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Genetic Polymorphism of CYP2A6 Gene and Tobacco-Induced Lung Cancer Risk in Male Smokers1

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Genetic Polymorphism of CYP2A6 Gene and Tobacco-Induced Lung Cancer Risk in Male Smokers1 890 Vol. 11, 890–894, September 2002 Cancer Epidemiology, Biomarkers & Prevention Genetic Polymorphism of CYP2A6 Gene and Tobacco-induced Lung Cancer Risk in Male Smokers1 Noritaka Ariyoshi, Masami Miyamoto, Yuri Umetsu, complete lack of CYP2A6 appeared to affect the smoking Hideo Kunitoh, Hirotoshi Dosaka-Akita, behavior. These data suggest that male smokers Yu-ichi Sawamura, Jun Yokota, Nobuo Nemoto, possessing the *1A/*1A genotype have higher risk for Kunio Sato, and Tetsuya Kamataki2 tobacco-induced lung cancers. Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812 [N. A., M. M., Y. U., T. K.]; Introduction Department of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, Tokyo 104-0045 [H. K.]; First Department of Internal CYP2A63 is one of the forms of CYP expressed in the human Medicine, Hokkaido University School of Medicine, Sapporo 060-0815 respiratory tract (1, 2) and is responsible for the metabolic [H. D-A.]; Maruyama Clinic, Sapporo 064-0820 [Y. S.]; Biology Division, activation of tobacco-specific nitrosamines, including 4-(meth- National Cancer Center Research Institute, Tokyo 104-0045 [J. Y.]; Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, ylnitrosamino)-1-(3-pyridyl)-1-butanone (1, 3, 4), a potent pul- Toyama 930-0152 [N. N.]; and Department of Internal Medicine, Gunma monary-specific carcinogen (5), to yield genotoxic metabolites. University School of Medicine, Gunma 371-0034 [K. S.], Japan This enzyme was also found to be involved in nicotine metab- olism (6). A genetic polymorphism of CYP2A6 was recognized as Abstract one of the causes for the interindividual differences in the Cytochrome P450 2A6 (CYP2A6) is the principal enzyme metabolism of coumarin (7, 8). The wild type of the CYP2A6 involved in the metabolic activation of tobacco-specific gene was termed CYP2A6*1A. The CYP2A6*2 variant, which nitrosamines to their ultimate carcinogenic forms and has 1-base substitution in exon 3 leading to amino acid change metabolism of nicotine. We investigated the effects of L160H, appears to be one of the causal polymorphisms ac- the CYP2A6*4, an entire CYP2A6 gene deletion-type counting for poor metabolizers of coumarin in Caucasians (9). polymorphism, on lung cancer risk and daily cigarette Recently, we found that an entire CYP2A6 gene deletion, a consumption in Japanese male smokers via a hospital- novel genetic polymorphism (CYP2A6*4), was responsible for based case control study. The frequency of the CYP2A6*4 the lack of CYP2A6 activity in Japanese (10–12). Upon con- variant was compared in 370 lung cancer patients and sideration of these observations, it appeared possible that a lack 380 control smokers. A markedly reduced adjusted odds of or reduced CYP2A6 activity caused by genetic polymor- ratio for lung cancer risk, 0.23 [95% confidence interval, phism might lead to a decrease in tobacco-induced lung cancer 0.08–0.67], was seen in the group with homozygous risk, either by reduced smoking because of lower nicotine deletion (*4/*4) when the odds ratio for a group with catabolism or as a result of a decreased capacity to activate homozygous wild (*1A/*1A) was defined to be 1.00 by carcinogens such as nitrosamines present in tobacco smoke, or logistic regression. The subjects with lung cancer were both. additionally divided into three groups according to the The CYP2A6*1B (13–15) is recognized as another wild- histological classification of the cancer and examined for type allele and is not thought to lead to a decreased enzyme an association with the CYP2A6 polymorphism. The *4/ activity thus far because the mutation is located in the 3Ј- *4 genotype was not found in patients with squamous cell untranslated region of the CYP2A6 gene. If CYP2A6 activity carcinoma (0 of 105) or small cell carcinoma (0 of 44), affects genetic susceptibility to tobacco-induced lung cancer, indicating that subjects with the *4/*4 genotype have low individuals possessing the CYP2A6*4 allele, but not the risk for lung cancers, particularly those caused by CYP2A6*1A or the CYP2A6*1B allele, would be expected to tobacco smoke. Furthermore, a significant reduction of have low risk for lung cancer, particularly squamous cell car- daily cigarette consumption was observed in smokers cinoma and small cell carcinoma, which are believed to be with the *4/*4 genotype, suggesting a possibility that caused by smoking (16). Materials and Methods Received 10/19/01; revised 4/23/02; accepted 5/14/02. Study Population. This study was approved by the ethics The costs