Tumor Biol. DOI 10.1007/s13277-014-1681-y
RESEARCH ARTICLE
APE1 Asp148Glu polymorphism and lung cancer susceptibility Liyun Cai & Yingjv Fu & Yuanyue Zhang
Received: 11 December 2013 / Accepted: 22 January 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract Apurinic/apyrimidinic endonuclease 1 (APE1) is a key enzyme in base excision repair (BER) pathway for the removal of many oxidized and alkylated bases. Singlenucleotide polymorphisms of the APE1gene have been demonstrated to be involved in carcinogenesis. However, the association between APE1 Asp148Glu polymorphism and lung cancer risk remains inconclusive. To derive a precise estimate for this association, we carried out an updated meta-analysis by pooling data thus far published. The pooled odds ratio (OR) with 95 % confidence interval (95 % CI) was calculated to assess the role of APE1 Asp148Glu polymorphism in lung carcinogenesis. The pooled ORs suggested that variant genotypes of APE1 Asp148Glu were modestly associated with an elevated risk of lung cancer (GluGlu vs. AspAsp, OR=1.22, 95 % CI 1.01–1.48, P=0.038; GluGlu vs. AspAsp + AspGlu, OR=1.19, 95 % CI 1.02–1.39, P=0.023). The relationship was also observed in studies conducted among Asians, but not Caucasians. Sensitivity analysis further confirmed the findings. The meta-analysis shows that the polymorphism of APE1 Asp148Glu exerts risk effect on lung cancer development. Keywords Lung cancer . Polymorphism . Meta-analysis . Apurinic/apyrimidinic endonuclease 1
Introduction Lung cancer is a major cause of cancer-related death worldwide with poor overall survival rate [1, 2]. Cigarette smoking has been clearly and unambiguously identified as a direct cause of lung cancer [2]. Besides, it has been well documented that alcohol consumption, diet, radon radiation, and chronic airway L. Cai (*) : Y. Fu : Y. Zhang Department of Emergency Internal Medicine, Tangshan Worker’s Hospital, No. 27 Wenhua Road, Tangshan, Hebei 063000, China e-mail: [email protected]
inflammation also exert risk effects on lung cancer development [3, 4]. What remains an issue is that not all exposed individuals develop lung cancer, and indeed, a fraction of lifelong nonsmokers die from this deadly disease. Despite advances in the diagnosis and management of lung cancer in the past few decades, the underlying molecular mechanisms for it has not yet been understood. Increasing evidence implicates that the polymorphisms of a number of susceptible genes are involved in the development of lung cancer [5–7]. Apurinic/apyrimidinic endonuclease 1 (APE1) is a key enzyme in base excision repair (BER) pathway, responsible for the repair of damaged DNA caused by oxidative reagents and alkylation [8, 9]. Accordingly, APE1 is competent in protecting cells against toxic effects of endogenous and exogenous carcinogens. However, mutation in this gene may lead to reduced or missed enzymatic activity and thus contributes to tumorigenesis. The polymorphism Asp148Glu is one of the most common mutations in APE1 gene related to carcinogenesis [10, 11]. During the last decade, many individual studies have investigated the role of APE1 Asp148Glu polymorphism in lung cancer risk [12–26]. Nevertheless, the findings across independent publications vary in diverse ethnic populations. In the present study, we performed an updated metaanalysis by pooling all available published data to precisely estimate the effect of APE1 Asp148Glu mutation on lung carcinogenesis. In addition, the susceptibility of APE1 Asp148Glu to lung cancer was also assessed among Asians and Caucasians, respectively.
Materials and methods Identification of eligible studies We performed a comprehensive literature search in databases of PubMed, Embase, and China National Knowledge
Tumor Biol.
Infrastructure (CNKI) from their inception up to now by use of the following keywords: “apurinic/apyrimidinic endonuclease 1/APE1/APEX1/APE1 Asp148Glu/APE1 rs1130409,” “lung cancer/lung carcinoma,” and “polymorphism/single-nucleotide polymorphism/SNP.” Additional relevant studies on the association between APE1 Asp148Glu polymorphism and lung cancer risk were identified by checking the references of all eligible studies. In case of publications with overlapping data, the most recent or complete one was included into our study. Inclusion criteria The included studies must meet the inclusion criteria as follows: (1) studies were based on case-control design; (2) studies on the risk of lung cancer; (3) studies on the susceptibility of APE1 Asp148Glu polymorphism to cancer; and (4) studies presented sample size in cases and controls and the frequency of GluGlu, AspAsp, and AspGlu genotypes among cases and controls, respectively.
