Elsevier

Oral Oncology

Volume 41, Issue 5, May 2005, Pages 515-519
Oral Oncology

Association between GSTT-1 gene deletion and the susceptibility to oral squamous cell carcinoma in cigarette-smoking subjects

https://doi.org/10.1016/j.oraloncology.2004.12.014Get rights and content

Summary

Oral squamous cell carcinoma (OSCC) is related to tobacco use and alcohol consumption and the individual susceptibility for development of this tumor has been associated with xenobiotic-metabolizing enzymes polymorphisms. Glutathione S-transferase Theta-1 (GSTT1) is a phase II metabolic enzyme that catalyzes detoxification reactions of carcinogenic compounds. A genetic polymorphism of the GSTT1 gene is characterized by a complete gene deletion and consequent absence of the enzyme. The null genotype (gene deleted) of GSTT1 has a decreased capacity in detoxifying carcinogens present in tobacco smoke, leading the formation of DNA-adducts and DNA damage. The purpose of the present study was to evaluate the association between GSTT1 polymorphism and risk for OSCC development in a Brazilian population. We investigated the GSTT1 polymorphism in 87 patients with OSCC and 81 age-sex matched controls. The genotypes were studied by PCR-based methods. Individuals homozygous for the wild type GSTT1 (+/+) and heterozygous (+/0) were grouped together. The prevalence of GSTT1 deficiency (null) was significantly higher in the group with OSSC patients with oral cancer of the floor of the mouth. The results suggest that GSTT1 polymorphism increases the risk for OSCC development.

Introduction

Oral squamous cell carcinoma (OSCC) results from a combination of environmental factors such as tobacco use and alcohol consumption and genetic damage resulting in the accumulation of DNA alterations involving key cellular genes. These changes generate genetic instability that can result in an uncontrolled cellular growth.1 It is recognized that individual variability related to the capacity of metabolizing xenobiotic substances may influence the susceptibility for the development of esophageal adenocarcinomas.2 Indeed, it has been suggested that genetic polymorphisms are able to affect the risk of a wide range of cancers.3, 4, 5, 6, 7 The environment-gene relationship in carcinogenesis is associated with phase I and phase II metabolic enzymes that are involved in the metabolism of carcinogens. Since xenobiotic substances metabolism can affect the potency of most carcinogens by activating or detoxifying them, carcinogen-metabolizing enzyme polymorphisms have an important role in susceptibility to such xenobiotic-related cancers.4

Human glutathione S-transferase class Theta-1 (GSTT1) is a phase II enzyme that catalyzes the conjugation of glutathione to a broad variety of carcinogenic compounds, resulting in increased water solubility allowing excretion of carcinogenic metabolites formed during phase I reactions.8 The first evidence of the existence of a human GSTT1 came from the purification of a distinct protein9 and the cloning of a cDNA encoding human GSTT1 gene.10 The GSTT1 gene is characterized by a genetic polymorphism causing a complete gene deletion and consequent absence of the enzyme.10 The null genotype (gene deleted) of GSTT1 has a decreased capacity in detoxifying carcinogens present in tobacco smoke,1 leading to the formation of DNA-adducts and DNA damage.11 The frequencies of the null genotype have been determined in different human populations, varying from 0.197 in Caucasians to 0.47 in Asians.12

The association of GSTT1 polymorphism and risk for oral squamous cell carcinoma has been studied and the results are inconsistent. Positive association between GSTT1 deletion and oral cancer risk was observed in different populations with odds ratio ranging from 1.47 to 3.3.1, 13, 14, 15 However, other studies did not establish a positive correlation.11, 16, 17 Therefore, we aimed to determine the frequencies of GSTT1 genotypes in a case-control study in a population comprised of heavy smokers and evaluated the association between GSTT1 deletion and the risk for squamous cell carcinoma.

Section snippets

Human subjects

The study included 87 patients (mean age 55.7 yr; range 40–84 yr) with histological diagnosis of oral squamous cell carcinoma (OSCC) and 81 age- and sex-matched control subjects (mean age 51.8 yr; range 34–86 yr) of the same geographical region as well as socio-economic status. No patient had had previous chemotherapy and/or radiation therapy. All subjects in both groups had smoked at least 10 cigarettes/day over a 20 yr period. There were 76 males (87.3%) and 11 females (12.7%) in the OSCC group.

Results

The frequencies of the GSTT1 genotypes are shown in Table 1. Individuals homozygous for the wild type GSTM1 (+/+) and heterozygous (+/0) were grouped together. The percentage of cases of null genotype the OSCC group (83.9%) was statistically different from the control subjects (42.0%) (Odds ratio, O.R. = 7.20%, 95% CI = 3.50–14.84, P < 0.05). The relationship between GSTT1 polymorphism and oral cancer risk were further evident after segregation by sex. The difference between the prevalence of GSTT1

Discussion

Polymorphisms in genes coding for xenobiotic metabolizing enzymes may influence individual susceptibility to various types of human cancers.3, 5, 6, 7 Our results suggest a strong relationship between the GSTT1 polymorphism and an increased risk for oral cancer development. Previous studies with different populations have also shown this association,1, 13, 14, 15 although other studies could not confirm this positive correlation.11, 16, 17 The conflicting results regarding to GSTT1 polymorphism

Acknowledgement

This study was supported in part by grants from Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), Programa de Excelência (PRONEX) and Conselho Nacional de Desenvolvimento Cientı́fico e Tecnológico (CNPq), Brazil. Dr. L. De Marco, R.S. Gomez and I. Pordeus are research fellows of CNPq.

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