IJC International Journal of Cancer

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1 IJC International Journal of Cancer Genetic variation of XPA gene and risk of cancer: a systematic review and pooled analysis Dapeng Ding 1 *, Ying Zhang 2 *, Hailang Yu 1, Yunbo Guo 3, Ling Jiang 4, Xiaofeng He 5, Wenli Ma 1 and Wenling Zheng 6 1 Institute of Genetic Engineering, Southern Medical University, Guangzhou, People s Republic of China 2 College of Pharmacy, Jinan University, Guangzhou, People s Republic of China 3 Institute of Bioinformatics, School of Basic Medical Science, Southern Medical University, Guangzhou, People s Republic of China 4 Department of Hematology, Nanfang Hospital of Southern Medical University, Guangzhou, People s Republic of China 5 Central Laboratory, Peace Hospital of Changzhi Medical College, Shanxi, People s Republic of China 6 Genome Centre of Southern China, Guangzhou, People s Republic of China XPA, a zinc-finger DNA-binding protein, play an important role in both global genome and transcription-coupled repair pathways. XPA 24G>A polymorphism was identified in the 5 0 noncoding region, located four nucleotides upstream of the ATG start codon. Previous studies have shown that this polymorphism may affect mrna tertiary structure and stability and play a role in susceptibility to cancer. However, the results remained controversial. To derive a more precise estimation of association between this polymorphism and risk of different types of cancer, we performed a meta-analysis based on 36 case control or case cohort studies, including a total of 11,700 cases and 15,033 controls. We used odds ratios with 95% confidence intervals to assess the strength of the association. Overall, no significantly elevated cancer risk was found in all genetic models when eligible studies were pooled into the meta-analysis. In the stratified analyses, we found that individuals with A-allele had a higher risk of lung cancer (AA versus GG: OR , 95% CI ; recessive model: OR , 95% CI ). When stratified by ethnicity, significantly elevated risks were observed among Asian populations (AA versus GG: OR , 95% CI ; dominant model: OR , 95% CI ). This meta-analysis suggests that XPA 24G>A polymorphism is associated with increased lung cancer risk and may be a low-penetrant risk factor in Asian ethnicity for cancer development. Key words: XPA, polymorphism, susceptibility, meta-analysis Abbreviations: 95% CI: 95% confidence interval; BCC: basal cell carcinoma of the skin; ERCC1 XPF: excision repair cross complementing group 1 xeroderma pigmentosum group F; OR: odds ratio; RPA: replication protein A; SCC: squamous cell carcinoma of the skin; TFIIH: transcription factor II H; XPA: xeroderma pigmentosum group A *D.D. and Y.Z. contributed equally to this study and should be considered as co-first authors Conflict of interest: None Grant sponsor: Guangdong Natural Science Foundation; Grant number: S DOI: /ijc History: Received 24 May 2011; Accepted 15 Aug 2011; Online 22 Aug 2011 Correspondence to: Wenli Ma, Institute of Genetic Engineering, Southern Medical University, Guangzhou , People s Republic of China, genidustry@gmail.com DNA repair systems play critical roles in protecting against mutations and are essential for maintaining the integrity of the genome. Certain common genetic polymorphisms within the genes involved in DNA damage responses may contribute to the development of cancer and be associated with an increased risk of the disease. Because reduced DNA repair capacity may lead to genetic instability and carcinogenesis, genes involved in DNA repair have been proposed as candidate cancer susceptibility genes. 1 The nucleotide excision repair (NER) pathway is the primary mechanism for removal of bulky adducts from DNA, and thus is an important part of the cellular defence against a large variety of structural unrelated DNA lesions. 2 The NER pathway consists of >30 proteins involved in DNA damage recognition, incision, DNA ligation and resynthesis. The xeroderma pigmentosum group A (XPA) protein is involved in a step of damage recognition after the initial damage recognition by XPC-hHR23B, and XPA plays a central role in NER through its interaction with replication protein A (RPA), transcription factor II H (TF II H) and excision repair cross complementing group 1-xeroderma pigmentosum group F (ERCC1 XPF) protein complex. 3,4 The most extensively studied A23G polymorphism, also referred to as the XPA ( 4) G-to-A polymorphism (rs ), is located in the 5 0 -untranslated region (UTR) and is four nucleotides upstream of the start codon. Polymorphisms in this area proximal to the start codon, referred to as the Kozak sequence, could have implications for the binding of the 40S ribosomal subunit and as a result influence protein levels in the cell. 5 To date, a number of molecular epidemiological studies have been done to evaluate the association between XPA 4G>A polymorphism and different types of cancer risk in diverse populations The tumor types included lung cancer, 6,13,22,24,29 34 gastric cancer, 7,17 colorectal cancer, 8,12,23 squamous cell carcinoma of the head Int. J. Cancer: 131, (2012) VC 2011 UICC

