Lung cancer remains the deadliest cancer worldwide despite

Transcription

1 ORIGINAL ARTICLE ERCC2/XPD Lys751Gln and Asp312Asn Gene Polymorphism and Lung Cancer Risk A Meta-Analysis Involving 22 Case Control Studies Ping Zhan, MD,* Qin Wang, MD, Shu-Zhen Wei, MD, Jing Wang, MD, Qian Qian, MD, Li-Ke Yu, MD,* and Yong Song, MD, PhD Introduction: Published data on the association between XPD Lys751Gln and Asp312Asn gene polymorphism and lung cancer risk are inconclusive. Methods: To derive a more precise estimation of the relationship, a meta-analysis was performed. Results: A total of 22 studies including 15,507 subjects for XPD Lys751Gln genotype and 13,198 subjects for XPD Asp312Asn genotype were examined. For XPD Lys751Gln genotype, significantly increased lung cancer risk was associated with two variant genotypes (CC versus AA: odds ratio [OR] 1.26, 95% confidence interval [CI] , p for heterogeneity; C allele carriers versus AA: OR 1.18, 95% CI , p for heterogeneity). When stratified by ethnicity, significantly increased risks were found among Caucasians but not in Asians. For XPD Asp312Asn genotype, significantly increased lung cancer risk was associated with two variant genotypes (AA versus GG: OR 1.24, 95% CI , p for heterogeneity; the A allele carriers versus GG: OR 1.35, 95% CI , p for heterogeneity). When stratified analysis by ethnicity, significantly increased risks were found among Asians but not in Caucasians. In the subgroup analyses by smoking status, there were no significant associations among the nonsmoker subgroup; however, significantly increased lung cancer risks were found in the smoking group. Conclusion: This meta-analysis suggests that the XPD Lys751Gln and Asp312Asn gene polymorphisms are associated with lung cancer risk, the C allele of XPD Lys751Gln genotype is an increased risk factor for developing lung cancer among Caucasians and in smokers, *First Department of Respiratory Medicine, Nanjing Chest Hospital; Department of Respiratory Medicine, No. 81 Hospital of PLA, Nanjing, China; Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine; and Department of Hematology, The Affiliated DrumTower Hospital of Nanjing University School of Medicine, Nanjing, China. Disclosure: The authors declare no conflicts of interest in this research. Address for correspondence: Li-ke Yu, First Department of Respiratory Medicine, Nanjing Chest Hospital, 215 Guangzhou Road, Nanjing , China; Yong Song, Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing , China. yulike66@163.com/yong_ song6310@ yahoo.com The first two authors contributed equally to this work and should be considered as co-first authors. Copyright 2010 by the International Association for the Study of Lung Cancer ISSN: /10/ and the A allele of XPD 312 genotype is also an increased risk factor among Asians and in smokers. Key Words: ERCC2/XPD, Polymorphism, Lung cancer, Susceptibility, Meta-analysis. (J Thorac Oncol. 2010;5: ) Lung cancer remains the deadliest cancer worldwide despite improvements in diagnostic and therapeutic techniques. 1 Incidence has yet to peak in many parts of the world, particularly in China where lung cancer and tobacco smoking has become a major public health challenge. 2 The mechanism of lung carcinogenesis is still not fully understood. Smoking status has been well established as the single most important factor in causing lung cancer; however, host factors including genetic polymorphisms have been recently implicated in contributing to tumorigenesis of lung cancer. 3 In recent years, several common low-penetrant genes have been identified as potential lung cancer susceptibility genes. Polymorphisms of the genes belonging to the base excision repair pathway, such as x-ray repair cross-complementing group 1 (XRCC1), and the nucleotide excision repair (NER) pathway, such as excision repair cross-complementing group 1 (ERCC1) and xeroderma pigmentosum group D (ERCC2/XPD), have been extensively studied. ERCC2/XPD exhibits dual functionality in the cell because it is involved in NER and cell cycle regulation through Cdk-activating kinase. 