and HNSCC. Although the confused effect of these polymorphisms may be a result of various reasons such as demographic features of subjects and different life styles, comparatively small sample size in individual study might lead to lower statistical power and bias. The present meta-analyses of 42 studies including 7584 cases and 8651 controls for analysis of GSTM1, 32 studies including 6255 cases and 7138 controls for analysis of GSTT1, and 15 studies including 2657 cases and 3092 controls provide more comprehensive information on the relationships between two genes and HNSCC.

This meta-analysis showed that both GSTM1 and GSTT1 null genotype confers susceptibility to HNSCC in the overall analysis. GSTM1 can deals with large hydrophobic electrophiles including polycyclic aromatic hydrocarbons derived epoxides (PAH) [68], [69], while GSTT1 targets a more restricted kind of compounds, like monohalomethane and ethylene oxide [70]. Different GST isoforms exhibit overlapping substrate specificity, combinations of GSTM1 and GSTT1 null genotype may theoretically confer a higher risk to HNSCC. Comparing to homozygous deletion of GSTM1 and GSTT1 alone, deletion of two genes in combination significantly increases the risk of HNSCC as showed in our combined analysis, indicating a synergenic role of GSTT1 and GSTM1 in cancergenesis.

Analyses after stratification by ethnicity revealed ethnicity-specific associations between two genes and HNSCC. Our findings indicate that GSTM1 may be an important factor in Asians in the development of HNSCC, which is similar to the results reported by Hashibe et al. [4]. However, GSTT1 but not GSTM1 may be important in South Americans, while GSTM1 and GSTT1 in combination play a vital role in Europeans and Asians. This result may be attributed to the different habits of smoking, alcohol consumption, intake of food and different genetic backgrounds in different ethnic groups.

Both GSTT1 and GSTM1 can prevent the accumulation of tobacco smoke carcinogens, and compared with non-smokers, mutations of these two genes theoretically increase the risk of HNSCC in smokers. To investigate potential gene-environment interaction, we stratified the data by smoking status. A significant association was observed in smokers with GSTM1, whereas no difference was observed between smokers and non-smokers for GSTT1. Previous studies showed that GSTT1 and GSTM1 are involved in the detoxification of carcinogens such as smoking by-products, and polymorphisms in these two genes with a result of loss of enzyme activity may increase risk of carcinogenesis and have different role in detoxification. [68][70]. Although we found higher risk of GSTM1 null genotype in smokers (OR = 1.51) than non-smokers (OR = 1.14), further individual large study are required to evaluate the interaction of GSTM1 and smoking on HNSCC risk.

Although our result of this meta-analysis is constructive, its limitations and some potential bias should be addressed. First, despite that a well-designed search strategy was used to identify eligible studies, it was possible that some relevant studies were not included. This study only focused on full-text papers published in English and Chinese in PubMed, so some eligible studies in other languages or in other databases might be missed. Second, adjustments over age, gender and other environmental factors such as alcohol drinking might help better detect the association between GSTM1, GSTT1 and HNSCC. If available detailed individual data are enough for an adjusted estimate in the future, a more precise analysis should be conducted. Third, ethnicity was determined roughly by subject's country due to inadequate available data, and this classification can help us have a regional concept of these genes functions. Fourth, the controls in the included studies were recruited in different ways and not uniformly defined, which may have distorted the meta-analysis. Finally, because all the studies were designed with retrospective studies, we cannot clearly determine the causal relationship between the risk factor and HNSCC. Given the limitations and biases above, the conclusions or interpretations made from the results of this meta-analysis should be explained with caution.


The results of this meta-analysis suggest that GSTM1 and GSTT1 null genotypes may be associated with an increased risk of HNSCC. Further large well-designed studies are warranted to confirm these findings.

Supporting Information

Prisma Checklist S1.



Author Contributions

Conceived and designed the experiments: JM LW. Analyzed the data: YZ YN HZ. Wrote the paper: JM YP.