Results Characteristics of all studies After the comprehensive search of the PubMed, Embase, and CNKI databases, we identified 16 relevant publications totally [12–26, 35]. However, one study was excluded due to case-only design [35]. Accordingly, 15 case-control studies with a total of 4,984 cases and 6,281 controls were included into the present meta-analysis [12–26]. They were published between 2003 and 2013 and were mainly conducted in Asians and Caucasians. The genotype distribution in controls of all studies was in agreement with HWE [12–18, 21–23, 25, 26], except three of them [19, 20, 24]. The characteristics of all included studies were shown in Table 1, including frequency of cases and controls, ethnicity, country of origin, first author, and publication year.
Overall analysis Data extraction The data were carefully extracted from each eligible publication, primarily including the following information: authors; year; country; ethnicity; study design; P values for HardyWeinberg equilibrium (HWE) in controls; sample size of cases and controls; the diagnosis of lung cancer; and the frequency of GluGlu, AspAsp, and AspGlu genotypes in cases and controls. Two authors independently extracted data, and disagreement was settled down by consensus on all terms.
The association between APE1 Asp148Glu polymorphism and lung cancer risk was assessed by calculating pooled ORs with corresponding 95 % CIs. The overall analysis suggested that variant genotypes of APE1 Asp148Glu were associated with an elevated risk of lung cancer in the following gene models: for GluGlu vs. AspAsp: OR=1.22, 95 % CI 1.01–1.48, P=0.038; and for GluGlu vs. AspAsp + AspGlu: OR=1.19, 95 % CI 1.02–1.39, P=0.023 (Table 2 and Fig. 1). The stability and reliability of all pooled ORs were confirmed by sensitivity analysis (data not shown).
Statistical analysis We strictly conformed to the guidelines and recommendations for quality assessment in meta-analyses of genetic association studies [27, 28]. Pooled odds ratios (ORs) with corresponding 95 % confidence intervals (CIs) were calculated to assess the strength of association between APE1 Asp148Glu polymorphism and lung cancer risk. The between-study heterogeneity was analyzed by both chi-square-based Q test and I2 test [29, 30]. The fixed-effects model (the Mantel-Haenszel method) was used to calculate the pooled ORs when the between-study heterogeneity was not significant [31]; otherwise, the randomeffects model (the DerSimonian and Laird method) was adopted [32]. We also conducted stratified analysis by ethnicity and sensitivity analysis to further estimate the effect of APE1 Asp148Glu mutation on lung carcinogenesis. The publication bias risk was evaluated by Begg’s funnel plots and Egger’s test, and a P
RESEARCH ARTICLE
APE1 Asp148Glu polymorphism and lung cancer susceptibility Liyun Cai & Yingjv Fu & Yuanyue Zhang
Received: 11 December 2013 / Accepted: 22 January 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract Apurinic/apyrimidinic endonuclease 1 (APE1) is a key enzyme in base excision repair (BER) pathway for the removal of many oxidized and alkylated bases. Singlenucleotide polymorphisms of the APE1gene have been demonstrated to be involved in carcinogenesis. However, the association between APE1 Asp148Glu polymorphism and lung cancer risk remains inconclusive. To derive a precise estimate for this association, we carried out an updated meta-analysis by pooling data thus far published. The pooled odds ratio (OR) with 95 % confidence interval (95 % CI) was calculated to assess the role of APE1 Asp148Glu polymorphism in lung carcinogenesis. The pooled ORs suggested that variant genotypes of APE1 Asp148Glu were modestly associated with an elevated risk of lung cancer (GluGlu vs. AspAsp, OR=1.22, 95 % CI 1.01–1.48, P=0.038; GluGlu vs. AspAsp + AspGlu, OR=1.19, 95 % CI 1.02–1.39, P=0.023). The relationship was also observed in studies conducted among Asians, but not Caucasians. Sensitivity analysis further confirmed the findings. The meta-analysis shows that the polymorphism of APE1 Asp148Glu exerts risk effect on lung cancer development. Keywords Lung cancer . Polymorphism . Meta-analysis . Apurinic/apyrimidinic endonuclease 1
Introduction Lung cancer is a major cause of cancer-related death worldwide with poor overall survival rate [1, 2]. Cigarette smoking has been clearly and unambiguously identified as a direct cause of lung cancer [2]. Besides, it has been well documented that alcohol consumption, diet, radon radiation, and chronic airway L. Cai (*) : Y. Fu : Y. Zhang Department of Emergency Internal Medicine, Tangshan Worker’s Hospital, No. 27 Wenhua Road, Tangshan, Hebei 063000, China e-mail: [email protected]
inflammation also exert risk effects on lung cancer development [3, 4]. What remains an issue is that not all exposed individuals develop lung cancer, and indeed, a fraction of lifelong nonsmokers die from this deadly disease. Despite advances in the diagnosis and management of lung cancer in the past few decades, the underlying molecular mechanisms for it has not yet been understood. Increasing evidence implicates that the polymorphisms of a number of susceptible genes are involved in the development of lung cancer [5–7]. Apurinic/apyrimidinic endonuclease 1 (APE1) is a key enzyme in base excision repair (BER) pathway, responsible for the repair of damaged DNA caused by oxidative reagents and alkylation [8, 9]. Accordingly, APE1 is competent in protecting cells against toxic effects of endogenous and exogenous carcinogens. However, mutation in this gene may lead to reduced or missed enzymatic activity and thus contributes to tumorigenesis. The polymorphism Asp148Glu is one of the most common mutations in APE1 gene related to carcinogenesis [10, 11]. During the last decade, many individual studies have investigated the role of APE1 Asp148Glu polymorphism in lung cancer risk [12–26]. Nevertheless, the findings across independent publications vary in diverse ethnic populations. In the present study, we performed an updated metaanalysis by pooling all available published data to precisely estimate the effect of APE1 Asp148Glu mutation on lung carcinogenesis. In addition, the susceptibility of APE1 Asp148Glu to lung cancer was also assessed among Asians and Caucasians, respectively.
