Polymorphisms of the CYP1A1 and GSTM1 gene involved in oral squamous cell carcinoma in association with a cigarette dose

Abstract

The genetic polymorphisms of CYP1A1 and GSTM1 genes among 100 Japanese patients with oral squamous cell carcinomas (SCC) were investigated to evaluate the role of genetic susceptibility in carcinogenesis of the oral cavity. The presence of the rare homozygote of CYP1A1, m2/m2, was significantly more frequent in the patient group (15.0%) than the control group (8.0%) (Odds ratio (ORs) =3.6 95% Confidential Interval (CI):1.4–9.5). The heterozygotic variant, m1/m2, was also frequently seen in oral SCC patients. This meant that the m2 allele was observed in more than half of the patients. The null genotype of GSTM1 was found in 43.0% of the patient group. This was not significantly different from the controls (40.0%). When the life time cigarette consumption dose of the patients was considered with respect to genotypes of CYP1A1, the mean smoking index (SI) of oral SCC patients with m2/m2 was found to be less than half of the mean SI among the patients with m1/m1 genotype (P < 0.02). The ORs of the m2/m2 genotype was found to be significantly high in a comparison of various subsites of the oral cavity, except for the floor of the mouth. Our results indicate that the rare homozygote of CYP1A1, m2/m2, is associated with increased risk of oral SCC, in particular, at low cigarette dose levels. The results also suggested that the involvement of such susceptibility in oral carcinogenesis might be different between the subsites of the oral cavity.

Introduction

Most environmental procarcinogens require metabolic activation to convert into their respective reactive electrophilic intermediates. Cytochrome P450s (CYP) are the phase I enzymes in the activation pathway. CYP1A1, one of the various forms of CYP, is considered to play an important role in the activation of poly aromatic hydrocarbon compounds (PAH) such as benzo(a)pyrene (BP)[1]. The polymorphic locus at the 264th base downstream from additional polyadenylation signal in the 3′-flanking region of CYP1A1 gene (MspI polymorphism) has been reported to be associated with susceptibility to lung cancer, in particular the histological types of squamous cell carcinoma (SCC) and adenocarcinoma with a low grade differentiation in the Japanese population2, 3. Furthermore, a similar association has been observed in the null genotype of a mu-class isozyme of glutathione S-transferases (GSTM1), which was involved in the detoxification of reactive metabolites of BP[4]. These results suggested that genetically determined variation among individuals in the metabolic activation of such chemical carcinogens makes it possible to explain the individual difference in susceptibility to chemical carcinogenesis.

As the upper aero-digestive tract, the oral cavity has many functions and frequently comes into contact with various chemical compounds. The smoking of tobacco has been commonly regarded as a major risk factor for carcinogenesis of the oral cavity, as has the drinking of alcohol5, 6. However, the pathogenesis of oral cancer, more than 90% of which are SCCs, has not been well understood. In this paper, the genetic polymorphisms of the CYP1A1 and GSTM1 genes among oral SCC patients are considered in order to evaluate the role of the genetic susceptibility in carcinogenesis of the oral cavity.