Association between CYP2A13 Polymorphisms and Lung Cancer Risk: A Systematic Review and Meta-Analysis of Case–Control Studies

Abstract

Objectives

Lung cancer remains a leading cause of cancer-related deaths worldwide, with cigarette smoking as a major risk factor. Genetic variations in the cytochrome P450 family, particularly CYP2A13 polymorphisms, have been suggested to influence lung cancer susceptibility. However, their role remains unclear, particularly in relation to smoking status and regional populations differences. This systematic review and meta-analysis aimed to evaluate the association between CYP2A13 combination and homozygous variants and lung cancer risk, stratified by smoking status and geographic region.

Materials and Methods

A comprehensive search of electronic databases (PubMed, ScienceDirect, SCOPUS, and Google Scholar) was conducted up to November 11, 2024, to identify eligible case–control studies on CYP2A13 polymorphisms and lung cancer. Inclusion and exclusion criteria were based on exposure of interest, study design, language, type of publication, and reported outcome. Data from 10 studies (2,853 lung cancer cases and 3,651 controls) were pooled to calculate odds ratios (OR) with 95% confidence intervals (CIs), using a random-effects model. Subgroup analyses were performed by smoking status and geographic region. Publication bias was assessed using Egger's test and funnel plots.

Results

A significant association was observed between CYP2A13 polymorphisms and lung cancer risk in specific populations. In East Asian populations, the homozygous variant was associated with an increased lung cancer risk (pooled OR: 1.37, 95% CI: 1.13–1.66). Among smokers in Europe, the combination variant showed a pooled OR of 1.64 (95% CI: 1.21–2.23). In East Asian smokers, the homozygous variant had a pooled OR of 1.52 (95% CI: 1.17–1.96). No significant publication bias was detected.

Conclusion

This meta-analysis suggests that CYP2A13 polymorphisms may contribute to lung cancer susceptibility, with smoking serving as a key modifier. The findings are particularly relevant in East Asian and European populations, but given the heterogeneity between studies and limited sample sizes, further large-scale investigations are necessary. These insights provide a foundation for future research on CYP2A13 as a potential biomarker for lung cancer risk.

Keywords

CYP2A13 - lung cancer - genetic polymorphism - smoking - meta-analysis - East Asian - European

