Effects of ADH1C, ALDH2, and CYP2A6 Polymorphisms on Individual Risk of Tobacco-Related Lung Cancer in Male Japanese Smokers

DOI: 10.4236/jct.2013.48A005   PDF   HTML     3,224 Downloads   4,832 Views   Citations


Recent genome-wide association studies have identified several lung cancer susceptibility loci. We previously carried out a replication study in male Japanese smokers that focused on chromosome 5p15 (telomerase reverse transcriptase) and 3q28 (tumor protein p63) (Shimizu et al., Journal of Cancer Therapy, Vol. 2, No. 5, 2011, pp. 690-696). The current study was performed to confirm the association of traditional susceptibility loci [i.e., alcohol dehydrogenase 1C (ADH1C) and aldehyde dehydrogenase 2 (ALDH2)] in 1039 male Japanese smokers (573 lung cancer patients and 466 healthy control subjects) who were previously enrolled in a study to investigate the low odds ratio for lung cancer risk associated with functionally impaired and deletion polymorphisms in cytochrome P450 2A6 (CYP2A6). The minor allele frequency of rs671 in ALDH2 (0.304) was significantly higher in lung cancer cases than in controls (0.226), with an odds ratio of 1.42 [95% confidence interval (CI) of 1.12 - 1.80, p = 0.0033]. No significant association of rs698 in ADH1C with lung cancer risk was found in this population of male Japanese smokers. For light smokers categorized according to the 50th percentile Brinkman index value among the control subjects (620 daily cigarettes × years) and for the CYP2A6*1 wild-type non-carrier sub-population, significantly high odds ratios of 1.98 and 1.68 (95% CI of 1.28 - 3.06, p = 0.0022, and 1.07 - 2.66, p = 0.025), respectively, were observed for rs671 in ALDH2. The present results support the association of ALDH2 loci with lung cancers and suggest a specific effect of ALDH2 loci resulting in a higher risk of lung cancer in light smokers. CYP2A6 polymorphisms, including copy number polymorphisms, may lower the risk of heavy tobacco use-related lung cancer.

Share and Cite:

Shimizu, M. , Ishii, Y. , Okubo, M. , Kunitoh, H. , Kamataki, T. and Yamazaki, H. (2013) Effects of ADH1C, ALDH2, and CYP2A6 Polymorphisms on Individual Risk of Tobacco-Related Lung Cancer in Male Japanese Smokers. Journal of Cancer Therapy, 4, 29-35. doi: 10.4236/jct.2013.48A005.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] M. Munaka, K. Kohshi, T. Kawamoto, S. Takasawa, N. Nagata, H. Itoh, et al., “Genetic Polymorphisms of Tobaccoand Alcohol-Related Metabolizing Enzymes and the Risk of Hepatocellular Carcinoma,” Journal of Cancer Research and Clinical Oncology, Vol. 129, No. 6, 2003, pp. 355-360. doi:10.1007/s00432-003-0439-5
[2] J. D. McKay, T. Truong, V. Gaborieau, A. Chabrier, S. C. Chuang, G. Byrnes, et al., “A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium,” PLoS Genetics, Vol. 7, No. 3, 2011, Article ID: e1001333. doi:10.1371/journal.pgen.1001333
[3] A. Yokoyama, T. Muramatsu, T. Ohmori, T. Yokoyama, K. Okuyama, H. Takahashi, et al., “Alcohol-Related Cancers and Aldehyde Dehydrogenase-2 in Japanese Alcoholics,” Carcinogenesis, Vol. 19, No. 8, 1998, pp. 1383-1387. doi:10.1093/carcin/19.8.1383
[4] J. Y. Choi, J. Abel, T. Neuhaus, Y. Ko, V. Harth, N. Hamajima, et al., “Role of Alcohol and Genetic Polymorphisms of CYP2E1 and ALDH2 in Breast Cancer Development,” Pharmacogenetics, Vol. 13, No. 2, 2003, pp. 67-72. doi:10.1097/00008571-200302000-00002
[5] J. Kanda, K. Matsuo, T. Suzuki, T. Kawase, A. Hiraki, M. Watanabe, et al., “Impact of Alcohol Consumption with Polymorphisms in Alcohol-Metabolizing Enzymes on Pancreatic Cancer Risk in Japanese,” Cancer Science, Vol. 100, No. 2, 2009, pp. 296-302. doi:10.1111/j.1349-7006. 2008.01044.x
[6] E. J. Duell, N. Sala, N. Travier, X. Munoz, M. C. Boutron-Ruault, F. Clavel-Chapelon, et al., “Genetic Variation in Alcohol Dehydrogenase (ADH1A, ADH1B, ADH1C, ADH7) and Aldehyde Dehydrogenase (ALDH2), Alcohol Consumption and Gastric Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) Cohort,” Carcinogenesis, Vol. 33, No. 2, 2012, pp. 361-367. doi:10.1093/carcin/bgr285
[7] T. Asakage, A. Yokoyama, T. Haneda, M. Yamazaki, M. Muto, T. Yokoyama, et al., “Genetic Polymorphisms of Alcohol and Aldehyde Dehydrogenases, and Drinking, Smoking and Diet in Japanese Men with Oral and Pharyngeal Squamous Cell Carcinoma,” Carcinogenesis, Vol. 28, No. 4, 2007, pp. 865-874. doi:10.1093/carcin/bgl206
[8] S. Zienolddiny, D. Campa, H. Lind, D. Ryberg, V. Skaug, L. B. Stangeland, et al., “A Comprehensive Analysis of Phase I and Phase II Metabolism Gene Polymorphisms and Risk of Non-Small Cell Lung Cancer in Smokers,” Carcinogenesis, Vol. 29, No. 6, 2008, pp. 1164-1169. doi:10.1093/carcin/bgn020
[9] R. J. Hung, D. C. Christiani, A. Risch, O. Popanda, A. Haugen, S. Zienolddiny, et al., “International Lung Cancer Consortium: Pooled Analysis of Sequence Variants in DNA Repair and Cell Cycle Pathways,” Cancer Epidemiology, Biomarkers & Prevention, Vol. 17, 2008, pp. 3081-3089. doi:10.1158/1055-9965.EPI-08-0411
[10] The Tobacco and Genetic Consortium, “Genome-Wide Meta-Analyses Identify Multiple Loci Associated with Smoking Behavior,” Nature Genetics, Vol. 42, 2010, pp. 441-447. doi:10.1038/ng.571
[11] J. Z. Liu, F. Tozzi, D. M. Waterworth, S. G. Pillai, P. Muglia, L. Middleton, et al., “Meta-Analysis and Imputation Refines the Association of 15q25 with Smoking Quantity,” Nature Genetics, Vol. 42, 2010, pp. 436-440. doi:10.1038/ng.572
[12] N. L. Saccone, R. C. Culverhouse, T. H. Schwantes-An, D. S. Cannon, X. Chen, S. Cichon, et al., “Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity: A Meta-Analysis and Comparison with Lung Cancer and COPD,” PLoS Genetics, Vol. 6, No. 8, 2010, Article ID: e1001053. doi:10.1371/journal.pgen.1001053
[13] E. D. Pleasance, P. J. Stephens, S. O’Meara, D. J. McBride, A. Meynert, D. Jones, et al., “A Small-Cell Lung Cancer Genome with Complex Signatures of Tobacco Exposure,” Nature, Vol. 463, 2009, pp. 184-190. doi:10.1038/nature08629
[14] T. Truong, R. J. Hung, C. I. Amos, X. Wu, H. Bickeboller, A. Rosenberger, et al., “Replication of Lung Cancer Susceptibility Loci at Chromosomes 15q25, 5p15, and 6p21: A Pooled Analysis from the International Lung Cancer Consortium,” Journal of the National Cancer Institute, Vol. 102, No. 13, 2010, pp. 959-971. doi:10.1093/jnci/djq178
