Effect of Genetic Polymorphism of CYP2A6 on Individual Susceptibility to Colorectal Tumors in Japanese Smokers


Tobacco smoking is a risk factor for colorectal cancer and adenomas. To clarify the effect of genetic factors on the risk for tobacco-related colorectal tumors in a Japanese population, we performed a case-control study on 300 patients with two or more tumors and 181 healthy controls; all were genotyped for CYP2A6*4, CYP2A6*7 and CYP2A6*9. Cigarette smoking increased colorectal tumor risk (trend-test P < 0.0000005). Current smokers plus ex-smokers (ever-smokers) with the CYP2A6*4/*4 genotype (whole gene deletion) showed the lowest risk among smokers [odds ratio (OR), 0.17; 95% confidence interval (CI), 0.05 - 0.62 compared to ever-smokers with the wild-type CYP2A6*1/*1]. When the participants were classified into four phenotype groups based on estimated CYP2A6 activity [i.e., normal (*1/*1), intermediate (heterozygotes for the *1 and a variant allele), slow (heterozygotes and homozygotes for variant alleles except for *4/*4) and poor (*4/*4)], the ORs (95% CIs) in ever-smokers of the normal, intermediate, slow and poor groups were 6.75 (2.73 - 16.76), 4.59 (2.10 - 10.06), 3.89 (1.69 - 8.95) and 1.17 (0.31 - 4.40), respectively, compared with never-smokers with normal CYP2A6 activity. The susceptibility to colorectal tumors was dependent on the predicted phenotype among ever-smokers (trend-test P = 0.015), but not among never-smokers (trend-test P = 0.47). Stratifying the subjects with respect to cumulative tobacco exposure and estimated CYP2A6 activity, we found the highest risk of colorectal tumors in subjects with higher CYP2A6 activity and higher cumulative tobacco exposure (trend-test P = 0.000023); the lowest risk was found in subjects with the lowest estimated CYP2A6 activity independent of tobacco exposure (trend-test P = 1.00). These results suggest that the gene-environment interaction (i.e. , the CYP2A6-smoking interaction) strongly affects the individual susceptibility to tobacco-related colorectal tumors.

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A. Muroi, K. Kiyotani, M. Fujieda, H. Ishikawa, T. Takeshita, S. Iwano, H. Yamazaki and T. Kamataki, "Effect of Genetic Polymorphism of CYP2A6 on Individual Susceptibility to Colorectal Tumors in Japanese Smokers," Journal of Cancer Therapy, Vol. 3 No. 4, 2012, pp. 207-215. doi: 10.4236/jct.2012.34030.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] P. Pisani, D. M. Parkin, F. Bray and J. Ferlay, “Estimates of the Worldwide Mortality from 25 Cancers in 1990,” International Journal of Cancer, Vol. 83, No. 1, 1999, pp. 18-29. doi:10.1002/(SICI)1097-0215(19990924)83:1<18::AID-IJC5>3.0.CO;2-M
[2] M. S. Sandhu, I. R. White and K. McPherson, “Systematic Review of the Prospective Cohort Studies on Meat Consumption and Colorectal Cancer Risk: A Meta-Analytical Approach,” Cancer Epidemiology, Biomarkers & Prevention, Vol. 10, No. 5, 2001, pp. 439-446.
[3] G. R. Howe, K. J. Aronson, E. Benito, R. Castelleto, J. Cornee, S. Duffy, R. P. Gallagher, J. M. Iscovich, J. Deng-ao, R. Kaaks, et al., “The Relationship between Dietary Fat Intake and Risk of Colorectal Cancer: Evidence from the Combined Analysis of 13 Case-Control Studies,” Cancer Causes and Control, Vol. 8, No. 2, 1997, pp. 215-228. doi:10.1023/A:1018476414781
[4] E. Giovannucci, “Alcohol, One-Carbon Metabolism, and Colorectal Cancer: Recent Insights from Molecular Studies,” Journal of Nutrition, Vol. 134, No. 9, 2004, pp. 2475S- 2481S.
[5] E. Giovannucci, “An Updated Review of the Epidemiological Evidence that Cigarette Smoking Increases Risk of Colorectal Cancer,” Cancer Epidemiology, Biomarkers & Prevention, Vol. 10, No. 7, 2001, pp. 725-731.
[6] B. Morson, “President’s Address. The Polyp-Cancer Sequence in the Large Bowel,” Proceedings of the Royal Society of Medicine, Vol. 67, No. 6, 1974, pp. 451-457.
