Gene 538 (2014) 361–365

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DNA repair pathway genes and lung cancer susceptibility: A meta-analysis Wusheng Li, Kai Li, Li Zhao, Huawei Zou ⁎ Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110023, China

a r t i c l e

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Article history: Accepted 13 December 2013 Available online 22 December 2013 Keywords: DNA repair pathway genes Lung cancer Meta-analysis Polymorphism

a b s t r a c t Objective: DNA repair pathway genes have been implicated to play an important role in the development of lung cancer. However, contradictory results are often reported by various studies, making it difficult to interpret them. So in this meta-analysis, we have assessed the association between lung cancer risk and two DNA repair pathway genes. XRCC1 and ERCC2, by analyzing 67 published case–control studies. Research design and methods: We searched PubMed, Embase and Web of Science using terms “XRCC1” or “XPD” or “ERCC2” and “lung cancer” on August 1, 2012. Three criteria were applied to select included studies for resulting studies. Information was carefully extracted by two investigators independently. We used pooled odds ratio (OR) to assess the effect of a polymorphism, and a dominant model was applied where genotypes that contain the non-reference allele were combined together. All the calculations were performed using STATA version 11.0. Main outcome measures and results: Three common nonsynonymous polymorphisms in XRCC1, codon 194, codon 280 and codon 399, and two common nonsynonymous polymorphisms in ERCC2, codon 312 and codon 751, were analyzed. The result showed in total population, Lys751Gln in ERCC2 is associated with an increase of lung cancer risk, with a summary OR as 1.15. No association was found for any other polymorphisms. When studies were stratified by ethnicity, the risk effect of Lys751Gln in ERCC2 was found only in Caucasians, not in Asians. Conclusions: In conclusion, Lys751Gln in ERCC2 is associated with lung cancer, and the risk effect probably exists in Caucasians. By contrast, polymorphisms in XRCC1 are less likely to be susceptible to lung cancer risks. © 2013 Elsevier B.V. All rights reserved.

1. Introduction Lung cancer is one of the most prevalent cancers in the world which accounts for ~12% of all cancer incidences and 17.6% of cancer deaths (Herbst et al., 2008; Molina et al., 2008). As a result of the increased use of tobacco products, lung cancer is becoming a serious public health challenge in Asian countries and costs a great amount of resources including money and human labor for prevention and cure. Although the underlying mechanism of lung cancer still remains largely unknown, nicotine in cigarettes is well established as the most important factor in carcinogenesis. Besides, a large amount of studies have reported associations between genetic polymorphisms and tumorigenesis of lung cancers, providing valuable information for molecular diagnosis and further prevention. Among them, variants residing on coding genes and changing their encoding amino acids are of great interest, which may radically modify functions of these genes and thus result in abnormal functions in biological pathways where they are involved.

Abbreviations: OR, odds ratio; BER, base excision repair pathway; SNPs, single nucleotide polymorphisms; NER, nucleotide excision repair pathway; ORs, odds ratios. ⁎ Corresponding author at: No.39 Huaxiang Road, Shenyang, Liaoning Province, 110023, China. Tel./fax: +86 24 96615 63115. E-mail address: [email protected] (H. Zou). 0378-1119/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.gene.2013.12.028

Recently, extensive cancer association studies have been done on the DNA repair pathway, as a reduction of DNA repair capability caused by genetic polymorphisms that increase susceptibility to various cancers (Chacko et al., 2005; Duell et al., 2001). XRCC1 is one of the most studied DNA repair genes, which is an important member of the base excision repair pathway (BER) and encodes X-ray repair crosscomplementing group 1 protein (Schreiber et al., 2002; Sturgis et al., 1999). More than 50 non-synonymous single nucleotide polymorphisms (SNPs) have been identified in XRCC1 coding region, and three of them are common variants (minor allele frequency N0.05) at codon 194, codon 280 and codon 399 (Dai et al., 2012). Various studies have suggested functional importance of these codons (Abdel-Rahman and El-Zein, 2000; Duell et al., 2000; Fan et al., 2004; Lamerdin et al., 1995; Lunn et al., 1999; Masson et al., 1998; Savas et al., 2004; Tuimala et al., 2002), however, contradicting results on their associations with lung cancer risk have been reported in previous studies, making it difficult to move forward. A similar scenario is also found for another important DNA repair gene ERCC2/XPD, the xeroderma pigmentosum group D gene, which belongs to the nucleotide excision repair pathway (NER). Two amino acid alternating polymorphisms (Lys751Gln and Asp312Asn) in ERCC2 have been extensively investigated regarding their impact on lung cancer susceptibility, but the results are still inconclusive (Yin et al., 2007b; Zhan et al., 2010a). One possibility of this dichotomy is caused by the small sample size in some studies, where random bias