  1. 1. Walker DM, Boey G, McDonald LA (2003) The pathology of oral cancer. Pathology 35: 376–383.
  2. 2. Casiglia J, Woo SB (2001) A comprehensive review of oral cancer. Gen Dent 49: 72–82.
  3. 3. Reichart PA (2001) Identification of risk groups for oral precancer and cancer preventive measures. Clin Oral Investig 5: 207–213.
  4. 4. Hashibe M, Brennan P, Strange RC, Bhisey R, Cascorbi I, et al. (2003) Meta- and Pooled Analyses of GSTM1, GSTT1, GSTP1, and CYP1A1 Genotypes and Risk of Head and Neck Cancer. Cancer Epidemiol Biomarkers Prev 12: 1509–1517.
  5. 5. Ruwali M, Singh M, Pant MC, Parmar D (2011) Polymorphism in glutathione S-transferases: susceptibility and treatment outcome for head and neck cancer. Xenobiotica 41: 1122–1130.
  6. 6. Lourenço GJ, Silva EF, Rinck-Junior JA, Chone CT, Lima CS (2011) CYP1A1, GSTM1 and GSTT1 polymorphisms, tobacco and alcohol status and risk of head and neck squamous cell carcinoma. Tumor Biol 32: 1209–1215.
  7. 7. Singh M, Shah PP, Singh AP, Ruwali M, Mathur N, et al. (2008) Association of genetic polymorphisms in glutathione S-transferases and susceptibility to head and neck cancer. Mutat Res 638: 184–194.
  8. 8. Suzen HS, Guvenc G, Turanli M, Comert E, Duydu Y, et al. (2007) The role of GSTM1 and GSTT1 polymorphisms in head and neck cancer risk. Oncol Res 16: 423–429.
  9. 9. Boccia S, Cadoni G, Sayed-Tabatabaei FA, Volante M, Arzani D, et al. (2008) CYP1A1, CYP2E1, GSTM1, GSTT1, EPHX1 exons 3 and 4, and NAT2 polymorphisms, smoking, consumption of alcohol and fruit and vegetables and risk of head and neck cancer. J Cancer Res Clin Oncol 134: 93–100.
  10. 10. Biselli JM, de Angelo Calsaverini Leal RC, Ruiz MT, Goloni-Bertollo EM, Maníglia JV, et al. (2006) GSTT1 and GSTM1 polymorphism in cigarette smokers with head and neck squamous cell carcinoma. Braz J Otorhinolaryngol 72: 654–658.
  11. 11. Zintzaras E, Ioannidis JP (2005) HEGESMA: genome search meta-analysis and heterogeneity testing. Bioinformatics 21: 3672–3673.
  12. 12. Trizna Z, Clayman GL, Spitz MR, Briggs KL, Goepfert H (1995) Glutathione s-transferase genotypes as risk factors for head and neck cancer. Am J Surg 170: 499–501.
  13. 13. Oude Ophuis MB, van Lieshout EM, Roelofs HM, Peters WH, Manni JJ (1998) Glutathione S-transferase M1 and T1 and cytochrome P4501A1 polymorphisms in relation to the risk for benign and malignant head and neck lesions. Cancer 82: 936–943.
  14. 14. McWilliams JE, Evans AJ, Beer TM, Andersen PE, Cohen JI, et al. (2000) Genetic polymorphisms in head and neck cancer risk. Head Neck 22: 609–617.
  15. 15. Ko Y, Abel J, Harth V, Bröde P, Antony C, et al. (2001) Association of CYP1B1 codon 432 mutant allele in head and neck squamous cell cancer is reflected by somatic mutations of p53 in tumor tissue. Cancer Res 61: 4398–4404.
  16. 16. Gaudet MM, Olshan AF, Poole C, Weissler MC, Watson M, et al. (2004) Diet, GSTM1 and GSTT1 and head and neck cancer. Carcinogenesis 25: 735–740.
  17. 17. Capoluongo E, Almadori G, Concolino P, Bussu F, Santonocito C, et al. (2007) GSTT1 and GSTM1 allelic polymorphisms in head and neck cancer patients from Italian Lazio Region. Clin Chim Acta 376: 174–178.
  18. 18. Ruwali M, Khan AJ, Shah PP, Singh AP, Pant MC, et al. (2009) Cytochrome P450 2E1 and head and neck cancer: interaction with genetic and environmental risk factors. Environ Mol Mutagen 50: 473–482.
  19. 19. Singh AP, Shah PP, Ruwali M, Mathur N, Pant MC, et al. (2009) Polymorphism in cytochrome P4501A1 is significantly associated with head and neck cancer risk. Cancer Invest 27: 869–876.