4 Several XPD polymorphisms (located in codons 156, 312, 711, and 751) were recently identified in the coding regions with relatively high allele frequencies ( 25%). 5,6 Two particular XPD polymorphisms (Lys751Gln and Asp312Asn) have been the focus of investigations into their relationship with phenotypic endpoints relevant to lung carcinogenesis. The predominant homozygous allele, the heterozygous allele, and the homozygous rare allele of the Lys751Gln gene polymorphism are named accordingly: the homozygous wild-type genotype (AA or Lys/Lys); the heterozygote (AC or Lys/Gln); and the rare homozygote (CC or Gln/Gln). For the Asp312Asn gene polymorphism, the variant genotype was the homozygous wild-type genotype (GG or Asp/Asp), the heterozygote (AG or Asp/Asn), and the rare homozygote (AA or Asn/Asn). Journal of Thoracic Oncology Volume 5, Number 9, September

2 Zhan et al. Journal of Thoracic Oncology Volume 5, Number 9, September 2010 A number of studies reported the role of XPD Lys751Gln and Asp312Asn polymorphisms in lung cancer risk, but the results were largely inconclusive. This dichotomy could be the result of a possible small effect of the polymorphism on lung cancer risk or the relatively small sample size in each published studies. Hu et al. 7 found an increase in cancer risk for the XPD 751 C, 312 A alleles, XPD 751 CC, and 312 AA genotypes through a meta-analysis of data from nine case control lung cancer populations. However, in Benhamou and Sarasin s meta-analysis using seven studies, 8 no statistically significant associations were found. When these meta-analyses were performed, the pooled sample size was relatively small. Since then, several additional studies with large cohort populations have been reported. Furthermore, the previous studies lacked proper controls for the potential confounding effect of smoking, the main risk determinant for lung cancer. Simple differences in cohort populations and study design may also contribute to the disparate findings. Therefore, we performed a large and comprehensive meta-analysis including the most recent published studies to derive a more precise estimation of the phenotype association. MATERIALS AND METHODS Publication Search The electronic databases PubMed, Embase, Web of Science, and China National Knowledge Infrastructure were searched for studies to include in this meta-analysis by using the terms ERCC2, XPD, polymorphism, and lung cancer. An upper date limit of September 30, 2009, was applied; no lower date limit was defined. The search was carried out without restriction on language but was focused on studies that had been conducted on human subjects. We also reviewed the Cochrane Library for relevant articles. The reference lists of reviews and retrieved articles were also manually reviewed. Only published studies with full-text articles were included. When more than one of the same patient population was included in several publications, only the most recent or complete study was used in this metaanalysis. Inclusion Criteria Studies were required to meet the following criteria for inclusion: (1) evaluated the ERCC2/XPD gene polymorphism and lung cancer risk; (2) case control studies; (3) supplied the number of individual genotypes for ERCC2/XPD Lys751Gln and Asp312Asn gene in lung cancer cases and controls, respectively; and (4) the distribution of genotypes among controls were in Hardy-Weinberg equilibrium. Data Extraction Information was carefully extracted from all eligible publications independently by two authors according to the inclusion criteria listed above. Disagreement was resolved by discussion between the two authors. The following data were collected from each study: first author s surname; year of publication; ethnicity; characteristics of matching criteria in controls; total numbers of cases and controls; and numbers of cases and controls with the ERCC2/XPD Lys751Gln and Asp312Asn genotypes, respectively. If data from any of the above categories were not reported in the primary study, items were treated as not applicable. We did not contact the author of the primary study to request missing or additional information. Ethnicity was categorized as Asian, Caucasian, and