[7] M. L. Slattery, J. D. Potter, G. D. Friedman, K. N. Ma and S. Edwards, “Tobacco Use and Colon Cancer,” International Journal of Cancer, Vol. 70, No. 3, 1997, pp. 259-264. doi:10.1002/(SICI)1097-0215(19970127)70:3<259::AID-IJC2>3.0.CO;2-W
[8] A. Chao, M. J. Thun, E. J. Jacobs, S. J. Henley, C. Rodriguez and E. E. Calle, “Cigarette Smoking and Colorectal Cancer Mortality in the Cancer Prevention Study II,” Journal of the National Cancer Institute, Vol. 92, No. 23, 2000, pp. 1888-1896. doi:10.1093/jnci/92.23.1888
[9] D. Hoffmann and I. Hoffmann, “The Changing Cigarette, 1950-1995,” Journal of Toxicology and Environmental Health, Vol. 50, No. 4, 1997, pp. 307-364. doi:10.1080/009841097160393
[10] C. L. Crespi, B. W. Penman, J. A. Leakey, M. P. Arlotto, A. Stark, A. Parkinson, T. Turner, D. T. Steimel, K. Rudo, R. L. Davies, et al., “Human Cytochrome P450IIA3: cDNA Sequence, Role of the Enzyme in the Metabolic Activation of Promutagens, Comparison to Nitrosamine Activation by Human Cytochrome P450IIE1,” Carcinogenesis, Vol. 11, No. 8, 1990, pp. 1293-1300. doi:10.1093/carcin/11.8.1293
[11] H. Yamazaki, Y. Inui, C. H. Yun, F. P. Guengerich and T. Shimada, “Cytochrome P450 2E1 and 2A6 Enzymes as Major Catalysts for Metabolic Activation of N-Nitrosodialkylamines and Tobacco-Related Nitrosamines in Human Liver Microsomes,” Carcinogenesis, Vol. 13, No. 10, 1992, pp. 1789-1794. doi:10.1093/carcin/13.10.1789
[12] H. Kushida, K. Fujita, A. Suzuki, M. Yamada, T. Endo, T. Nohmi and T. Kamataki, “Metabolic Activation of N-Alkylnitrosamines in Genetically Engineered Salmonella typhimurium Expressing CYP2E1 or CYP2A6 Together with Human NADPH-Cytochrome P450 Reductase,” Carcinogenesis, Vol. 21, No. 6, 2000, pp. 1227-1232. doi:10.1093/carcin/21.6.1227
[13] J. E. Henningfield, K. Miyasato and D. R. Jasinski, “Abuse Liability and Pharmacodynamic Characteristics of Intravenous and Inhaled Nicotine,” Journal of Pharmacology and Experimental Therapeutics, Vol. 234, No. 1, 1985, pp. 1-12.
[14] M. Nakajima, T. Yamamoto, K. Nunoya, T. Yokoi, K. Nagashima, K. Inoue, Y. Funae, N. Shimada, T. Kamataki and Y. Kuroiwa, “Role of Human Cytochrome P4502A6 in C-Oxidation of Nicotine,” Drug Metabolism and Disposition, Vol. 24, No. 11, 1996, pp. 1212-1217.
[15] M. Nakajima, T. Yamamoto, K. Nunoya, T. Yokoi, K. Nagashima, K. Inoue, Y. Funae, N. Shimada, T. Kamataki and Y. Kuroiwa, “Characterization of CYP2A6 Involved in 3’-Hydroxylation of Cotinine in Human Liver Microsomes,” Journal of Pharmacology and Experimental Therapeutics, Vol. 277, No. 2, 1996, pp. 1010-1015.
[16] M. Fujieda, H. Yamazaki, T. Saito, K. Kiyotani, M. A. Gyamfi, M. Sakurai, H. Dosaka-Akita, Y. Sawamura, J. Yokota, H. Kunitoh, et al., “Evaluation of CYP2A6 Genetic Polymorphisms as Determinants of Smoking Behavior and Tobacco-Related Lung Cancer Risk in Male Japanese Smokers,” Carcinogenesis, Vol. 25, No. 12, 2004, pp. 2451-2458. doi:10.1093/carcin/bgh258
[17] K. Nunoya, T. Yokoi, Y. Takahashi, K. Kimura, M. Kinoshita and T. Kamataki, “Homologous Unequal Cross-Over within the Human CYP2A Gene Cluster as a Mechanism for the Deletion of the Entire CYP2A6 Gene Associated with the Poor Metabolizer Phenotype,” The Journal of Biochemistry, Vol. 126, No. 2, 1999, pp. 402-407. |doi:10.1093/oxfordjournals.jbchem.a022464
[18] K. I. Nunoya, T. Yokoi, K. Kimura, T. Kainuma, K. Satoh, M. Kinoshita and T. Kamataki, “A New CYP2A6 Gene Deletion Responsible for the in Vivo Polymorphic Metabolism of (+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one Hydrochloride in Humans,” Journal of Pharmacology and Experimental Therapeutics, Vol. 289, No. 1, 1999, pp. 437-442.
