Tandem repeat polymorphism of the CYP2E1 gene: an association study with esophageal cancer and lung cancer.

Abstract

Cytochrome P-450 (CYP) enzymes have been shown to play important roles in chemical carcinogenesis. Reports have indicated that polymorphism in CYP1A1, CYP1A2, CYP2A6, CYP2E1, and CYP2D6 are associated with an altered risk of developing cancers of the lung, bladder, liver, and colon. CYP2E1 plays an important role in alcohol metabolism and participates in the metabolic activation of various carcinogens, such as N-nitrosodimethylamine. Recently, we found repeated sequences that consist of four alleles (A1, A2, A3, and A4) and six genotypes (A1/A2, A2/A2, A2/A3, A2/A4, A3/A4 and A4/A4) of the CYP2E1 gene. In the present study, we investigated whether these polymorphisms are associated with lung cancer and esophageal cancer. DNA was isolated from blood samples of 192 healthy control subjects, 85 patients with lung cancer, and 82 patients with esophageal cancer in Japanese males. DNA samples were amplified by polymerase chain reaction in the 5'-flanking region of the CYP2E1 gene and in exon 12 in the ALDH2 gene. The tandem repeat polymorphisms were examined using DNA fragment analysis. Missense mutations in exon 12 of the ALDH2 gene were examined using fluorescence-based single strand conformational change polymorphism analysis. Written informed consent was obtained from all the subjects. In the CYP2E1 gene 5'-flanking region polymorphism, patients with esophageal cancer showed significantly higher frequency of the A4/A4 genotype compared with the control subjects (p = 0.02), but no difference was found in patients with lung cancer. The frequencies of the mutant ALDH2*2 allele were significantly higher in patients with esophageal cancer (27.7%) than in healthy control subjects (7.3%; p< 0.0001; habitual alcohol drinkers). The distribution of genotypes and allele frequencies of the tandem repeats of the 5'-flanking region of the CYP2E1 gene was significantly different in patients with esophageal cancer.