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Tumor Biology

, Volume 34, Issue 5, pp 2651–2657 | Cite as

CYP2A6 deletion polymorphism is associated with decreased susceptibility of lung cancer in Asian smokers: a meta-analysis

  • Yu-liang Liu
  • Yu Xu
  • Fan Li
  • Hong Chen
  • Shu-liang Guo
Research Article

Abstract

Cytochrome P450 2A6 (CYP2A6) is an enzyme involved in the metabolism of some tobacco carcinogens, which is an important risk factor of lung cancer. Among CYP2A6 allelic variants, CYP2A6*4 presents a whole gene deletion that accounts for the majority of poor metabolizer. In this study, a meta-analysis was performed to assess the association between CYP2A6*4 and risk of lung cancer. Literature searches were conducted to identify peer-reviewed manuscripts published up to December 20, 2012. Pooled odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were calculated in a fixed-effects model and a random-effects model when appropriate. Eight eligible studies with 3,203 lung cancer cases and 2,839 controls were included in this study. Overall, no significant association was observed in CYP2A6*4 with the risk of lung cancer under any genetic model for all samples after correction. However, subgroup analysis showed that significant associations were observed in Asian with pooled OR (95 %CI) of 0.761 (0.672–0.861) for allele comparison, 0.769 (0.668–0.886) for dominant model, and 0.522 (0.359–0.760) for recessive model. Furthermore, after stratifying Asian samples according to smoking status, significant associations were only observed in smokers with pooled OR (95 %CI) of 0.713 (0.607–0.838) for allele comparison, 0.720 (0.596–0.869) for dominant model, and 0.444 (0.275–0.715) for recessive model. This meta-analysis suggests that the CYP2A6*4 polymorphism was associated with susceptibility of lung cancer for smokers in Asian. The whole gene deletion of CYP2A6 might decrease the risk of tobacco-related lung cancer in Asian.

Keywords

Lung cancer CYP2A6*4 Cytochrome P450 2A6 CYP2A6 deletion Meta-analysis Smoker 

Notes

Acknowledgments

This work was supported by the General program of National Natural Science Foundation of China (No. 81100259, 81201684, 81201841), CSTC(2011jjA055) and Innovation Fund 2010XQN31.