• References

• 1 Bade BC, Dela Cruz CS. Lung cancer 2020: epidemiology, etiology, and prevention. Clin Chest Med 2020; 41 (01) 1-24
• 2 Raunio H, Rahnasto-Rilla M. CYP2A6: genetics, structure, regulation, and function. Drug Metabol Drug Interact 2012; 27 (02) 73-88
• 3 Smith BD, Sanders JL, Porubsky PR, Lushington GH, Stout CD, Scott EE. Structure of the human lung cytochrome P450 2A13. J Biol Chem 2007; 282 (23) 17306-17313
• 4 Chiang HC, Wang CK, Tsou TC. Differential distribution of CYP2A6 and CYP2A13 in the human respiratory tract. Respiration 2012; 84 (04) 319-326
• 5 Hecht SS. Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosamines. Chem Res Toxicol 1998; 11 (06) 559-603
• 6 Chiang HC, Wang CY, Lee HL, Tsou TC. Metabolic effects of CYP2A6 and CYP2A13 on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced gene mutation–a mammalian cell-based mutagenesis approach. Toxicol Appl Pharmacol 2011; 253 (02) 145-152
• 7 Su T, Bao Z, Zhang QY, Smith TJ, Hong JY, Ding X. Human cytochrome P450 CYP2A13: predominant expression in the respiratory tract and its high efficiency metabolic activation of a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Cancer Res 2000; 60 (18) 5074-5079
• 8 Fukami T, Nakajima M, Matsumoto I, Zen Y, Oda M, Yokoi T. Immunohistochemical analysis of CYP2A13 in various types of human lung cancers. Cancer Sci 2010; 101 (04) 1024-1028
• 9 Sun L, Fan X. Expression of cytochrome P450 2A13 in human non-small cell lung cancer and its clinical significance. J Biomed Res 2013; 27 (03) 202-207
• 10 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) 8057-8061
• 11 Ramadhani N, Soeroso NN, Tarigan SP, Eyanoer PC, Hidayat H. Correlation between genetic polymorphism of CYP2A13 genotype and lung cancer in female passive smokers. Molecular and Cellular Biomedical Sciences 2022; 6 (02) 89
• 12 Kiyohara C, Takayama K, Nakanishi Y. CYP2A13, CYP2A6, and the risk of lung adenocarcinoma in a Japanese population. J Health Sci 2005; 51 (06) 658-666
• 13 Hua F, Guo Y, Sun Q, Yang L, Gao F. HapMap-based study: CYP2A13 may be a potential key metabolic enzyme gene in the carcinogenesis of lung cancer in non-smokers. Thorac Cancer 2019; 10 (04) 601-606
• 14 Pathak AK, Husain N, Kant S, Bala L. Independent and interactive effect of CYPs and GSTs genetic variants and tobacco smoking on the risk of non-small cell lung carcinoma. Arch Med Res 2021; 52 (07) 719-730
• 15 Cao Y, Miao XP, Zeng YX, Lin DX, Shao JY. Association between genetic polymorphisms of CYP2A13, CYP2A6 and risk of nasopharyngeal carcinoma in southern Chinese population. Cancer Biology 2011;1(1)
• 16 Jiang JH, Jia WH, Chen HK. et al. Genetic polymorphisms of CYP2A13 and its relationship to nasopharyngeal carcinoma in the Cantonese population. J Transl Med 2004; 2 (01) 24
• 17 Kumondai M, Hosono H, Orikasa K. et al. CYP2A13 genetic polymorphisms in relation to the risk of bladder cancer in Japanese smokers. Biol Pharm Bull 2016; 39 (10) 1683-1686
• 18 Song DK, Xing DL, Zhang LR, Li ZX, Liu J, Qiao BP. Association of NAT2, GSTM1, GSTT1, CYP2A6, and CYP2A13 gene polymorphisms with susceptibility and clinicopathologic characteristics of bladder cancer in Central China. Cancer Detect Prev 2009; 32 (5-6): 416-423
• 19 Mohelnikova-Duchonova B, Vrana D, Holcatova I, Ryska M, Smerhovsky Z, Soucek P. CYP2A13, ADH1B, and ADH1C gene polymorphisms and pancreatic cancer risk. Pancreas 2010; 39 (02) 144-148
• 20 Moher D, Shamseer L, Clarke M. et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Revista Espanola de Nutricion Humana y Dietetica 2016; 20 (02) 148-160
• 21 Sim CC, Sim EUH. Over-expression of cyclo-oxygenase-2 predicts poor survival of patients with nasopharyngeal carcinoma: a meta-analysis. J Laryngol Rhinol Otol 2020; 134 (04) 338-343
• 22 Wells G, Shea B, O'Connell D. et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Accessed April 17, 2025 at: https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
• 23 Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315 (7109) 629-634
• 24 R Core Team. R: A language and environment for statistical computing. Published online 2023. Accessed October 18, 2023 at: https://www.R-project.org/
• 25 Balduzzi S, Rücker G, Schwarzer G. How to perform a meta-analysis with R: a practical tutorial. Evid Based Ment Health 2019; 22 (04) 153-160
• 26 Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw 2010; 36 (03) 1-48
• 27 Cheng XY, Chen GL, Zhang WX, Zhou G, Wang D, Zhou HH. Arg257Cys polymorphism of CYP2A13 in a Chinese population. Clin Chim Acta 2004; 343 (1-2): 213-216
• 28 Chiang HC, Lee H, Chao HR, Chiou YH, Tsou TC. Pulmonary CYP2A13 levels are associated with early occurrence of lung cancer-Its implication in mutagenesis of non-small cell lung carcinoma. Cancer Epidemiol 2013; 37 (05) 653-659
• 29 Soeroso NN, Zain-Hamid R, Sinaga BY, Sadewa AH. The CYP2A13 Arg257Cys polymorphism in Bataknese lung cancer patients and its relationship with nicotine dependence. National Published Articles 2017; 1-7
• 30 Timofeeva MN, Kropp S, Sauter W. et al; LUCY-Consortium. CYP450 polymorphisms as risk factors for early-onset lung cancer: gender-specific differences. Carcinogenesis 2009; 30 (07) 1161-1169
• 31 Soeroso NN, Sinaga BYM, Zain-Hamid R, Sadewa AH, Syahruddin E. The CYP2A13 Arg257Cys polymorphism and its relationship to lung cancer. Stem Cell Oncology 2018; 265-269
• 32 Cauffiez C, Lo-Guidice JM, Quaranta S. et al. Genetic polymorphism of the human cytochrome CYP2A13 in a French population: implication in lung cancer susceptibility. Biochem Biophys Res Commun 2004; 317 (02) 662-669
• 33 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 Pharmacokinet 2011; 26 (05) 516-522