[19] M. Oscarson, R. A. McLellan, H. Gullsten, Q. Y. Yue, M. A. Lang, M. L. Bernal, B. Sinues, A. Hirvonen, H. Raunio, O. Pelkonen, et al., “Characterisation and PCR-Based Detection of a CYP2A6 Gene Deletion Found at a High Frequency in a Chinese Population,” FEBS Letters, Vol. 448, No. 1, 1999, pp. 105-110. doi:10.1016/S0014-5793(99)00359-2
[20] N. Ariyoshi, Y. Takahashi, M. Miyamoto, Y. Umetsu, S. Daigo, T. Tateishi, S. Kobayashi, Y. Mizorogi, M. A. Loriot, I. Stucker, et al., “Structural Characterization of a New Variant of the CYP2A6 Gene (CYP2A6*1B) Apparently Diagnosed as Heterozygotes of CYP2A6*1A and CYP2A6*4C,” Pharmacogenetics, Vol. 10, No. 8, 2000, pp. 687-693. doi:10.1097/00008571-200011000-00003
[21] M. Nakajima, J. T. Kwon, N. Tanaka, T. Zenta, Y. Yamamoto, H. Yamamoto, H. Yamazaki, T. Yamamoto, Y. Kuroiwa and T. Yokoi, “Relationship between Interindividual Differences in Nicotine Metabolism and CYP2A6 Genetic Polymorphism in Humans,” Clinical Pharmacology & Therapeutics, Vol. 69, No. 1, 2001, pp. 72-78. doi:10.1067/mcp.2001.112688
[22] K. Kiyotani, H. Yamazaki, M. Fujieda, S. Iwano, K. Matsumura, S. Satarug, P. Ujjin, T. Shimada, F. P. Guengerich, A. Parkinson, et al., “Decreased Coumarin 7-hydroxylase Activities and CYP2A6 Expression Levels in Humans Caused by Genetic Polymorphism in CYP2A6 Promoter Region (CYP2A6*9),” Pharmacogenetics, Vol. 13, No. 11, 2003, pp. 689-695. doi:10.1097/00008571-200311000-00005
[23] M. A. Gyamfi, M. Fujieda, K. Kiyotani, H. Yamazaki and T. Kamataki, “High Prevalence of Cytochrome P450 2A- 6*1A Alleles in a Black African Population of Ghana,” European Journal of Clinical Pharmacology, Vol. 60, No. 12, 2005, pp. 855-857. doi:10.1007/s00228-004-0854-9
[24] M. Miyamoto, Y. Umetsu, H. Dosaka-Akita, Y. Sawamura, J. Yokota, H. Kunitoh, N. Nemoto, K. Sato, N. Ariyoshi and T. Kamataki, “CYP2A6 Gene Deletion Reduces Susceptibility to Lung Cancer,” Biochemical and Biophysical Research Communications, Vol. 261, No. 3, 1999, pp. 658-660. doi:10.1006/bbrc.1999.1089
[25] N. Ariyoshi, M. Miyamoto, Y. Umetsu, H. Kunitoh, H. Dosaka-Akita, Y. Sawamura, J. Yokota, N. Nemoto, K. Sato and T. Kamataki, “Genetic Polymorphism of CYP2A6 Gene and Tobacco-Induced Lung Cancer Risk in Male Smokers,” Cancer Epidemiology, Biomarkers & Prevention, Vol. 11, No. 9, 2002, pp. 890-894.
[26] Z. Topcu, I. Chiba, M. Fujieda, T. Shibata, N. Ariyoshi, H. Yamazaki, F. Sevgican, M. Muthumala, H. Kobayashi and T. Kamataki, “CYP2A6 Gene Deletion Reduces Oral Cancer Risk in Betel Quid Chewers in Sri Lanka,” Carcinogenesis, Vol. 23, No. 4, 2002, pp. 595-598. doi:10.1093/carcin/23.4.595
[27] J. D. Potter, J. Bigler, L. Fosdick, R. M. Bostick, E. Kampman, C. Chen, T. A. Louis and P. Grambsch, “Colorectal Adenomatous and Hyperplastic Polyps: Smoking and N- Acetyltransferase 2 Polymorphisms,” Cancer Epidemiology, Biomarkers & Prevention, Vol. 8, No. 1, 1999, pp. 69-75.
[28] O. L. van der Hel, H. B. Bueno de Mesquita, M. Roest, B. Slothouber, C. van Gils, P. A. van Noord, D. E. Grobbee and P. H. Peeters, “No Modifying Effect of NAT1, GSTM1, and GSTT1 on the Relation between Smoking and Colorectal Cancer Risk,” Cancer Epidemiology, Biomarkers & Prevention, Vol. 12, No. 7, 2003, pp. 681-682.