Conflicts of interest

None

References

  1. 1.
    Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture. Eur J Cancer. 2001;37 Suppl 8:S4–66.CrossRefPubMedGoogle Scholar
  2. 2.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. Cancer J Clinicians. 2012;62(1):10–29.CrossRefGoogle Scholar
  3. 3.
    Law MR, Hackshaw AK. Environmental tobacco smoke. British Med Bull. 1996;52(1):22–34.CrossRefGoogle Scholar
  4. 4.
    Boyle P, Maisonneuve P. Lung cancer and tobacco smoking. Lung Cancer. 1995;12(3):167–81.CrossRefPubMedGoogle Scholar
  5. 5.
    Nakajima M, Yamamoto T, Nunoya K, et al. Role of human cytochrome P4502A6 in C-oxidation of nicotine. Drug Metab Dispos Biol Fate Chem. 1996;24(11):1212–7.PubMedGoogle Scholar
  6. 6.
    Yamazaki H, Inoue K, Hashimoto M, Shimada T. Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes. Arch Toxicol. 1999;73(2):65–70.CrossRefPubMedGoogle Scholar
  7. 7.
    Hoffman SM, Nelson DR, Keeney DS. Organization, structure and evolution of the CYP2 gene cluster on human chromosome 19. Pharmacogenetics. 2001;11(8):687–98.CrossRefPubMedGoogle Scholar
  8. 8.
    Kushida H, Fujita K, Suzuki A, et al. Metabolic activation of N-alkylnitrosamines in genetically engineered Salmonella typhimurium expressing CYP2E1 or CYP2A6 together with human NADPH-cytochrome P450 reductase. Carcinogenesis. 2000;21(6):1227–32.CrossRefPubMedGoogle Scholar
  9. 9.
    Koskela S, Hakkola J, Hukkanen J, et al. Expression of CYP2A genes in human liver and extrahepatic tissues. Biochem Pharmacol. 1999;57(12):1407–13.CrossRefPubMedGoogle Scholar
  10. 10.
    Ding X, Kaminsky LS. Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts. Annu Rev Pharmacol Toxicol. 2003;43:149–73.CrossRefPubMedGoogle Scholar
  11. 11.
    Oscarson M, McLellan RA, Gullsten H, et al. Identification and characterisation of novel polymorphisms in the CYP2A locus: implications for nicotine metabolism. FEBS Lett. 1999;460(2):321–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Ariyoshi N, Sekine H, Nakayama K, Saito K, Miyamoto A, Kamataki T. Identification of deletion-junction site of CYP2A6*4B allele lacking entire coding region of CYP2A6 in Japanese. Pharmacogenetics. 2004;14(10):701–5.CrossRefPubMedGoogle Scholar
  13. 13.
    Kamataki T, Fujieda M, Kiyotani K, Iwano S, Kunitoh H. Genetic polymorphism of CYP2A6 as one of the potential determinants of tobacco-related cancer risk. Biochem Biophys Res Commun. 2005;338(1):306–10.CrossRefPubMedGoogle Scholar
  14. 14.
    Miyamoto M, Umetsu Y, Dosaka-Akita H, et al. CYP2A6 gene deletion reduces susceptibility to lung cancer. Biochem Biophys Res Commun. 1999;261(3):658–60.CrossRefPubMedGoogle Scholar
  15. 15.
    Loriot MA, Rebuissou S, Oscarson M, et al. Genetic polymorphisms of cytochrome P450 2A6 in a case–control study on lung cancer in a French population. Pharmacogenetics. 2001;11(1):39–44.CrossRefPubMedGoogle Scholar
  16. 16.
    Wang H, Tan W, Hao B, et al. Substantial reduction in risk of lung adenocarcinoma associated with genetic polymorphism in CYP2A13, the most active cytochrome P450 for the metabolic activation of tobacco-specific carcinogen NNK. Cancer Res. 2003;63(22):8057–61.PubMedGoogle Scholar
  17. 17.
    Fujieda M, Yamazaki H, Saito T, et al. Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behavior and tobacco-related lung cancer risk in male Japanese smokers. Carcinogenesis. 2004;25(12):2451–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Gu Y, Zhang S, Lai B, Zhan X, Zhang Y. Frequency of CYP2A6 gene deletion and its relation to risk of lung cancer. Zhongguo fei ai za zhi Chinese J Lung cancer. 2005;8(4):297–9.Google Scholar
  19. 19.
    Tamaki Y, Arai T, Sugimura H, et al. Association between cancer risk and drug-metabolizing enzyme gene (CYP2A6, CYP2A13, CYP4B1, SULT1A1, GSTM1, and GSTT1) polymorphisms in cases of lung cancer in Japan. Drug Metab Pharm. 2011;26(5):516–22.CrossRefGoogle Scholar
  20. 20.
    Wassenaar CA, Dong Q, Wei Q, Amos CI, Spitz MR, Tyndale RF. Relationship between CYP2A6 and CHRNA5-CHRNA3-CHRNB4 variation and smoking behaviors and lung cancer risk. J Natl Cancer Inst. 2011;103(17):1342–6.PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Islam MS, Ahmed MU, Sayeed MS, et al. Lung cancer risk in relation to nicotinic acetylcholine receptor, CYP2A6 and CYP1A1 genotypes in the Bangladeshi population. Clin Chim Acta. 2013;416:11–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Vasconcelos GM, Struchiner CJ, Suarez-Kurtz G. CYP2A6 genetic polymorphisms and correlation with smoking status in Brazilians. Pharmacogenomics J. 2005;5(1):42–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics Med. 2002;21(11):1539–58.CrossRefGoogle Scholar
  24. 24.
    Light RJ, Pillemer DB. Summing up: the science of reviewing research. Cambridge, MA: Harvard University Press; 1984.Google Scholar
  25. 25.
    Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34.PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Liu T, Xie CB, Ma WJ, Chen WQ. Association between CYP2A6 genetic polymorphisms and lung cancer: a meta-analysis of case–control studies. Env Mol Mutag. 2012;54(2):133–40.CrossRefGoogle Scholar
  27. 27.
    Schoedel KA, Hoffmann EB, Rao Y, Sellers EM, Tyndale RF. Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. Pharmacogenetics. 2004;14(9):615–26.CrossRefPubMedGoogle Scholar
  28. 28.
    Takeuchi H, Saoo K, Yokohira M, et al. Pretreatment with 8-methoxypsoralen, a potent human CYP2A6 inhibitor, strongly inhibits lung tumorigenesis induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in female A/J mice. Cancer Res. 2003;63(22):7581–3.PubMedGoogle Scholar
  29. 29.
    Nakajima M, Kwon JT, Tanaka N, et al. Relationship between interindividual differences in nicotine metabolism and CYP2A6 genetic polymorphism in humans. Clin Pharmacol Ther. 2001;69(1):72–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Yoshida R, Nakajima M, Watanabe Y, Kwon JT, Yokoi T. Genetic polymorphisms in human CYP2A6 gene causing impaired nicotine metabolism. Br J Clin Pharmacol. 2002;54(5):511–7.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Peamkrasatam S, Sriwatanakul K, Kiyotani K, et al. In vivo evaluation of coumarin and nicotine as probe drugs to predict the metabolic capacity of CYP2A6 due to genetic polymorphism in Thais. Drug Metab Pharm. 2006;21(6):475–84.CrossRefGoogle Scholar
  32. 32.
    Xu C, Rao YS, Xu B, et al. An in vivo pilot study characterizing the new CYP2A6*7, *8, and *10 alleles. Biochem Biophys Res Commun. 2002;290(1):318–24.CrossRefPubMedGoogle Scholar
  33. 33.
    Gambier N, Batt AM, Marie B, Pfister M, Siest G, Visvikis-Siest S. Association of CYP2A6*1B genetic variant with the amount of smoking in French adults from the Stanislas cohort. Pharmacogenomics J. 2005;5(4):271–5.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Yu-liang Liu
    • 1
  • Yu Xu
    • 2
  • Fan Li
    • 3
  • Hong Chen
    • 1
  • Shu-liang Guo
    • 1
  1. 1.Department of Respiratory MedicineThe first affiliated Hospital of Chongqing Medical UniversityChongqingChina
  2. 2.Department of Respiratory Medicine, Xinqiao HospitalThe Third Military Medical UniversityChongqingChina
  3. 3.Department of General Surgery, Institute of Surgery Research, Daping HospitalThird Military Medical University, ChongqingChongqingChina

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