mixed population. We also abstracted the information regarding smoking status from available studies. Subjects were divided between a smokers group (including former and current smokers) or a nonsmokers group. No minimum number of patients to include from a study was applied to our meta-analysis. Statistical Analysis Odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of association between the ERCC2/XPD Lys751Gln and Asp312Asn gene polymorphisms and lung cancer risk. The pooled ORs for the risk associated with the genotypes of the rare homozygote and the allele carriers (AC CC for XPD Lys751Gln genotype and GA AA for XPD Asp312Asn genotype) with the homozygous wild-type genotype were calculated. Subgroup analyses were carried out according to ethnicity and smoking status. Heterogeneity assumption was verified by the 2 -based Q test. 9 A p value greater than 0.10 for the Q test indicates a lack of heterogeneity among studies, so the pooled OR estimate of each study was calculated by the fixed-effects model (the Mantel-Haenszel method). 10 Otherwise, the random-effects model (the DerSimonian and Laird method) was used. 11 One-way sensitivity analyses were performed to assess the stability of the results, namely, a single study in the meta-analysis was deleted each time to reflect the influence of the individual dataset on the pooled OR. 12 An estimate of potential publication bias was carried out using funnel plotting in which the standard error of log (OR) of each study was plotted against its log (OR). An asymmetric plot suggested a possible publication bias. Funnel plot asymmetry was assessed by the method of Egger s linear regression test, a well-established linear regression approach to measure the funnel plot asymmetry on the natural logarithm scale of the OR. The significance of the intercept was determined by the t test suggested by Egger (p 0.05 was considered representative of statistically significant publication bias). 13 All the calculations were performed using STATA version 10.0 (Stata Corporation, College Station, TX). RESULTS Study Characteristics A total of 22 publications met the inclusion criteria For XPD Lys751Gln genotype, a total of 21 studies involving 6824 lung cancer cases and 8683 controls were ultimately analyzed. A study by David-Beabes et al. 15 sorted the data among Caucasians and African Americans; therefore, each group in the study was considered separately for pooling subgroup analyses. For the ERCC2/XPD Asp312Asn genotype, a total of 17 studies involving 5820 lung cancer cases and 7378 controls were ultimately analyzed. Tables 1and 2 present the main characteristics of these studies Copyright 2010 by the International Association for the Study of Lung Cancer

3 Journal of Thoracic Oncology Volume 5, Number 9, September 2010 Gene Polymorphism and Lung Cancer Risk TABLE 1. Distribution of XPD Lys751Gln Genotype Among Lung Cancer Cases and Controls Included in the Meta-Analysis References Ethnicity (Country of Origin) Source of Controls Matching Criteria Sample Size (Case/Control) Lung Cancer Cases Controls AA AC CC AA AC CC Spitz et al. 14 American (mixed) Multispecialty managedcare organization Age, sex, and smoking status 341/ David-Beabes et al. 15 American (Caucasians) Population NA 178/ David-Beabes et al. 15 American (mixed) Population NA 153/ Park et al. 17 South Korea (Asian) Healthy volunteers Age 250/ Hou et al. 18 Sweden (Caucasians) Healthy population Hospital catchment area, gender, age, and smoking categories 185/ Chen et al. 19 China (Asian) Healthy volunteers Age, sex, and smoking status 109/ Zhou et al. 20 China (Asian) Friends and nonbloodrelated No specific matching characteristics 1092/ family members of lung cancer cases Xing et al. 21 China (Asian) Hospital Age, sex 351/ Misra et al. 22 American (Caucasians) Cohort participants Age, intervation group, study 310/ clinic, and date of blood draw Liang et al. 23 China (Asian) Population Age, sex, and ethnicity 1006/ Harms et al. 24 Germany (Caucasians) Hospital and population Age, sex, ethnicity, and smoking 110/ status Popanda et al. 25 Germany (Caucasians) Hospital Nonmatched 463/ Vogel et