2 Ding et al. 489 and neck, 8,10 basal and squamous cell carcinomas of the skin (BCC and SCC), 20,27 breast cancer, 8,18,26 esophageal cancer, 11,14,15 and so on. However, the results were inconsistent or even contradictory. Individual studies may have been underpowered to detect the effect of the polymorphism on the susceptibility of cancer. 35 Given the amount of accumulated data, we performed this meta-analysis of all eligible studies to derive a more precise estimation of the association between XPA 4G>A polymorphism and risk of different types of cancer that have been investigated. Material and Methods Identification and eligibility of relevant studies A comprehensive literature search was performed using the PubMed and Medline database for relevant articles published (the last search update was May 5, 2011) with the following key words polymorphism, XPA, NER, DNA repair gene, and cancer or carcinoma. The search was limited to human studies. In addition, studies were identified by a manual search of the reference lists of reviews and retrieved studies. We included all the case control studies and cohort studies that investigated the association between XPA polymorphism and cancer risk with genotyping data for 4G>A polymorphism. As studies with the same population by different investigators or overlapping data by the same authors were found, the most recent or complete articles with the largest numbers of subjects were included. 14,17,36 All eligible studies were examined carefully, and their bibliographies were checked for other relevant publications. Inclusion criteria All human-associated studies were included if they met the following criteria: (1) evaluate the association between XPA 4G>A polymorphism and the risk of cancer; (2) case control or case cohort studies; (3) studies with full-text article; and (4) sufficient data for estimating an odds ratio (OR) with 95% confidence interval (CI). Major reasons for exclusion of studies were as follows: (1) not for cancer research; (2) only case population; and (3) duplicate of previous publication. Data extraction Information was carefully extracted from all eligible publications independently by two of the authors according to the inclusion criteria listed above. For conflicting evaluation, an agreement was reached following discussion. For each study, the following characteristics were collected: first author s name, year of publication, country of origin, cancer type, ethnicity, source of control groups (population-based controls and hospital-based controls), number of cases and controls, matching variables and genotyping methods. For studies including subjects of different ethnic groups, data were extracted separately and categorized as Asians, Caucasians and Mixed. 33 Meanwhile, studies investigating more than one kind of cancer were counted as individual data set only in subgroup analyses by cancer type. 8,12,20,27,31 We did not define any minimum number of patients to include in our meta-analysis. Statistical methods For the control group of each study, we assessed the departure from the Hardy Weinberg equilibrium using Pearson s goodness-of-fit v 2 test with 1 degree of freedom. Heterogeneity among studies was checked by the random-effects model (the DerSimonian and Laird method) if there was significant heterogeneity. 37 A p value of more than the nominal level of 0.05 for the Q statistic indicated a lack of heterogeneity across studies, allowing for the use of the fixed-effects model (the Mantel Haenszel method). 38 We performed a meta-analysis to estimate the risk (ORs) of cancer associated with XPA 4G>A polymorphism. The most common G-allele was considered the reference genotype in our analysis, whereas the rare A-allele was examined as the variant. The risks (ORs) of cancers associated with the XPA 4G>A polymorphism were estimated for each study. First, the pooled ORs were performed for co-dominant model (AA versus GG, AG versus GG), dominant model (AG þ AA versus GG) and recessive model (AA versus AG þ GG), respectively. In addition to the comparison among all subjects, we also performed stratification analyses by cancer type (if one cancer type contained less than three individual studies, it was combined into the other cancers group), ethnicity and source of controls. The publication bias was diagnosed by the funnel plot, in which the standard error of log (OR) of each study was plotted against its log (OR). Funnel plot asymmetry was assessed by the method of Egger s linear regression test. 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). 