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could be the dominant effect. Therefore, meta-analysis with a large pooled sample size could be the easiest choice to give a better resolution in understanding the effects of these genetic variants. Here we present a comprehensive meta-analyses of XRCC1 and ERCC2 genes to estimate their effects on lung cancer risk. 2. Materials and methods 2.1. Literature search We searched PubMed, Embase and Web of Science using terms “XRCC1” or “XPD” or “ERCC2” and “lung cancer” on August 1, 2012. Only full-tet articles were considered. References of retrieved articles were also screened. 2.2. Inclusion criteria For resulting studies, three criteria were applied to select included studies. 1) Studies must evaluate the effect on lung cancer risk of Asp312Asn or Lys751Gln polymorphism in XRCC1, or Arg194Trp, Arg280His or Arg399Gln polymorphism in ERCC2. 2) Each study must offer the sample size (exact number of case and control referring to genotype or allele distribution), odd ratios (ORs) and other possible information that can help infer conclusions. 3) Studies must be published in English and in a peer-reviewed journal. Studies are excluded that not meet these three criteria. 2.3. Data extraction Information was carefully extracted by two investigators independently. When the two investigators were not in agreement, a third investigator was involved to reach an agreement. The following information was extracted and tabulated from each article: first author, year of publication, ethnicity, the total number of case and control groups, and genotype information for each polymorphism. Ethnicity was categorized as Asian, Caucasian and Others. When there is more than one studied population in a single article, we treat them as individual study. 2.4. Statistical analysis We used pooled odds ratio (OR) to assess the effect of a polymorphism, a dominant model was applied where genotypes that contains the non-reference allele were combined together. For each polymorphism, we first evaluated the heterogeneity of included studies by calculating the p value for Cochran's Q statistic (Cochran, 1954) and I2 statistic (Higgins and Thompson, 2002). The fixed-effects model (the Mantel-Haenszel method) (Mantel and Haenszel, 1959) was applied if heterogeneity can be ignored. Otherwise, the random-effects model (DerSimonian and Laird method) was used (DerSimonian and Laird, 1986). Publication bias was estimated by funnel plotting and Egger's test (Egger et al., 1997). All the calculations were performed using STATA version 11.0 (Stata Corporation, College Station, TX). 3. Results 3.1. Summary of meta-analysis data A total of 67 studies were selected for this meta-analysis, with 36 studies for XRCC1 and 31 studies for ERCC2. There are three articles that include two ethnic groups (Chang et al., 2009; Cote et al., 2009; David-Beabes and London, 2001), each treated as a different study. Most of the studies were conducted in Asians and Caucasians, with only 1 study in Latino (Chang et al., 2009), Indian (Sreeja et al., 2008), and Turkish (Karkucak, 2012), 3 studies in African/African-American (Chang et al., 2009; Cote et al., 2009; David-Beabes and London,