al. 26 Denmark (Caucasians) Population Age, sex, and smoking status 256/ Shen et al. 27 China (Asian) Population Sex, age, and type of fuel used for cooking and home heating 118/ Zienolddiny et al. 28 France(Caucasians) Population Age, sex, and smoking status 317/ Yin et al. 29 China (Asian) Hospital Age, 105/ Matullo et al. 30 UK (Caucasians) Population Gender, age, smoking status, country of recruitment and follow-up time 116/ Yin et al. 31 China (Asian) Population Age, sex, and ethnicity 201/ De Ruyck et al. 32 Belgium (Caucasians) Population Age, sex 110/ Lopez-Cima et al. 33 Northern Spain(Caucasians) Hospital Age, sex, and ethnicity 516/ Raaschou-Nielsen et al. 34 Denmark(Caucasians) Hospital NA 429/ Kong et al. 35 China (Asian) Hospital Age, sex 114/ NA, not applicable. Copyright 2010 by the International Association for the Study of Lung Cancer 1339

4 Zhan et al. Journal of Thoracic Oncology Volume 5, Number 9, September 2010 TABLE 2. Distribution of XPD Asp312Asn Genotype Among Lung Cancer Cases and Controls Included in the Meta-Analysis References Ethnicity (Country of Origin) Source of Controls Matching Criteria Sample Size (Case/Control) Lung Cancer Cases Controls GG GA AA GG GA AA Spitz et al. 14 American (Mixed) Multispecialty managed-care organization Butkiewicz et al. 16 American (Caucasians) Population Age, smoking status, and occupational exposure Age, sex, and smoking status 195/ / Hou et al. 18 Sweden (Caucasians) Healthy population Hospital catchment area, gender, 184/ age, and smoking categories Zhou et al. 20 China (Asian) The friends and nonbloodrelated No specific matching characteristics 1092/ family members of the lung cancer cases Xing et al. 21 China (Asian) Hospital Age and sex 351/ Misra et al. 22 American (Caucasians) Cohort participants Age, intervation group, study 313/ clinic, and date of blood draw Liang et al. 23 China (Asian) Population Age, sex, and ethnicity 1006/ Popanda et al. 25 Germany (Caucasians) Hospital Nonmatched 463/ Vogel et al. 26 Denmark (Caucasians) Population Age, sex, and smoking status 256/ Shen et al. 27 China (Asian) Population Sex, age, and type of fuel used for cooking and home heating 118/ Zienolddiny et al. 28 France(Caucasians) Population Age, sex, and smoking status 275/ Matullo et al. 30 UK (Caucasians) Population Gender, age, smoking status, 106/ country of recruitment, and follow-up time Yin et al. 31 China (Asian) Population Age, sex, and ethnicity 201/ De Ruyck et al. 32 Belgium (Caucasians) Population Age and sex 110/ Lopez-Cima et al. 33 Northern Spain (Caucasians) Hospital Age, sex, and ethnicity 516/ Raaschou-Nielsen et al. 34 Denmark (Caucasians) Hospital NA 424/ Kong et al. 35 China (Asian) Hospital Age and sex 114/ NA, not applicable Copyright 2010 by the International Association for the Study of Lung Cancer

5 Journal of Thoracic Oncology Volume 5, Number 9, September 2010 Gene Polymorphism and Lung Cancer Risk TABLE 3. Summary ORs for Various Contrasts of ERCC2/XPD 751and 312 Gene Polymorphisms in This Meta-Analysis XPD 751 Genotype XPD 312 Genotype Item Contrast Studies OR (95% CI), P h Contrast Studies OR (95% CI), P h Total CC vs. AA ( ), AA vs. GG ( ), (CC AC) vs. AA 1.18 ( ), (AA AG) vs. GG 1.35 ( ), Asian CC vs. AA ( ), AA vs. GG ( ), (CC AC) vs. AA 1.27 ( ), (AA AG) vs. GG 1.84 ( ), Caucasian CC vs. AA ( ), AA vs. GG ( ), (CC AC) vs. AA 1.32 ( ), (AA AG) vs. GG 1.04 ( ), No smoking CC vs. AA ( ), CC vs. AA ( ), (CC AC) vs. AA 2.38 ( ), (CC AC) vs. AA 1.47 ( ), Smoking CC vs. AA ( ), CC vs. AA ( ), (CC AC) vs. AA 1.89 ( ), (CC AC) vs. AA 1.56 ( ), P h, p value of Q test for heterogeneity test; OR, odds ratio; CI, confidence interval. Among the 22 publications, 19 were published in English and three were in Chinese. The sample sizes ranged from 190 to Almost all the cases were histologically confirmed. Controls were mainly healthy populations and matched for age, ethnicity, and/or smoking status. There were nine groups of Asians, 11 groups of Caucasians, and two of mixed population for XPD Lys751Gln genotype; for the ERCC2/ XPD Asp312Asn genotype, there were six groups of Asians, 10 groups of Caucasians, and one