  20. 20. Gronau S, Koenig-Greger D, Jerg M, Riechelmann H (2003) GSTM1 enzyme concentration and enzyme activity in correlation to the genotype of detoxification enzymes in squamous cell carcinoma of the oral cavity. Oral Dis 9: 62–67.
  21. 21. Jahnke V, Strange R, Matthias C, Fryer A (1997) Glutathione S-transferase and cytochrome P450 genotypes as risk factors for laryngeal carcinoma. Eur Arch Otorhinolaryngol 254 Suppl 1: S147–149.
  22. 22. Olivieri EH, da Silva SD, Mendonça FF, Urata YN, Vidal DO, et al. (2009) CYP1A2*1C, CYP2E1*5B, and GSTM1 polymorphisms are predictors of risk and poor outcome in head and neck squamous cell carcinoma patients. Oral Oncol 45: e73–79.
  23. 23. Jahnke V, Matthias C, Fryer A, Strange R (1996) Glutathione S-transferase and cytochrome-P-450 polymorphism as risk factors for squamous cell carcinoma of the larynx. Am J Surg 172: 671–673.
  24. 24. Park JY, Muscat JE, Ren Q, Schantz SP, Harwick RD, et al. (2009) CYP1A1 and GSTM1 polymorphisms and oral cancer risk. Cancer Epidemiol Biomarkers Prev 6: 791–797.
  25. 25. González MV, Alvarez V, Pello MF, Menéndez MJ, Suárez C, et al. (1998) Genetic polymorphism of N-acetyltransferase-2, glutathione S-transferase-M1, and cytochromes P450IIE1 and P450IID6 in the susceptibility to head and neck cancer. J Clin Pathol 51: 294–298.
  26. 26. Cheng L, Sturgis EM, Eicher SA, Char D, Spitz MR, et al. (1999) Glutathione-S-transferase polymorphisms and risk of squamous-cell carcinoma of the head and neck. Int J Cancer 84: 220–224.
  27. 27. Katoh T, Kaneko S, Kohshi K, Munaka M, Kitagawa K, et al. (1999) Genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and oral cavity cancer. Int J Cancer 83: 606–609.
  28. 28. Morita S, Yano M, Tsujinaka T, Akiyama Y, Taniguchi M, et al. (1999) Genetic polymorphisms of drug-metabolizing enzymes and susceptibility to head-and-neck squamous-cell carcinoma. Int J Cancer 80: 685–688.
  29. 29. Nazar-Stewart V, Vaughan TL, Burt RD, Chen C, Berwick M, et al. (1998) Glutathione S-transferase M1 and susceptibility to nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 8: 547–551.
  30. 30. Sato M, Sato T, Izumo T, Amagasa T (1999) Genetic polymorphism of drug-metabolizing enzymes and susceptibility to oral cancer. Carcinogenesis 20: 1927–1931.
  31. 31. Tanimoto K, Hayashi S, Yoshiga K, Ichikawa T (1999) Polymorphisms of the CYP1A1 and GSTM1 gene involved in oral squamous cell carcinoma in association with a cigarette dose. Oral Oncol 35: 191–196.
  32. 32. Hamel N, Karimi S, Hébert-Blouin MN, Brunet JS, Gilfix B, et al. (2000) Increased risk of head and neck cancer in association with GSTT1 nullizygosity for individuals with low exposure to tobacco. Int J Cancer 87: 452–454.
  33. 33. Olshan AF, Weissler MC, Watson MA, Bell DA (2000) GSTM1, GSTT1, GSTP1, CYP1A1, and NAT1 polymorphisms, tobacco use, and the risk of head and neck cancer. Cancer Epidemiol Biomarkers Prev 9: 185–191.
  34. 34. Hahn M, Hagedorn G, Kuhlisch E, Schackert HK, Eckelt U (2002) Genetic polymorphisms of drug-metabolizing enzymes and susceptibility to oral cavity cancer. Oral Oncol 38: 486–490.
  35. 35. To-Figueras J, Gené M, Gómez-Catalán J, Piqué E, Borrego N, et al. (2002) Microsomal epoxide hydrolase and glutathione S-transferase polymorphisms in relation to laryngeal carcinoma risk. Cancer Lett 187: 95–101.