2001). Hardy-Weinberg equilibrium has been tested for all polymorphisms for control subjects in each study, and studies were excluded if Hardy-Weinberg equilibrium is rejected. For ERCC1, 5925 cancer cases and 7629 controls from 16 studies were included for codon 194 (Chan et al., 2005; Chen et al., 2002; David-Beabes and London, 2001; De Ruyck et al., 2007; Hao et al., 2006; Hu et al., 2005; Hung et al., 2005; Li et al., 2008; Matullo et al., 2006; Pachouri et al., 2007; Ratnasinghe et al., 2001; Shen et al., 2005; Tanaka et al., 2010; Yin et al., 2007a; Zienolddiny et al., 2006), 4496 cases and 4964 controls from 10 studies were used for codon 280 (Chang et al., 2009; De Ruyck et al., 2007; Hao et al., 2006; Hung et al., 2005; Kim et al., 2010; Misra et al., 2003; Ratnasinghe et al., 2001; Shen et al., 2005; Vogel et al., 2004; Yin et al., 2007a), and 11025 cases and 13353 controls from 31 studies were eligible for codon 399 (Chan et al., 2005; Chang et al., 2009; Chen et al., 2002; Cote et al., 2009; David-Beabes and London, 2001; De Ruyck et al., 2007; Divine et al., 2001; Hao et al., 2006; Hu et al., 2005; Hung et al., 2005; Ito et al., 2004; Karkucak, 2012; Kim et al., 2010; Li et al., 2008, 2011; LopezCima et al., 2007; Matullo et al., 2006; Misra et al., 2003; Pachouri et al., 2007; Park et al., 2002; Popanda et al., 2004; Qian et al., 2011; Ratnasinghe et al., 2001; Shen et al., 2005; Vogel et al., 2004; Yin et al., 2007a; Zhou et al., 2003; Zienolddiny et al., 2006). For XRCC2, 8846 cancer cases and 11453 controls from 21 studies were used for codon 312 (Butkiewicz et al., 2001; Chang et al., 2008; De Ruyck et al., 2007; Hou et al., 2002; Hu et al., 2006; Huang et al., 2006; Liang et al., 2003; Lopez-Cima et al., 2007; Matullo et al., 2006; Misra et al., 2003; Popanda et al., 2004; Qian et al., 2011; Raaschou-Nielsen et al., 2008; Sakoda et al., 2012; Shen et al., 2005; Spitz et al., 2001; Xing et al., 2002; Yin et al., 2009; Zhou et al., 2003; Zienolddiny et al., 2006), and 10102 cases and 12917 controls from 27 studies for codon 751 (Chang et al., 2008; Chen et al., 2002; David-Beabes and London, 2001; De Ruyck et al., 2007; Harms et al., 2004; Hou et al., 2002; Hu et al., 2006; Huang et al., 2006; Liang et al., 2003; Lopez-Cima et al., 2007; Matullo et al., 2006; Misra et al., 2003; Park et al., 2002; Popanda et al., 2004; Raaschou-Nielsen et al., 2008; Sakoda et al., 2012; Shen et al., 2005; Spitz et al., 2001; Sreeja et al., 2008; Vogel et al., 2004; Yin et al., 2009; Zhou et al., 2002). 3.2. Test of heterogeneity To study lung cancer risk of these polymorphisms, we used a dominant model for non-reference alleles and decided heterogeneity across studies for each variant, according to the characteristics of these allele frequencies. I2 statistic was calculated by Stata 11.0 and we found that three polymorphisms (XRCC1 codon 280 and 399, ERCC2 codon 751) have heterogeneity with P value less 0.05 (Table 1), so random-effect models were applied to calculate summary ORs, for the rest two variants, fixed-effect models were used. 3.3. Meta-analysis result We used forest plots to demonstrate meta-analysis results for each genetic variant, and summary ORs for the pooling studies were calculated to evaluate the association between those variants and lung cancer risk in total population (Table 1). Among 5 variants tested here, codon 751 in ERCC2 showed a significantly increased risk for genotype Lys/ Gln + Gln/Gln compared with the wild type Lys/Lys (OR: 1.15; 95% CI: 1.07-1.24, Fig. 1). No associations were found for other polymorphisms. Since our meta-analysis contains diverse ethnicities, it is possible that the true effect of codon 751 in ERCC2 is overestimated. To exclude this, we further performed a stratified analysis according to ethnicity. 14 studies that were conducted in Caucasian were included in the stratified meta-analysis, and the result showed a same effect (OR: 1.09; 95% CI: 1.02-1.17, Fig. 2). However, no such association was observed in the stratified analysis of 9 studies in Asian (OR: 1.13; 95% CI: 0.91, 1.41).

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Table 1 Summary of meta-analysis for each polymorphism. Polymorphism

XRCC1 codon 194 XRCC1 codon 280 XRCC1 codon 399 ERCC2 codon 312 ERCC2 codon 751

Genotype

Arg/Arg Arg/Trp + Trp/Trp Arg/Arg Arg/His + His/His Arg/Arg Arg/Gln + Gln/Gln Asp/Asp Asp/Asn + Asn/Asn Lys/Lys Lys/Gln + Gln/Gln

Cases

4132 1793 3885 611 5324 5701 5336 3510 5686 4416

Controls

5439 2190 4256 708 6429 6924 6533 4920 7066 5851

Heterogeneity test

Model

Summary OR (95% CI)

Egger's test

Studies

0.118

Fixed-effect

0.948 (0.872, 1.030)

0.336

16

49.70%

0.036

Random-effect

1.037 (0.855, 1.258)

0.569

10

37%

0.022

Random-effect

0.974 (0.905, 1.049)

0.217

31

1.70%

0.437

Fixed-effect

1.021 (0.958, 1.088)

0.845

21

34.60%

0.041

Random-effect

1.144 (1.058, 1.237)