of mixed population. Nine studies contained enough information for subgroup analyses by smoking status. Hardy-Weinberg equilibrium had been tested for all polymorphisms in the control subjects, and all were in Hardy-Weinberg equilibrium. Meta-Analysis Results Table 3 lists the main results of this meta-analysis. For the XPD Lys751Gln genotype, overall, significantly increased lung cancer risk was associated with two variant genotypes when all studies were pooled into the meta-analysis (CC versus AA: OR 1.26, 95% CI , p for heterogeneity; C allele carriers versus AA: OR 1.18, 95% CI , p for heterogeneity) (Figure 1). When stratified by ethnicity, significantly increased risks were found among Caucasians for both the homozygote CC versus AA (OR 1.35, 95% CI ; p for heterogeneity) and the C allele carriers versus AA (OR 1.32, 95% CI ; p for heterogeneity). Among Asians, no significant association was found in homozygote CC versus AA (OR 1.14; 95% CI ; p for heterogeneity) or for the C allele carriers versus AA (OR 1.27; 95% CI ; p for heterogeneity). There were only two studies involving mixed populations and no significant associations were found (Table 3). For the XPD Asp312Asn genotype, overall, significantly increased lung cancer risk was associated with two variant genotypes when all studies were pooled into the meta-analysis (AA versus GG: OR 1.24, 95% CI , p for heterogeneity; A allele carriers versus GG: OR 1.35, 95% CI , p for heterogeneity) (Figure 2). When stratified by ethnicity, significantly increased risks were found among Asians for both the homozygote AA versus GG (OR 1.62, 95% CI ; p for heterogeneity) and the A allele carriers versus GG (OR 1.84, 95% CI ; p for heterogeneity). Among Caucasians, no significant association was found with homozygote AA versus GG (OR 1.14; 95% CI ; p for heterogeneity) or the A allele carriers versus GG (OR 1.04; 95% CI ; p for heterogeneity). There was only one study involving mixed populations and no significant associations were found (Table 3). In the subgroup analyses divided among smoking status, there were no significant associations among the nonsmoker subgroup; however, the smoking group revealed significantly increased lung cancer risks for both the XPD Lys751Gln genotype and XPD Asp312Asn genotype (Table 3). Sensitivity Analyses A single study that had been used in the meta-analysis was deleted each time to reflect the influence of the individual dataset on the pooled ORs. None of the corresponding pooled ORs were materially altered (data not shown). Publication Bias Begg s funnel plot and Egger s test were performed to access the publication bias of the literature used in the meta-analysis. The shapes of the funnel plots did not reveal any evidence of obvious asymmetry (Figures 3 and 4). Accordingly, the Egger s test was used to provide statistical evidence of the observed funnel plot symmetry. The results still did not suggest any evidence of publication bias (p for CC versus AA of XPD Lys751Gln genotype; p for AA versus GG of XPD Asp312Asn genotype). DISCUSSION This meta-analysis, including 15,507 subjects from 21 published case control studies for examining the XPD Lys751Gln genotype and 13,198 subjects from 17 case control studies for XPD Asp312Asn genotype, explored the association between the XPD Lys751Gln and Asp312Asn Copyright 2010 by the International Association for the Study of Lung Cancer 1341

6 Zhan et al. Journal of Thoracic Oncology Volume 5, Number 9, September 2010 FIGURE 1. Forest plot (random-effects model) of lung cancer risk associated with XPD Lys751Gln genotype for CC versus AA. Each box represents the odds ratio (OR) point estimate, and its area is proportional to the weight of the study. The diamond (and broken line) represents the overall summary estimate, with confidence interval (CI) represented by its width. The unbroken vertical line is set at the null value (OR 1.0). gene polymorphisms and lung cancer risk. The results indicated that XPD 751 C allele and XPD 312 A allele are all the low-penetrant risk factors for developing lung cancer identified to date. The results support the hypothesis that the polymorphisms of the DNA repair gene XPD which is known to be involved in the NER pathway may play a certain role in the development of lung cancer. Although the exact molecular mechanisms underlying these XPD polymorphisms and their affect on cancer risk remain to be elucidated, the published studies on the structure and functions of the XPD gene and their genetic variants could provide valuable insight. It has been proven that the XPD protein takes part in the unwinding of DNA and forms a complex with the basal transcription factor transcription factor II H during transcription-coupled repair. 