Relationship between genetic polymorphisms of drug-metabolizing enzymes (CYP1A1, CYP1B1, CYP2E1, GSTM1, GSTT1, and NAT2) and p53 gene point mutations in Taiwanese male patients with oral squamous cell carcinomas

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There are three major risk factors (cigarette smoking, areca quid chewing and alcohol drinking) in the development of oral cancer in Taiwan. In general, chemical carcinogens require metabolic activation by host enzymes to be genotoxic: phase I enzymes can activate carcinogens metabolically to form genotoxic electrophilic intermediates and then, in part, detoxified by phase II enzymes. Thus, the relative activity of the metabolizing enzymes is one of the important determinant host factors underlying cancer development. Furthermore, several studies have demonstrated the relationships between the metabolizing enzyme polymorphisms and the frequency of p53 gene mutations. In the present study, the genotypes of CYP1A1, CYP1B1, CYP2E1, GSTM1, GSTT1, and NAT2 were investigated in Taiwanese male patients with oral squamous cell carcinomas and in referent controls to examine whether any relationship exists between the genetic polymorphisms of these enzymes and individual susceptibility to oral cancer. The relationship between the metabolizing enzyme polymorphisms and the frequency of p53 gene mutations was also evaluated to understand the pathogenesis of oral cancer at a molecular level, with special reference to the genetic polymorphisms of metabolizing enzymes. For the present study, 670 male oral cancer patients diagnosed with squamous cell carcinoma and 372 referent controls selected from 3000 random samples of the Taiwanese general population collected to study blood lead concentrations were included. Polymorphisms of CYP1A1, CYP1B1, CYP2E1, GSTM1, GSTT1, and NAT2 gene were determined by PCR-RFLP and primer extension with DHPLC analysis. PCR-single strand conformation polymorphism and DNA sequencing was performed to analyze the most common mutated regions of the p53 gene (exons 4 - 10). We found that individuals with CYP1A1 Val allele (odds ratio (OR) = 1.64; 95% confidence interval (CI), 0.95 - 2.86), CYP2E1 c2 allele (OR = 1.44; 95% CI, 1.08 - 1.91) or GSTT1 null genotype (OR = 1.98; 95% CI, 1.52 - 2.58) had increased risk to develop oral cancer than those with CYP1A1 Il1/Ile, CYP2E1 c1/c1 or GSTT1 non-null genotype. Furthermore, individuals with at least 2 risk genotypes of these 3 genes had significant higher risk (OR = 2.21; 95% CI, 1.48 - 3.31) to develop oral cancer than those without any risk genotype. Among oral cancer patients, individuals with CYP1A1 Val allele had higher opportunity (OR = 1.97; 95% CI, 1.16 - 3.37) to have p53 gene mutations in their tumors than those with CYP1A1 Ile/Ile genotype. Taken together, the present study suggests that individuals with CYP1A1 Val allele have an increased risk to develop oral cancer and also have a higher frequency of p53 gene mutations in the tumors.