[15] J. D. McKay, R. J. Hung, V. Gaborieau, P. Boffetta, A. Chabrier, G. Byrnes, et al., “Lung Cancer Susceptibility Locus at 5p15.33,” Nature Genetics, Vol. 40, 2008, pp. 1404-1406. doi:10.1038/ng.254
[16] M. T. Landi, N. Chatterjee, K. Yu, L. R. Goldin, A. M. Goldstein, M. Rotunno, et al., “A Genome-Wide Association Study of Lung Cancer Identifies a Region of Chromosome 5p15 Associated with Risk for Adenocarcinoma,” American Society of Human Genetics, Vol. 85, No. 5, 2009 pp. 679-691. doi:10.1016/j.ajhg.2009.09.012
[17] D. Miki, M. Kubo, A. Takahashi, K. A. Yoon, J. Kim, G. K. Lee et al., “Variation in TP63 Is Associated with Lung Adenocarcinoma Susceptibility in Japanese and Korean Populations,” Nature Genetics, Vol. 42, 2010, pp. 893-896. doi:10.1038/ng.667
[18] N. Kumasaka, M. Aoki, Y. Okada, A. Takahashi, K. Ozaki, T. Mushiroda, et al., “Haplotypes with Copy Number and Single Nucleotide Polymorphisms in CYP2A6 Locus Are Associated with Smoking Quantity in a Japanese Population,” PLoS One, Vol. 7, No. 9, 2012, Article ID: e44507. doi:10.1371/journal.pone.0044507
[19] M. Fujieda, H. Yamazaki, T. Saito, K. Kiyotani, M. A. Gyamfi, M. Sakurai, 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
[20] M. Shimizu, K. Kiyotani, H. Kunitoh, T. Kamataki, H. Yamazaki, “Different Effects of TERT, TP63, and CYP2A6 Polymorphism on Individual Risk of TobaccoRelated Lung Cancer in Male Japanese Smokers,” Journal of Cancer Therapy, Vol. 2, No. 5, 2011, pp. 690-696. doi:10.4236/jct.2011.25093
[21] A. Groppi, J. Begueret and A. Iron, “Improved Methods for Genotype Determination of Human Alcohol Dehydrogenase (ADH) at ADH 2 and ADH 3 Loci by Using Polymerase Chain Reaction-Directed Mutagenesis,” Clinical Chemistry, Vol. 36, No. 10, 1990, pp. 1765-1768.
[22] J. C. Barrett, B. Fry, J. Maller and M. J. Daly, “Haploview: Analysis and Visualization of LD and Haplotype Maps,” Bioinformatics, Vol. 21, No. 2, 2005, pp. 263-265. doi:10.1093/ bioinformatics/bth457
[23] J. Y. Park, K. Matsuo, T. Suzuki, H. Ito, S. Hosono, T. Kawase, et al., “Impact of Smoking on Lung Cancer Risk Is Stronger in Those with the Homozygous Aldehyde Dehydrogenase 2 Null Allele in a Japanese Population,” Carcinogenesis, Vol. 31, No. 4, 2010, pp. 660-665. doi:10.1093/carcin/bgq021
[24] S. Y. Eom, Y. W. Zhang, S. H. Kim, K. H. Choe, K. Y. Lee, J. D. Park, et al., “Influence of NQO1, ALDH2, and CYP2E1 Genetic Polymorphisms, Smoking, and Alcohol Drinking on the Risk of Lung Cancer in Koreans,” Cancer Causes Control, Vol. 20, No. 2, 2009, pp. 137-145. doi:10.1007/s10552-008-9225-7
[25] Y. Xue, M. Wang, D. Zhong, N. Tong, H. Chu, X. Sheng, et al., “ADH1C Ile350Val Polymorphism and Cancer Risk: Evidence from 35 Case-Control Studies,” PLoS One, Vol. 7, No. 5, 2012, Article ID: e37227. doi:10.1371/journal.pone.0037227
[26] M. Wu, S. C. Chang, E. Kampman, J. Yang, X. S. Wang, et al., “Single Nucleotide Polymorphisms of ADH1B, ADH1C and ALDH2 Genes and Esophageal Cancer: A Population-Based Case-Control Study in China,” International Journal of Cancer, Vol. 132, No. 8, 2013, pp. 1868-1877. doi:10.1002/ijc.27803
[27] L. Wang, W. Zang, J. Liu, D. Xie, W. Ji, Y. Pan, et al., “Association of CYP2A6*4 with Susceptibility of Lung Cancer: A Meta-Analysis,” PLoS One, Vol. 8, No. 4, 2013, Article ID: e59556. doi:10.1371/journal. pone.0059556
[28] H. Sugimura, H. Tao, M. Suzuki, H. Mori, M. Tsuboi, S. Matsuura, et al., “Genetic Susceptibility to Lung Cancer,” Frontiers in Bioscience (Scholar Edition), Vol. 3, 2011, pp. 1463-1477.
[29] 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
[30] P. H. Chou, S. Kageyama, S. Matsuda, K. Kanemoto, Y. Sasada, M. Oka, et al., “Detection of Lipid PeroxidationInduced DNA Adducts Caused by 4-Oxo-2(E)-Nonenal and 4-Oxo-2(E)-Hexenal in Human Autopsy Tissues,” Chemical Research in Toxicology, Vol. 23, No. 9, 2010, pp. 1442-1448. doi:10.1021/tx100047d
[31] P. J. Branton, K. G. McAdam, D. B. Winter, C. Liu, M. G. Duke and C. J. Proctor, “Reduction of Aldehydes and Hydrogen Cyanide Yields in Mainstream Cigarette Smoke Using an Amine Functionalised Ion Exchange Resin,” Chemistry Central Journal, Vol. 5, 2011, p. 15. doi:10.1186/1752-153X-5-15

comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.