36 Mutations in the XPD gene cause a severe but variable depression of NER, as verified by different assay systems. 37 Recently, Hou et al. 38 and Qiao et al. 39 reported that the two common variant alleles (located in codons 751 and 312) of the XPD gene might lead to reduced repair of aromatic DNA adducts, and promotion of tumor formation. When stratified according to ethnicity, different results were found between Asians and Caucasians for the XPD Lys751Gln or the Asp312Asn genotype. For the XPD Lys751Gln genotype, significantly increased risks were identified among Caucasians for both the homozygote CC versus AA and the C allele carriers versus AA. Among Asians, however, no significant association was found in homozygote CC versus AA or the C allele carriers versus AA. For the Asp312Asn genotype, the increased risks were apparent with both the homozygote CC versus AA and the C allele carriers versus AA among Asians; however, the associations were not found among Caucasians. These findings indicated that polymorphisms of XPD may be important in regards to specific ethnicity of patients with lung cancer, and that XPD Lys751Gln and Asp312Asn may differentially affect individ Copyright 2010 by the International Association for the Study of Lung Cancer

7 Journal of Thoracic Oncology Volume 5, Number 9, September 2010 Gene Polymorphism and Lung Cancer Risk FIGURE 2. Forest plot (random-effects model) of lung cancer risk associated with XPD Asp312Asn genotype for AA versus GG. uals of different ethnic genetic backgrounds for risk of lung FIGURE 3. Begg s funnel plot of XPD Lys751Gln gene polymorphism and lung cancer risk for CC versus AA. FIGURE 4. Begg s funnel plot of XPD Asp312Asn gene polymorphism and lung cancer risk for AA versus GG. Copyright 2010 by the International Association for the Study of Lung Cancer 1343

8 Zhan et al. Journal of Thoracic Oncology Volume 5, Number 9, September 2010 cancer. The different genetic background in different populations may to some extent explain the different risk estimates associated with the XPD variant alleles. Prevalence of the variant XPD alleles and genotypes varies markedly with ethnicity. The 312A allele frequency was varied from 0.28 to 0.4 in Caucasians, 14,18,20,22 whereas it was only among Asians. 23 However, this XPD 751C variant was much less common among Asians than those among Caucasians and African Americans. 20,23 Population stratification is an area of concern in any complex disease association study because it can confound the linkage results between a molecular marker and phenotype. 40 The observed ethnic differences may also be a result of chance because studies with small sample size are likely to be insufficiently powered to detect a slight effect. Tobacco smoke contains many known carcinogens and procarcinogens, such as benzopyrene and nitrosamine. Our meta-analysis results showed that significantly increased risks were found to be associated with the XPD Lys751Gln and Asp312Asn gene polymorphisms and lung cancer risk in smokers. Only small number of studies examined the association between the XPD gene polymorphism and lung cancer risk in smokers or nonsmokers; moreover, the p value of Q test for heterogeneity test was significant. Considering the limited studies and p value of Q test for heterogeneity test included in this meta-analysis, our results should be interpreted with caution. Some limitations of this meta-analysis should be acknowledged. First, heterogeneity is a potential problem when interpreting the results of any meta-analyses. Although