  36. 36. Gronau S, Koenig-Greger D, Jerg M, Riechelmann H (2003) Gene polymorphisms in detoxification enzymes as susceptibility factor for head and neck cancer? Otolaryngol Head Neck Surg 128: 674–680.
  37. 37. Drummond SN, De Marco L, Noronha JC, Gomez RS (2004) GSTM1 polymorphism and oral squamous cell carcinoma. Oral Oncol 40: 52–55.
  38. 38. Evans AJ, Henner WD, Eilers KM, Montalto MA, Wersinger EM, et al. (2004) Polymorphisms of GSTT1 and related genes in head and neck cancer risk. Head Neck 26: 63–70.
  39. 39. Li L, Lin P, Deng YF, Zhu ZL, Lu HH (2004) Relationship between susceptibility and prognosis of laryngeal cancer and genetic polymorphisms in CYP1A1 and GSTM1. Zhonghua Er Bi Yan Hou Ke Za Zhi 39: 2–7.
  40. 40. Drummond SN, Gomez RS, Motta Noronha JC, Pordeus IA, Barbosa AA, et al. (2005) Association between GSTT-1 gene deletion and the susceptibility to oral squamous cell carcinoma in cigarette-smoking subjects. Oral Oncol 41: 515–519.
  41. 41. Gajecka M, Rydzanicz M, Jaskula-Sztul R, Kujawski M, Szyfter W, et al. (2005) CYP1A1, CYP2D6, CYP2E1, NAT2, GSTM1 and GSTT1 polymorphisms or their combinations are associated with the increased risk of the laryngeal squamous cell carcinoma. Mutat Res 574: 112–123.
  42. 42. Acar H, Ozturk K, Muslumanoglu MH, Yildirim MS, Cora T, et al. (2006) Relation of glutathione S-transferase genotypes (GSTM1 and GSTT1) to laryngeal squamous cell carcinoma risk. Cancer Genet Cytogenet. 2006 169: 89–93.
  43. 43. Gattás GJ, de Carvalho MB, Siraque MS, Curioni OA, Kohler P, et al. (2006) Genetic polymorphisms of CYP1A1, CYP2E1, GSTM1, and GSTT1 associated with head and neck cancer. Head Neck 28: 819–826.
  44. 44. Oude Ophuis MB, Manni JJ, Peters WH (2006) Glutathione S-transferase T1 null polymorphism and the risk for head and neck cancer. Acta Otolaryngol 126: 311–317.
  45. 45. Peters ES, McClean MD, Marsit CJ, Luckett B, Kelsey KT (2006) Glutathione S-transferase polymorphisms and the synergy of alcohol and tobacco in oral, pharyngeal, and laryngeal carcinoma. Cancer Epidemiol Biomarkers Prev 15: 2196–2202.
  46. 46. Sharma A, Mishra A, Das BC, Sardana S, Sharma JK (2006) Genetic polymorphism at GSTM1 and GSTT1 gene loci and susceptibility to oral cancer. Neoplasma 53: 309–315.
  47. 47. Sugimura T, Kumimoto H, Tohnai I, Fukui T, Matsuo K, et al. (2006) Gene-environment interaction involved in oral carcinogenesis: molecular epidemiological study for metabolic and DNA repair gene polymorphisms. J Oral Pathol Med 35: 11–18.
  48. 48. Anantharaman D, Chaubal PM, Kannan S, Bhisey RA, Mahimkar MB (2007) Susceptibility to oral cancer by genetic polymorphisms at CYP1A1, GSTM1 and GSTT1 loci among Indians: tobacco exposure as a risk modulator. Carcinogenesis 28: 1455–1462.
  49. 49. Cha IH, Park JY, Chung WY, Choi MA, Kim HJ, et al. (2007) Polymorphisms of CYP1A1 and GSTM1 genes and susceptibility to oral cancer. Yonsei Med J 48: 233–239.
  50. 50. Buch SC, Nazar-Stewart V, Weissfeld JL, Romkes M (2008) Case-control study of oral and oropharyngeal cancer in whites and genetic variation in eight metabolic enzymes. Head Neck 30: 1139–1147.
  51. 51. Harth V, Schafer M, Abel J, Maintz L, Neuhaus T, et al. (2008) Head and neck squamous-cell cancer and its association with polymorphic enzymes of xenobiotic metabolism and repair. J Toxicol Environ Health A 71: 887–897.
  52. 52. Hatagima A, Costa EC, Marques CF, Koifman RJ, Boffetta P, et al. (2008) Glutathione S-transferase polymorphisms and oral cancer: a case-control study in Rio de Janeiro, Brazil. Oral Oncol 44: 200–207.
