Cytochrome P450 2A6 whole-gene deletion (<i>CYP2A6*4</i> ) polymorphism reduces risk of lung cancer: A meta-analysis

Abstract

INTRODUCTION Lung cancer is the most commonly diagnosed cancer worldwide and is the leading cause of cancer death. Smoking is a major contributor to the pathogenesis of lung cancer. Cytochrome P450 2A6 (CYP2A6) is responsible for the metabolic activation of most tobacco carcinogens. CYP2A6 genetic polymorphism can cause variations in the human metabolism of xenobiotics. We performed this meta-analysis to determine the association between whole-gene CYP2A6 deletion polymorphism (CYP2A6*4) and lung cancer risk. METHODS The PubMed, SAGE, Science Direct, the Cochrane Library and Ovid databases were searched for observational studies before October 2018. Methodological quality was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS). RESULTS Nine case-control studies involving 4385 lung cancer cases and 4142 controls were included in the analysis. The random-effects model was used to combine results from individual studies. The pooled odds ratio was 0.39 (95% CI: 0.27-0.56). There was no heterogeneity across studies (χ 2 =2.49, p=0.96, I 2 =0%). CONCLUSIONS Current evidence from the case-control studies suggests that the CYP2A6 whole-gene deletion polymorphism decreases the risk of lung cancer. Further research is needed to identify any potential confounding factors that may impact this association.

Biochemistry of nicotine metabolism and its relevance to lung cancer

“…A number of epidemiology studies have confirmed the protective effect of the CYP2A6*4 deletion allele on a smoker's lung cancer risk (27,135,136,146,(148)(149)(150). A meta-analysis of nine case control studies reported a more than 60% reduction in lung cancer incidence among subjects with no functional P450 2A6 (genotype CYP2A6*4/*4 or CYP2A*2/*2) compared to those who carry neither of these alleles (135,136,146,148,(151)(152)(153)(154)(155).…”

“…A meta-analysis of nine case control studies reported a more than 60% reduction in lung cancer incidence among subjects with no functional P450 2A6 (genotype CYP2A6*4/*4 or CYP2A*2/*2) compared to those who carry neither of these alleles (135,136,146,148,(151)(152)(153)(154)(155). The lung cancer cases in most of these studies included a mixture of smokers and never smokers (typically defined as smoking <100 per lifetime) and, as would be expected, the significance of the protective effect was attenuated if it was not stratified by smoking status (149,150). A few studies have found no relationship between CYP2A6 genotype and lung cancer risk (151,(156)(157)(158).…”

Genetic Polymorphism of Cyp2a6 and Cyp2a13 Genes and Environmental Tobacco Smoke Induced Lung Cancer Risk in Indonesian Female Never Smokers

“…As polymorphism of CYP2A6 has wide variants, allele *4 was known as "loss function" enzymes in nicotine metabolism. People with CYP2A6*4 tend to smoke less intensively and having less risk of lung cancer [11], [12]. In this study, we found only two participants showed the expressions of CYP2A6*4 in the case group, and there were no expressions of CYP2A6*4 in the control group, so the risk analysis compares to the wild type of CYP2A6 (CYP2A6*1) could not be performed.…”

“…The polymorphism of these enzymes will undermine nicotine metabolism process that has several implications to its own metabolic rate, if polymorphism is presence in the alleles of CYP2A6*4, it could have a protective effect from developing lung cancer due to its nictonine slowly metabolism characteristic [11], [12], [13]. In addition, the CYP2A13 which is highly found in the respiratory epithelium in the upper airway has an inconsistent effect in the development of lung cancer.…”

Comprehensive Analysis of the Expression and Prognosis of 12 Cytochrome P450s in Human Hepatocellular Carcinoma from the Perspective of Network Pharmacology

“…CYP2A6 exerts a key effect on the outcome of resected gastric cancer [37] and HCC [38] via 5uorouracil metabolism. As the metabolic-activating enzyme of most tobacco carcinogens, CYP2A6 is notably involved with the risk of lung cancer [39] and is a crucial clinical consideration for personalized medicine [40]. The expression levels of CYP2A6 and CYP2A7 are lower in patients with hepatitis B virus and HCV than those in healthy people [41].…”