we minimized the likelihood by performing a careful search for published studies, using strict criteria for study inclusion and to perform data extraction and data analysis, significant between-study heterogeneity still existed in almost each comparison. The presence of heterogeneity may have resulted from differences in the selection of controls, age distribution, prevalent lifestyle factors, and so forth. Although most of the controls were selected from healthy populations, some studies had selected controls among friends or family members of patients with lung cancer or other diseases. Second, only published studies were included in this meta-analysis. The presence of publication bias may reflect the fact that nonsignificant or negative findings tend not to be published. Finally, our results were based on unadjusted estimates. A more precise analysis should be conducted if individual data were available, which would allow for the adjustment of other covariates including age, ethnicity, family history, environmental factors, and lifestyle. 41 Despite some limitations, this meta-analysis suggested that the XPD Lys751Gln and Asp312Asn gene polymorphisms were associated with lung cancer risk; the C allele of XPD Lys751Gln genotype was an increased risk factor for developing lung cancer among Caucasians and in smokers; and, the A allele of the XPD 312 genotype was also an increased risk factor for developing lung cancer among Asians and in smokers. However, it is necessary to conduct large clinical trials using standardized unbiased methods, patients with homogeneous lung cancer and well-matched controls, with the assessors blinded to the data. Moreover, gene gene and gene environment interactions should also be considered in the analysis. Taking these factors into account, such studies may eventually lead to a more comprehensive understanding of the association between the XPD gene polymorphism and lung cancer risk. ACKNOWLEDGMENTS This work was supported in part by a grant from the Major Program of Nanjing Medical Science and Technique Development Foundation (Personalized Therapy for Non- Small Cell Lung Cancer Patients), and the Jiangsu Province Natural Science Foundation of China (BK ). REFERENCES 1. Alberg AJ, Samet JM. Epidemiology of lung cancer. Chest 2003;123: Molina JR, Yang P, Cassivi SD, et al. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008;83: Toh CK, Gao F, Lim WT, et al. Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity. J Clin Oncol 2006; 24: Chen J, Larochelle S, Li X, et al. Xpd/Ercc2 regulates CAK activity and mitotic progression. Nature 2003;424: Shen MR, Jones IM, Mohrenweiser H. Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans. Cancer Res 1998;58: Mohrenweiser HW, Xi T, Vazquez-Matias J, et al. Identification of 127 amino acid substitution variants in screening 37 DNA repair genes in humans. Cancer Epidemiol Biomarkers Prev 2002;11: Hu Z, Wei Q, Wang X, et al. DNA repair gene XPD polymorphism and lung cancer risk: a meta-analysis. Lung Cancer 2004;46: Benhamou S, Sarasin A. ERCC2/XPD gene polymorphisms and lung cancer: a HuGE review. Am J Epidemiol 2005;161: Cochran WG. The combination of estimates from different experiments. Biometrics 1954;10: Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22: DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7: Tobias A. Assessing the influence of a single study in the meta-analysis estimate. Stata Tech Bull 1999;8: Egger M, Davey Smith G, Schneider M, et al. Bias in metaanalysis detected by a simple, graphical test. BMJ 1997;315: Spitz MR, Wu X, Wang Y, et al. Modulation of nucleotide excision repair capacity by XPD polymorphisms in lung cancer patients. Cancer Res 2001;61: David-Beabes GL, Lunn RM, London SJ. No association between the XPD (Lys751G1n) polymorphism or the XRCC3 (Thr241Met) polymorphism and lung cancer risk. Cancer Epidemiol Biomarkers Prev 2001; 10: Butkiewicz D, Rusin M, Enewold L, et al. Genetic polymorphisms in DNA repair genes and risk of lung cancer. Carcinogenesis 2001;22: Park JY, Lee SY, Jeon HS, et al. Lys751Gln polymorphism in the DNA repair gene XPD and risk of primary