of publication of this article were defrayed in part by the payment of committee of the National Cancer Center Hospital and Hok- page charges. This article must therefore be hereby marked advertisement in kaido University. All subjects used in this study were unrelated accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by a Grant-in-Aid from the Ministry of Education, Science, Sports male Japanese smokers. Smokers contained current and ex- and Culture of Japan, a grant from the Japan Health Science Foundation, a smokers and were defined as individuals who have ever smoked Grant-in-Aid from the Ministry of Health and Welfare for the 2nd-term Compre- cigarettes with a minimum smoking history of 0.5 pack/day for hensive 10-Year Strategy for Cancer Control, and Organization for Pharmaceu- tical Safety and Research Grant No. 99-2. 2 To whom requests for reprints should be addressed, at Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University, N12W6, Kita-ku, Sapporo 060-0812, Japan. Phone: 81-11-706-3233; Fax: 81- 3 The abbreviations used are: CYP2A6, cytochrome P450 2A6; CYP, cytochrome 11-706-4978; E-mail: [email protected]. P450; OR, odds ratio; CI, confidence interval. Downloaded from cebp.aacrjournals.org on September 26, 2021. © 2002 American Association for Cancer Research. Cancer Epidemiology, Biomarkers & Prevention 891 Table 1 Characteristics of lung cancer patients and control subjects Table 2 Difference in distribution of CYP2A6 genotypes in lung cancer patients Case Control Case Control Unadjusted OR Adjusted OR Genotype Total (n) 370 380 (n ϭ 370) (n ϭ 380) (95% CI) (95% CI)a Gender Male Male Age (yr) *1A/*1A 80 (21.3%) 54 (14.2%) 1.00 1.00 Ͻ40 5 0 *1A/*1B 127 (34.6%) 123 (32.4%) 0.70 (0.46–1.07) 0.68 (0.44–1.06) b b 40–49 46 0 *1B/*1B 60 (16.2%) 67 (17.6%) 0.60 (0.37–0.99) 0.56 (0.34–0.93) b 50–59 140 259 *1A/*4 43 (11.6%) 51 (13.4%) 0.57 (0.33–0.97) 0.59 (0.34–1.02) b b 60–69 179 88 *1B/*4 55 (14.9%) 66 (17.4%) 0.56 (0.34–0.92) 0.59 (0.35–0.97) b b Ն70 0 33 *4/*4 5 (1.4%) 19 (5.0%) 0.18 (0.06–0.50) 0.23 (0.08–0.67) ϫ Pack/day yr a Age and smoking amount were adjusted in this analysis. *1A, CYP2A6*1A; *1B, Ͻ500 46 50 CYP2A6*1B; *4, CYP2A6*4. 500–1000 153 199 b Significant decrease in OR is indicated by 95% CI. 1000–2000 138 121 2000–3000 30 8 3000–4000 2 2 Ն (null-type) and the CYP1A1 gene (*2A and *2C variants) was 4000 1 0 carried out according to the method reported by Bell et al. (18) Histological cell type Small cell carcinoma 44 and Cascorbi et al. (19), respectively. Squamous cell carcinoma 105 Statistical Analysis. To determine whether an association ex- Adenocarcinoma 193 isted between CYP2A6 genotypes and lung cancer risk, the Others 28 significance of the difference in the distribution of genotypes between cases and controls was calculated by ␹2 test and shown by P. All Ps were two-sided. P Ͻ 0.05 was considered to be at least 1 year. Most cases were recruited from 1997 to 1999 in statistically significant. Difference in allele frequency between the National Cancer Center Hospital (Tokyo, Japan). Both cases and controls was calculated by Fisher’s exact test. OR and incidental and prevalent cases were included without any se- 95% CI were calculated by logistic regression analysis with the lections. Among the lung cancer cases, incidental cases were statistical package, Stat View version 5.0 (Abacus Concepts, ϳ90% of the total population, with the remaining 10% con- Inc., Berkely, CA). A relationship between the number of sisting of prevalent cases. Control subjects recruited were com- cigarettes smoked and each CYP2A6 genotype was evaluated posed of healthy volunteers who visited one of the hospitals that by Student-Newman-Keuls test. took part in the research within the same time period described above for a health checkup. All subjects were then randomly Results selected. This procedure provided a natural balance between The distribution of CYP2A6 genotypes in lung cancer patients cases and controls regarding possible confounding factors such was significantly different (P Ͻ 0.01) from that in controls, as birthplace because the patients who visited the National indicating existence of a relationship between CYP2A6 geno- Cancer Center Hospital were from all regions of Japan. The age types and lung cancer risk (Table 2). The frequency of the of the lung cancer patients was defined when the lung cancer individuals with the *4/*4 genotype was lower in lung cancer was first pathologically diagnosed. Pathological classification patients than in controls, whereas the frequency of patients of lung cancer was determined according to the International homozygous for the CYP2A6*1A allele (*1A/*1A) was higher Association for the Study of Lung Cancer/WHO criteria (17).
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