  53. 53. Losi-Guembarovski R, Cólus IM, De Menezes RP, Poliseli F, Chaves VN, et al. (2008) Lack of association among polymorphic xenobiotic-metabolizing enzyme genotypes and the occurrence and progression of oral carcinoma in a Brazilian population. Anticancer Res 28: 1023–1028.
  54. 54. Amtha R, Ching CS, Zain R, Razak IA, Basuki B, et al. (2009) GSTM1, GSTT1 and CYP1A1 polymorphisms and risk of oral cancer: a case-control study in Jakarta, Indonesia. Asian Pac J Cancer Prev 10: 21–26.
  55. 55. Li Q, Wang L, Chen Y, Du Y, Kong P, et al. (2009) Polymorphisms of GSTM1, GSTT1 and susceptibility of laryngeal and hypopharyngeal carcinomas. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 23: :1105–7, 1111.
  56. 56. Chatzimichalis M, Xenellis J, Tzagaroulakis A, Sarof P, Banis K, et al. (2010) GSTT1, GSTM1, GSTM3 and NAT2 polymorphisms in laryngeal squamous cell carcinoma in a Greek population. J Laryngol Otol 124: 318–323.
  57. 57. Leme CV, Raposo LS, Ruiz MT, Biselli JM, Galbiatti AL, et al. (2010) GSTM1 and GSTT1 genes analysis in head and neck cancer patients. Rev Assoc Med Bras 56: 299–303.
  58. 58. Sam SS, Thomas V, Reddy KS, Surianarayanan G, Chandrasekaran A (2010) Gene-gene interactions of drug metabolizing enzymes and transporter protein in the risk of upper aerodigestive tract cancers among Indians. Cancer Epidemiol 34: 626–633.
  59. 59. Soucek P, Susova S, Mohelnikova-Duchonova B, Gromadzinska J, Moraviec-Sztandera A, et al. (2010) Polymorphisms in metabolizing enzymes and the risk of head and neck squamous cell carcinoma in the Slavic population of the central Europe. Neoplasma 57: 415–421.
  60. 60. Shukla D, Kale AD, Hallikerimath S, Vivekanandhan S, Venkatakanthaiah Y (2012) 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 [Epub ahead of print].
  61. 61. Puga A, Nebert DW, McKinnon RA, Menon AG (1997) Genetic polymorphisms in human drug-metabolizing enzymes: potential uses of reverse genetics to identify genes of toxicological relevance. Crit Rev Toxicol 27: 1999–2222.
  62. 62. Keen JH, Jakoby WB (1978) Glutathione transferases. Catalysis of nucleophilic reactions of glutathione. J Biol Chem 253: 5654–5657.
  63. 63. Hayes JD, Strange RC (2000) Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology 61: 154–166.
  64. 64. Seidegard J, Vorachek WR, Pero RW, Pearson WR (1988) Hereditary differences in the expression of the human glutathione transferase active on trans-stilbene oxide are due to a gene deletion. Proc Natl Acad Sci USA 85: 7293–7297.
  65. 65. Strange RC, Jones PW, Fryer AA (2000) Glutathione S-transferase. Genetics and role in toxicology. Toxicol Lett 112–113: 357–363.
  66. 66. Schroder KR, Hallier E, Meyer DJ, Wiebel FA, Muller AM, et al. (1996) Purification and characterization of a new glutathione S-transferase, class t, from human erythrocytes. Arch Toxicol 70: 559–566.
  67. 67. Pemble S, Schroeder KR, Spencer SR, Meyer DJ, Hallier E, et al. (1994) Human glutathione S-transferase t (GSTT1): cDNA cloning and the characterization of a genetic polymorphism. Biochem J 300: 271–276.
  68. 68. Hayes JD, Pulford DJ (1995) The glutathione S-transferase supergene family: Regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol 30: 445–600.
  69. 69. Hayes JD, Flanagan JU, Jowsey IR (2005) Glutathione transferases. Annu Rev Pharmacol Toxicol 45: 51–88.
  70. 70. Landi S (2000) Mammalian class theta GST and differential susceptibility to carcinogens: A review. Mutat Res 463: 247–283.