lung cancer. Lung Cancer 2002; 36: Hou SM, Falt S, Angelini S, et al. The XPD variant alleles are associated with increased aromatic DNA adduct level and lung cancer risk. Carcinogenesis 2002;23: Chen S, Tang D, Xue K, et al. DNA repair gene XRCC1 and XPD polymorphisms and risk of lung cancer in a Chinese population. Carcinogenesis 2002;23: Zhou W, Liu G, Miller DP, et al. Gene-environment interaction for the ERCC2 polymorphisms and cumulative cigarette smoking exposure in lung cancer. Cancer Res 2002;62: Xing DY, Qi J, Tan W, et al. Association of genetic polymorphisms in 1344 Copyright 2010 by the International Association for the Study of Lung Cancer

9 Journal of Thoracic Oncology Volume 5, Number 9, September 2010 Gene Polymorphism and Lung Cancer Risk the DNA repair gene XPD with risk of lung and esophageal cancer in a Chinese population in Beijing. Chin J Med Genet 2003;20: Misra RR, Ratnasinghe D, Tangrea JA, et al. Polymorphisms in the DNA repair genes XPD, XRCC1, XRCC3, and APE/ref-1, and the risk of lung cancer among male smokers in Finland. Cancer Lett 2003;191: Liang G, Xing D, Miao X, et al. Sequence variations in the DNA repair gene XPD and risk of lung cancer in a Chinese population. Int J Cancer 2003;105: Harms C, Salama SA, Sierra-Torres CH, et al. Polymorphisms in DNA repair genes, chromosome aberrations, and lung cancer. Environ Mol Mutagen 2004;44: Popanda O, Schattenberg T, Phong CT, et al. Specific combinations of DNA repair gene variants and increased risk for non-small cell lung cancer. Carcinogenesis 2004;25: Vogel U, Laros I, Jacobsen NR, et al. Two regions in chromosome 19q are associated with risk of lung cancer. Mutat Res 2004;546: Shen M, Berndt SI, Rothman N, et al. Polymorphisms in the DNA nucleotide excision repair genes and lung cancer risk in Xuan Wei, China. Int J Cancer 2005;116: Zienolddiny S, Campa D, Lind H, et al. Polymorphisms of DNA repair genes and risk of non-small cell lung cancer. Carcinogenesis 2006;27: Yin ZH, Ma R, Cui ZS, et al. Accocitation of genetic polymorphism in the DNA repair gene XPD with risk of lung cancer in nonsmoking females. Chin J Lung Cancer 2006;9: Matullo G, Dunning AM, Guarrera S, et al. DNA repair polymorphisms and cancer risk in non-smokers in a cohort study. Carcinogenesis 2006;27: Yin J, Vogel U, Ma Y, et al. A haplotype encompassing the variant allele of DNA repair gene polymorphism ERCC2/XPD Lys751Gln but not the variant allele of Asp312Asn is associated with risk of lung cancer in a northeastern Chinese population. Cancer Genet Cytogenet 2007;175: De Ruyck K, Szaumkessel M, De Rudder I, et al. Polymorphisms in base-excision repair and nucleotide-excision repair genes in relation to lung cancer risk. Mutat Res 2007;631: Lopez-Cima MF, Gonzalez-Arriaga P, Garcia-Castro L, et al. Polymorphisms in XPC, XPD, XRCC1, and XRCC3 DNA repair genes and lung cancer risk in a population of northern Spain. BMC Cancer 2007;7: Raaschou-Nielsen O, Sorensen M, Overvad K, et al. Polymorphisms in nucleotide excision repair genes, smoking and intake of fruit and vegetables in relation to lung cancer. Lung Cancer 2008;59: Kong FJ, Xu WS, Wang HL, et al. Association of the mono-nucleotide polymorrphism ha DNA repair gone XPD with the risk ef lung cancer. Prac J Med Pharm 2008;10: Reardon JT, Sancar A. Molecular anatomy of the human excision nuclease assembled at sites of DNA damage. Mol Cell Biol 2002;22: De Boer J, Hoeijmakers JH. Nucleotide excision repair and human syndromes. Carcinogenesis 2000;21: Hou SM, Falt S, Angelini S, et al. The XPD variant alleles are associated withincreased aromatic DNA adduct level and lung cancer risk. Carcinogenesis 2002;23: Qiao Y, Spitz MR, Shen H, et al. Modulation of repair of ultraviolet damage in the host-cell reactivation assay by polymorphic XPC and XPD/ERCC2 genotypes. Carcinogenesis 2002;23: Hirschhorn JN, Lohmueller K, Byrne E. A comprehensive review of genetic association studies. Genet Med 2002;4: Rodriguez C, Calle EE, Miracle-McMahill HL, et al. Family history and risk of fatal prostate cancer. Epidemiology 1997;8: Copyright 2010 by the International Association for the Study of Lung Cancer 1345