Dataset Information

Association of CYP2A6*4 with susceptibility of lung cancer: a meta-analysis.

ABSTRACT: To assess the association between the variant of Cytochrome P450 2A6 whole gene deletion (CYP2A6*4) polymorphism and risk of lung cancer.Two investigators independently searched the PubMed, Elsevier, EMBASE, Web of Science, Wiley Online Library and Chinese National Knowledge Infrastructure (CNKI). Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) for CYP2A6*4 and lung cancer were calculated in a fixed-effects model (the Mantel-Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate.This meta-analysis included seven eligible studies, which included 2524 lung cancer cases and 2258 controls (cancer-free). Overall, CYP2A6*4 was associated with the risk of lung cancer (allele*4 vs. allele non-*4, pooled OR ?=?0.826, 95% CI ?=?0.725-0.941, P-value ?=?0.004). When stratifying for population, significant association was observed in Asian (additive model, pooled OR ?=?0.794, 95% CI ?=?0.694-0.909, P-value ?=?0.001; dominant model, pooled OR ?=?0.827, 95% CI ?=?0.709-0.965, P-value ?=?0.016; recessive model (pooled OR ?=?0.444, 95% CI ?=?0.293-0.675, P-value <0.0001). In the overall analysis, a comparably significant decrease in the frequency of *4/*4 genotype was detected between cases and controls in Asian while no *4/*4 genotype was detected in Caucasian in collected data.This meta-analysis suggests that the CYP2A6*4 polymorphism is associated with susceptibility of lung cancer in Asian. The whole gene deletion of CYP2A6 may decrease the risk of lung cancer in Asian samples.

SUBMITTER: Wang L

PROVIDER: S-EPMC3622000 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Association of CYP2A6*4 with susceptibility of lung cancer: a meta-analysis.

Wang Lishan L

PloS one 20130409 4

<h4>Objectives</h4>To assess the association between the variant of Cytochrome P450 2A6 whole gene deletion (CYP2A6*4) polymorphism and risk of lung cancer.<h4>Methods</h4>Two investigators independently searched the PubMed, Elsevier, EMBASE, Web of Science, Wiley Online Library and Chinese National Knowledge Infrastructure (CNKI). Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) for CYP2A6*4 and lung cancer were calculated in a fixed-effects model (the Mantel-Haenszel method) and ...[more]

PMID: 23585826

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Project description:Cigarette smoke, containing both nicotine and carcinogens, causes lung cancer. However, not all smokers develop lung cancer, highlighting the importance of the interaction between host susceptibility and environmental exposure in tumorigenesis. Here, we aimed to delineate the interaction between metabolizing ability of tobacco carcinogens and smoking intensity in mediating genetic susceptibility to smoking-related lung tumorigenesis. Single-variant and gene-based associations of 43 tobacco carcinogen-metabolizing genes with lung cancer were analyzed using summary statistics and individual-level genetic data, followed by causal inference of Mendelian randomization, mediation analysis, and structural equation modeling. Cigarette smoke-exposed cell models were used to detect gene expression patterns in relation to specific alleles. Data from the International Lung Cancer Consortium (29,266 cases and 56,450 controls) and UK Biobank (2,155 cases and 376,329 controls) indicated that the genetic variant rs56113850 C>T located in intron 4 of CYP2A6 was significantly associated with decreased lung cancer risk among smokers (OR = 0.88, 95% confidence interval = 0.85-0.91, P = 2.18 × 10-16), which might interact (Pinteraction = 0.028) with and partially be mediated (ORindirect = 0.987) by smoking status. Smoking intensity accounted for 82.3% of the effect of CYP2A6 activity on lung cancer risk but entirely mediated the genetic effect of rs56113850. Mechanistically, the rs56113850 T allele rescued the downregulation of CYP2A6 caused by cigarette smoke exposure, potentially through preferential recruitment of transcription factor helicase-like transcription factor. Together, this study provides additional insights into the interplay between host susceptibility and carcinogen exposure in smoking-related lung tumorigenesis.SignificanceThe causal pathway connecting CYP2A6 genetic variability and activity, cigarette consumption, and lung cancer susceptibility in smokers highlights the need for behavior modification interventions based on host susceptibility for cancer prevention.

Project description:Previous studies have suggested that DNA double-strand break (DSB) repair is an important protective pathway after damage. The ataxia telangiectasia mutated (ATM) gene plays an important role in the DNA DSB repair pathway. DNA damage is a major cytotoxic effect that can be caused by radiation, and the ability to repair DNA after damage varies among different tissues. Impaired DNA repair pathways are associated with high sensitivity to radiation exposure. Hence, ATM gene polymorphisms are thought to influence the risk of cancer and radiation-induced pneumonitis (RP) risk in cancer patients treated with radiotherapy. However, the results of previous studies are inconsistent. We therefore conducted this comprehensive meta-analysis.A systematic literature search was performed in the PubMed, Embase, China National Knowledge Internet (CNKI) and Wanfang databases to identify studies that investigated the association between the ATM gene polymorphisms and both lung cancer and RP radiotherapy-treated lung cancer (the last search was conducted on Dec.10, 2015). The odds ratio (OR) and 95% confidence interval (CI) were used to investigate the strength of these relationships. Funnel plots and Begg's and Egger's tests were conducted to assess the publication bias. All analyses were performed in STATA 13.0 software.Ten eligible case-control studies (4731 cases and 5142 controls) on lung cancer susceptibility and four (192 cases and 772 controls) on RP risk were included. The results of the overall and subgroup analyses indicated that in the ATM gene, the rs189037 (-111G?>?A, -4519G?>?A), rs664677 (44831C?>?T, 49238C?>?T) and rs664143 (131,717 T?>?G) polymorphisms were significantly associated with lung cancer susceptibility (OR?=?1.21, 95% CI?=?1.04-1.39, P?=?0.01; OR?=?1.26, 95% CI?=?1.06-1.49, P?=?0.01; OR?=?1.43, 95% CI?=?1.15-1.78, P?<?0.01). Additionally, the rs189037 variant was significantly associated with RP risk (OR?=?1.74, 95% CI?=?1.02-2.97, P?=?0.04). No publication bias was found in the funnel plots, Begg's tests or Egger's tests.The results indicate that the ATM rs189037, rs664677 and rs664143 gene polymorphisms are risk factors for lung cancer, while the ATM rs189037 variant was significantly associated with RP risk.

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Dataset Information

Association of CYP2A6*4 with susceptibility of lung cancer: a meta-analysis.

Publications

Association of CYP2A6*4 with susceptibility of lung cancer: a meta-analysis.

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