[29] E. W. Tiemersma, A. Bunschoten, F. J. Kok, H. Glatt, S. Y. de Boer and E. Kampman, “Effect of SULT1A1 and NAT2 Genetic Polymorphism on the Association between Cigarette Smoking and Colorectal Adenomas,” International Journal of Cancer, Vol. 108, No. 1, 2004, pp. 97-103. doi:10.1002/ijc.11533
[30] H. Inoue, C. Kiyohara, T. Marugame, S. Shinomiya, E. Tsuji, K. Handa, H. Hayabuchi, K. Onuma, H. Hamada, H. Koga, et al., “Cigarette smoking, CYP1A1 Mspl and GSTM1 Genotypes, and Colorectal Adenomas,” Cancer Research, Vol. 60, No. 14, 2000, pp. 3749-3752.
[31] L. Hou, N. Chatterjee, W. Y. Huang, A. Baccarelli, S. Yadavalli, M. Yeager, R. S. Bresalier, S. J. Chanock, N. E. Caporaso, B. T. Ji, et al., “CYP1A1 Val462 and NQO1 Ser187 Polymorphisms, Cigarette Use, and Risk for Colorectal Adenoma,” Carcinogenesis, Vol. 26, No. 6, 2005, pp. 1122- 1128. doi:10.1093/carcin/bgi054
[32] C. M. Ulrich, J. Bigler, J. A. Whitton, R. Bostick, L. Fosdick and J. D. Potter, “Epoxide Hydrolase Tyr113His Polymorphism Is Associated with Elevated Risk of Colorectal Polyps in the Presence of Smoking and High Meat Intake,” Cancer Epidemiology, Biomarkers & Prevention, Vol. 10, No. 8, 2001, pp. 875-882.
[33] G. J. Tranah, E. Giovannucci, J. Ma, C. Fuchs, S. E. Hankinson and D. J. Hunter, “Epoxide Hydrolase Polymorphisms, Cigarette Smoking and Risk of Colorectal Adenoma in the Nurses’ Health Study and the Health Professionals Follow-Up Study,” Carcinogenesis, Vol. 25, No. 7, 2004, pp. 1211-1218. doi:10.1093/carcin/bgh126
[34] S. Nowell, C. Sweeney, G. Hammons, F. F. Kadlubar and N. P. Lang, “CYP2A6 Activity Determined by Caffeine Phenotyping: Association with Colorectal Cancer Risk,” Cancer Epidemiology, Biomarkers & Prevention, Vol. 11, No. 4, 2002, pp. 377-383.
[35] C. Sachse, G. Smith, M. J. Wilkie, J. H. Barrett, R. Waxman, F. Sullivan, D. Forman, D. T. Bishop and C. R. Wolf, “A Pharmacogenetic Study to Investigate the Role of Dietary Carcinogens in the Etiology of Colorectal Cancer,” Carcinogenesis, Vol. 23, No. 11, 2002, pp. 1839-1849. doi:10.1093/carcin/23.11.1839
[36] R. W. Haile, J. S. Witte, M. P. Longnecker, N. Probst- Hensch, M. J. Chen, J. Harper, H. D. Frankl and E. R. Lee, “A Sigmoidoscopy-Based Case-Control Study of Polyps: Macronutrients, Fiber and Meat Consumption,” International Journal of Cancer, Vol. 73, No. 4, 1997, pp. 497-502. doi:10.1002/(SICI)1097-0215(19971114)73:4<497::AID-IJC7>3.0.CO;2-V
[37] H. Autrup, C. C. Harris and B. F. Trump, “Metabolism of Acyclic and Cyclic N-Nitrosamines by Cultured Human Colon,” Proceedings of the Society for Experimental Biology and Medicine, Vol. 159, No. 1, 1978, pp. 111-115.
[38] S. C. Chen, L. Zhou, X. Ding and S. S. Mirvish, “Depentylation of the Rat Esophageal Carcinogen, Methyl-n- Pentylnitrosamine, by Microsomes from Various Human and Rat Tissues and by Cytochrome P450 2A3,” Drug Metabolism and Disposition, Vol. 29, No. 9, 2001, pp. 1221-1228.
[39] M. Kumarakulasingham, P. H. Rooney, S. R. Dundas, C. Telfer, W. T. Melvin, S. Curran and G. I. Murray, “Cytochrome p450 Profile of Colorectal Cancer: Identification of Markers of Prognosis,” Clinical Cancer Research, Vol. 11, No. 10, 2005, pp. 3758-3765. doi:10.1158/1078-0432.CCR-04-1848

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