0.11

27

I2

P

30.70%

This difference in lung cancer risk may suggest under diverse genetic background, ERCC2 gene has different effects. 3.4. Publication bias and sensitivity analysis It is well known that meta-analysis may have biased estimates if publication bias exists, thus we used Begg's funnel plot and Egger's test to investigate publication bias in our data. For all polymorphisms, we didn't find evidence of obvious asymmetry regarding the shape of funnel plots (Fig. 3). Consistently, the results from Egger's test confirmed that observation (P N 0.05 for all variants, Table 1). We also tested sensitivity of meta-analysis by excluding a single study each time and examining the influence on pooled ORs. No evidence was observed of pooled ORs shift. 4. Discussion and Conclusion DNA repair genes have been considered to play important roles in tumorigenesis and are the focus of many genetic association studies.

In this study, we presented a comprehensive meta-analysis of two DNA repair genes (XRCC1 and ERCC2), including 36 published case– control studies for XRCC1 and 31 studies for ERCC2, to examine the association between these gene polymorphisms and lung cancer risk. The result indicates that ERCC2 751C allele conveys risk factor for lung tumor development in Caucasian population, but not in Asian population. None polymorphism in XRCC1 was associated with lung cancer risk in our study, which is consistent for codon 280 and 399 with a recent meta-analysis reported by Dai et al. (Dai et al., 2012). For codon 194, different conclusions from meta-analysis have been reported (Dai et al., 2012; Jiang et al., 2010; Wang et al., 2009). Since the current statistical power (5925 cancer cases and 7629 controls in total population) is still weak, we argument that more samples from different population are necessary to resolve this inconsistency. It is hypothesized that polymorphisms of the DNA repair gene ERCC2 in the NER pathway may be an important contributor to the development of lung cancer. Functional studies showed that the ERCC2 protein is involved in transcription-coupled repair by unwinding of DNA and forming a complex with transcription factor II H (Reardon and Sancar,

Fig. 1. Forest plot (random-effects model) of lung cancer risk associated with ERCC2 codon 751. Each box represents the odds ratio (OR) estimate, and its area is proportional to the weight of the study. The diamond and the red broken line represents the overall summary OR, with confidence interval (CI) represented by the width of the diamond. The solid vertical line is set at the null value (OR = 1.0).

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Fig. 2. Forest plot (random-effects model) of lung cancer risk associated with ERCC2 codon 751 in Caucasians. Each box represents the odds ratio (OR) estimate in each study, and its area is proportional to the weight of the study. The diamond and the red broken line represents the overall summary OR, with confidence interval (CI) represented by the width of the diamond. The solid vertical line is set at the null value (OR = 1.0).

2002), and two common variant alleles in ERCC2 (codon 312 and 751) might be associated with reduced repair of aromatic DNA adducts, resulting in tumor formation (Hou et al., 2002; Qiao et al., 2002). Combined these with result from meta-analysis, at least gene polymorphism in ERCC2 codon 751 is associated with lung cancer risk. One important factor in the development of cancer is genetic background. To understand its influence in lung cancer, we stratified studies according to ethnicity, and found different results between Asians and Caucasians for the effect of genetic variant ERCC2 751 codon: increased lung cancer risk was identified for genotypes carrying the C allele in Caucasians, however, no such pattern was found in Asian subjects, consistent with an earlier study (Zhan et al., 2010b). Although the underlying mechanism still remains unknown, local environmental factors may interact with those C-allele bearing genotypes and result in an increase of lung cancer risk.

In the present study, we have put considerable effort on carefully searching for published studies, setting strict criteria for study inclusion, some limitations should not be ignored. First, all of the studies were published in English, exclusion of studies in other languages may influence effects of polymorphisms tested here. Second, heterogeneity exists for several polymorphisms investigated here, which may reflect differences in the selection of controls, age distributions, and some other lifestyle characteristics. Hence, result presented here should be interpreted with care and future studies with more covariates, such as age, gender, lifestyle, etc., should be encouraged. Despite these limitations, we analyzed up to date studies and demonstrated an association between codon 751 in ERCC2 and lung cancer risk in Caucasians, and no evidence was found for XRCC1 gene regarding lung cancer susceptibility. Further studies on gene-gene interaction, gene-environment interaction and functional essay would help to better understand the mechanism of ERCC2 in lung cancer development. Conflict of interest We have no conflict of interest. References

Fig. 3. Begg's funnel plot of ERCC2 codon 751 and lung cancer risk. The X axis represents the logarithm of ORs, while the Y axis represents the standard error.

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