Materials and methods Identification of eligible studies We performed a comprehensive literature search in databases of PubMed, Embase, and China National Knowledge
Tumor Biol.
Infrastructure (CNKI) from their inception up to now by use of the following keywords: “apurinic/apyrimidinic endonuclease 1/APE1/APEX1/APE1 Asp148Glu/APE1 rs1130409,” “lung cancer/lung carcinoma,” and “polymorphism/single-nucleotide polymorphism/SNP.” Additional relevant studies on the association between APE1 Asp148Glu polymorphism and lung cancer risk were identified by checking the references of all eligible studies. In case of publications with overlapping data, the most recent or complete one was included into our study. Inclusion criteria The included studies must meet the inclusion criteria as follows: (1) studies were based on case-control design; (2) studies on the risk of lung cancer; (3) studies on the susceptibility of APE1 Asp148Glu polymorphism to cancer; and (4) studies presented sample size in cases and controls and the frequency of GluGlu, AspAsp, and AspGlu genotypes among cases and controls, respectively.
Results Characteristics of all studies After the comprehensive search of the PubMed, Embase, and CNKI databases, we identified 16 relevant publications totally [12–26, 35]. However, one study was excluded due to case-only design [35]. Accordingly, 15 case-control studies with a total of 4,984 cases and 6,281 controls were included into the present meta-analysis [12–26]. They were published between 2003 and 2013 and were mainly conducted in Asians and Caucasians. The genotype distribution in controls of all studies was in agreement with HWE [12–18, 21–23, 25, 26], except three of them [19, 20, 24]. The characteristics of all included studies were shown in Table 1, including frequency of cases and controls, ethnicity, country of origin, first author, and publication year.
Overall analysis Data extraction The data were carefully extracted from each eligible publication, primarily including the following information: authors; year; country; ethnicity; study design; P values for HardyWeinberg equilibrium (HWE) in controls; sample size of cases and controls; the diagnosis of lung cancer; and the frequency of GluGlu, AspAsp, and AspGlu genotypes in cases and controls. Two authors independently extracted data, and disagreement was settled down by consensus on all terms.
The association between APE1 Asp148Glu polymorphism and lung cancer risk was assessed by calculating pooled ORs with corresponding 95 % CIs. The overall analysis suggested that variant genotypes of APE1 Asp148Glu were associated with an elevated risk of lung cancer in the following gene models: for GluGlu vs. AspAsp: OR=1.22, 95 % CI 1.01–1.48, P=0.038; and for GluGlu vs. AspAsp + AspGlu: OR=1.19, 95 % CI 1.02–1.39, P=0.023 (Table 2 and Fig. 1). The stability and reliability of all pooled ORs were confirmed by sensitivity analysis (data not shown).
Statistical analysis We strictly conformed to the guidelines and recommendations for quality assessment in meta-analyses of genetic association studies [27, 28]. Pooled odds ratios (ORs) with corresponding 95 % confidence intervals (CIs) were calculated to assess the strength of association between APE1 Asp148Glu polymorphism and lung cancer risk. The between-study heterogeneity was analyzed by both chi-square-based Q test and I2 test [29, 30]. The fixed-effects model (the Mantel-Haenszel method) was used to calculate the pooled ORs when the between-study heterogeneity was not significant [31]; otherwise, the randomeffects model (the DerSimonian and Laird method) was adopted [32]. We also conducted stratified analysis by ethnicity and sensitivity analysis to further estimate the effect of APE1 Asp148Glu mutation on lung carcinogenesis. The publication bias risk was evaluated by Begg’s funnel plots and Egger’s test, and a P
