Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behavior and tobacco-related lung cancer risk in male Japanese smokers.

We reported previously that subjects homozygous for the cytochrome P450 2A6 (CYP2A6) (*)4 have a lower risk of lung cancer. The purpose of this study was to clarify whether or not the alterations of smoking behavior and risk for lung cancer could be found in subjects possessing novel CYP2A6 variants discovered recently. An epidemiological study was performed with 1094 cases and 611 controls in male Japanese smokers. It was found that the amounts of daily cigarette consumption in subjects who harbored CYP2A6(*)4/(*)7, (*)4/(*)10, (*)7/(*)7, (*)7/(*)9 and (*)4/(*)4 genotypes were significantly less than those in subjects carrying the (*)1/(*)1 genotype (P < 0.01). Even after adjustment with cigarette consumption, the adjusted odds ratios (ORs) for lung cancer were significantly lower in subjects who harbored CYP2A6(*)1/(*)4, (*)1/(*)7, (*)1/(*)9, (*)1/(*)10, (*)4/(*)4, (*)4/(*)7, (*)4/(*)9, (*)7/(*)7 and (*)7/(*)9 genotypes than those who possessed the (*)1/(*)1 genotype (P < 0.05). When participants were classified into four groups according to the CYP2A6 genotypes, group 1 ((*)1/(*)1), group 2 (heterozygotes for the (*)1 and a variant allele), group 3 (heterozygotes and homozygotes for variant alleles except for (*)4/(*)4) and group 4 ((*)4/(*)4), lung cancer risk was found to be less in subjects with the variant of CYP2A6 alleles [group 2, OR of 0.59 [95% confidence interval (CI), 0.44-0.79]; group 3, OR of 0.52 (95% CI, 0.37-0.72); group 4, OR of 0.30 (95% CI, 0.16-0.57)]. The reduced risk for lung cancer was seen more clearly in heavy smokers than in light smokers. Additional stratification analysis showed that the ORs for squamous cell carcinoma (OR of 0.07) and small cell carcinoma (OR of 0.10) were lower than that of adenocarcinoma (OR of 0.39) in group 4. These results suggest that the CYP2A6 is one of the principal determinants affecting not only smoking behavior but also susceptibility to tobacco-related lung cancer.

Eighteen novel polymorphisms of the CYP2A13 gene in Japanese.

We sequenced all nine exons, exon-intron junctions including a part of introns, 5'-flanking and 3'-untranslated regions of the cytochrome P450 (CYP) 2A13 gene from 192 Japanese individuals. We found eighteen novel genetic polymorphisms including five single nucleotide polymorphisms (SNP) and one three base pair insertion causing amino acid substitution and one amino acid insertion, respectively, one silent SNP in exon 4, four SNPs in a 5'-flanking region, and seven SNPs in introns. The five SNPs (74G>A in exon 1, 579G>A in exon 2, 1706C>G in exon 3, and 7343T>A and 7465C>T in exon 9) causing amino acid substitutions (Arg(25)Gln, Arg(101)Gln, Asp(158)Glu, Phe(453)Tyr, and Arg(494)Cys), respectively. The one three base pair insertion (1634_1635 ACC insertion in exon 3) caused one amino acid insertion ((133_134)Thr ins). These sequences are as follows:SNP, 021125Fujieda005; GENE NAME, CYP2A13; ACCESSION NUMBER, NG_000008; LENGTH, 25 base;5'-TGTCAGTCTGGCG/AGCAGAGGAAGAG-3'.SNP, 021125Fujieda007; GENE NAME, CYP2A13; ACCESSION NUMBER, NG_000008; LENGTH, 25 base; 5'-AGTTCAGCGGGCG/AAGGCGAGCAGGC-3'.SNP, 021125Fujieda009; GENE NAME, CYP2A13; ACCESSION NUMBER, NG_000008; LENGTH, 25 base; 5'-CTTCCTCATCGAC/GGCCCTCCGGGGC-3'.SNP, 021125Fujieda017; GENE NAME, CYP2A13; ACCESSION NUMBER, NG_000008; LENGTH, 25 base; 5'-TCTTTCTCTTCTT/ACACCACCATCAT-3'.SNP, 021125Fujieda018; GENE NAME, CYP2A13; ACCESSION NUMBER, NG_000008; LENGTH, 25 base; 5'-AGCTTCCTGCCCC/TGCTGAGCGAGGG-3'.SNP, 021125Fujieda008; GENE NAME, CYP2A13; ACCESSION NUMBER, NG_000008; LENGTH, 25 base; 5'-CTCCATCGCCACC-/ACCCTAAGGGGTTTT-3'.

Genetic polymorphism of CYP2A6 gene and tobacco-induced lung cancer risk in male smokers.

Cytochrome P450 2A6 (CYP2A6) is the principal enzyme involved in the metabolic activation of tobacco-specific nitrosamines to their ultimate carcinogenic forms and metabolism of nicotine. We investigated the effects of the CYP2A6*4, an entire CYP2A6 gene deletion-type polymorphism, on lung cancer risk and daily cigarette consumption in Japanese male smokers via a hospital-based case control study. The frequency of the CYP2A6*4 variant was compared in 370 lung cancer patients and 380 control smokers. A markedly reduced adjusted odds ratio for lung cancer risk, 0.23 [95% confidence interval, 0.08-0.67], was seen in the group with homozygous deletion (*4/*4) when the odds ratio for a group with homozygous wild (*1A/*1A) was defined to be 1.00 by logistic regression. The subjects with lung cancer were additionally divided into three groups according to the histological classification of the cancer and examined for an association with the CYP2A6 polymorphism. The *4/*4 genotype was not found in patients with squamous cell carcinoma (0 of 105) or small cell carcinoma (0 of 44), indicating that subjects with the *4/*4 genotype have low risk for lung cancers, particularly those caused by tobacco smoke. Furthermore, a significant reduction of daily cigarette consumption was observed in smokers with the *4/*4 genotype, suggesting a possibility that complete lack of CYP2A6 appeared to affect the smoking behavior. These data suggest that male smokers possessing the *1A/*1A genotype have higher risk for tobacco-induced lung cancers.