39 All the statistical tests were performed with SPSS version 13.0 and STATA version10.0 (Stata Corporation, College Station, TX). Results Eligible studies and meta-analysis databases A total of 35 publications with 44 case control or case cohort studies examined the association of XPA 4G>A polymorphism with cancer was found. 6 34,36,40 44 Among them, five studies were excluded because the data of genotyping distribution were missing And two studies were excluded because they investigated the same population reported. 29,36 As summarized in Table 1, 36 eligible studies were selected for this meta-analysis, including 11,700 cases and 15,033 controls. Of these were 13 hospital-based studies and 23 population-based studies. There were 12 lung cancer studies, three breast cancer studies, four skin cancer studies, four colorectal studies and 13 studies with the other cancers. Twenty-three of 36 studies were conducted in Europeans and nine studies were conducted in Asians. The

3 490 XPA 4G>A polymorphism and cancer risk Table 1. Characteristics of studies included in the meta-analysis References Ethnicity Cancer types Matching criteria Source of control Genotyping methods Case-control MAF HWE 6 Asian Lung cancer Age, gender HB PCR-RFLP European Gastric cancer Gender PB Taqman European Colon cancer Age, gender PB PCR-RFLP European Head and neck cancer Age, gender PB PCR-RFLP European Breast cancer Age, gender PB PCR-RFLP Asian Uterus Age HB PCR-RFLP European Head and neck cancer Age, gender PB PCR-RFLP European Esophageal cancer Age, gender HB Direct sequencing European Colon cancer Age, gender PB Taqman Yes 12 European Rectum cancer Age, gender PB Taqman Yes 13 European Lung cancer Gender PB Taqman Asian Esophageal cancer Age, gender PB PCR-RFLP Asian Esophageal cancer Age, gender HB PCR-RFLP European Renal cancer Age, gender PB Taqman Asian Gastric cancer Age, gender PB PCR-RFLP Mixed Breast cancer Age PB Taqman Asian Oral cancer Age, gender HB PCR-RFLP European Skin cancer (BCC) Age, gender PB Taqman Yes 20 European Skin cancer (SCC) Age, gender PB Taqman Yes 21 European Oral cancer Age, gender HB PCR-RFLP European Lung cancer Age, gender HB PCR-RFLP European Colorectal cancer Gender PB Direct sequencing European Lung cancer Age, gender PB APEX Asian Oral cancer Age HB Direct sequencing Mixed Breast cancer Age PB Taqman European Skin cancer (BCC) Age, gender PB PCR-RFLP European Skin cancer (SCC) Age, gender PB PCR-RFLP European Endometrial cancer Age PB PCR-RFLP Asian Lung cancer Age, gender HB PCR-RFLP European Lung cancer Age HB PCR-RFLP European Lung cancer Age HB PCR-RFLP European Lung cancer Age, gender HB PCR-RFLP African Lung cancer Age, gender PB PCR-RFLP Mixed Lung cancer Age, gender PB PCR-RFLP European Lung cancer Age, gender PB PCR-RFLP Asian Lung cancer Age, gender HB PCR-RFLP Abbreviations: HB: hospital-based; PB: population-based; PCR-RFLP: polymerase chain reaction-restriction fragment length polymorphism; MAF: minor allele frequency; APEX: arrayed primer extensions. remained four studies were populations with mixed ethnicity (from three studies) and one African study. These studies indicate that the distribution of genotypes in controls was consistent with Hardy Weinberg equilibrium. And the subjects of controls were matched for age and gender. All of the cases were pathologically confirmed. Quantitative synthesis There was a wide variation in the A-allele frequency of the XPA 4G>A polymorphism among the controls across different ethnicities. For Asian populations, the 4A-allele frequency was 50.3% (95% CI ¼ ), which was significantly higher than that in European populations (36.3%, 95%

4 Ding et al. 491 CI ¼ , p < 0.001). The evaluations of the association of XPA 4G>A polymorphism with cancer risk are shown in Table 2. Overall, no significant association was found between XPA 4G>A polymorphism and cancer susceptibility (AA versus GG: OR ¼ 0.96, 95% CI ¼ ; dominant model: OR ¼ 0.92, 95% CI ¼ ; recessive model: OR ¼ 1.01, 95% CI ¼ ). In the stratified analysis by cancer type, we found that individuals with the minor variant genotypes had a higher risk of lung cancer (AA versus GG: OR ¼ 1.25, 95% CI ¼ ; recessive model: OR ¼ 1.31, 95% CI ¼ ), as shown in Table 2. And reduced risk was found to be associated with the XPA 4G>A polymorphism among basal and squamous cell carcinomas of the skin (AG versus GG: OR ¼ 0.86, 95% CI ¼ ; AA versus GG: OR ¼ 0.78, 95% CI ¼ ; dominant model: OR ¼ 0.84, 95% CI ¼ ; recessive model: OR ¼ 0.84, 95% CI ¼ ). There was no evidence for the association between XPA 4G>A polymorphism and cancer risk in subgroup analyses based on source of controls (population-based controls and hospital-based controls). In a stratified analysis by ethnicity (also shown in Table 2), significantly elevated risks were observed among Asian populations (AA versus GG: OR ¼ 1.31, 95% CI ¼ ; dominant model: OR ¼ 1.14, 95% CI ¼ ; recessive model: OR ¼ 1.25, 95% CI ¼ ). And for the additive model (XPA 4 A-allele carrier versus G-allele carrier), the 4 A-allele was associated with a significantly increased lung cancer risk (OR ¼ 1.08, 95% CI ¼ ), as shown in Table 3. When the data were analyzed in subgroup of subjects stratified by smoking status, sex and histological type of lung cancer (Table 4), we did not find that smokers with XPA 4 A-allele had significantly increased risk of lung cancer (OR ¼ 1.05, 95% CI ¼ ). The evaluation of the association of A-allele carrier with cancer risk is shown in Table 5. Interestingly, we found that the A-allele was a protective factor for skin cancer risk (OR ¼ 0.87, 95% CI ¼ ). Test for heterogeneity and sensitivity There was significant heterogeneity among these studies for homozygote comparison (AA versus GG: p heterogeneity < 0.001), dominant model comparison (AG þ AA versus GG: p heterogeneity < 0.001) and recessive model comparison (AA versus AG þ GG: p heterogeneity < 0.001). Then, we assessed the source of heterogeneity for homozygote comparison (AA versus GG) by ethnicity, cancer type and source of controls. We found that cancer type (v 2 ¼ 26.08, df ¼ 4, p ¼ 0.005) and ethnicity (v 2 ¼ 29.00, df ¼ 3, p ¼ 0.026) but not the source of controls (v 2 ¼ 1.71, df ¼ 1, p ¼ 0.257) contributed to substantial heterogeneity. Although the sample size for cases and controls in 36 studies ranged from 47 to 1,102, the corresponding pooled ORs were not qualitatively altered with or without the study of small sample. Similarly, no other single study influenced the pooled OR materially as indicated by sensitivity analysis. Publication bias We performed Begg s funnel plot and Egger s test to assess the publication bias of literatures. As shown in Figure 1, the shape of the funnel plots did not reveal any evidence of obvious asymmetry. And the results of Egger s test did not suggest any evidence of publication bias (p ¼ for AG versus GG, p ¼ for AA versus GG; p ¼ for dominant model; p ¼ for recessive model). Discussion The XPA protein is a zinc-finger DNA-binding protein, which is involved in both global genome and transcriptioncoupled repair pathways. It seems to play a central role in NER through its interaction with several proteins, such as replication protein A, TFIIH and ERCC1 XPF. XPA 4G>A polymorphism was identified in the 5 0 noncoding region of the XPA gene, located four nucleotides upstream of the ATG start codon. It has been demonstrated that the 5 0 noncoding region may regulate gene expression through transcriptional and posttranscriptional control mechanism and this polymorphism might affect the mrna tertiary structure and stability or affect the binding between translational factors and mrna. 45 A number of epidemiological studies have evaluated the association between XPA 4G>A polymorphism and cancer risk, but the results remain inconclusive. In order to resolve this conflict, this meta-analysis of 36 eligible studies including 11,700 cases and 15,033 controls was performed to derive a more precise estimation of the association between XPA 4G>A polymorphism and risk of different types of cancer. Our results showed that XPA 4G>A polymorphism is not associated with cancer risk when all studies were pooled together. In the stratified analysis by cancer type, no significant associations were found in any genetic model among studies of breast cancer and colorectal cancer. However, we observed an increase in lung cancer risk among the XPA 4A-allele carriers. Several previous studies assessed the effect of XPA 4G>A polymorphism on lung cancer risk, which finding is consistent with our results of the 4A-allele being associated with increased risk of lung cancer. Furthermore, there are several indications that the G-allele is protective against risk of lung cancer. In a study of Korean lung cancer patients and healthy volunteers, homozygous carriers of the G-allele had 0.58-fold (95% CI ¼ ) risk of lung cancer compared with homozygous carriers of the A-allele. 34 And in another study of Caucasian population, homozygous carriers of the G-allele had an OR of lung cancer of 0.69 (95% ¼ ). 33 It is possible that XPA 4G>A polymorphism may exert its effect by modifying the translation initiation frequency through a modified Kozak sequence. The G-allele contains an improved Kozak sequence, which could increase the translation initiation frequency, resulting

5 Table 2. Stratified analysis of the XPA 4 G>A polymorphism on cancer risk Genetic Model Heterozygote Homozygote Dominant model Recessive model No.comparisons AG vs. GG AAvs. GG AGþ AA vs. GG AAvs. AGþ GG (sample sizes XPA A23G case/control) OR(95%) p value P het I 2 (%) OR(95%)p value P het I 2 (%) OR(95%) p value P het I 2 (%) OR(95%) p value P het I 2 (%) Total 36 (11,700/15,033) 0.91 ( ) ( ) ( ) ( ) Cancer types Lung cancer 12 (3,511/4,360) 0.92 ( ) ( ) ( ) ( ) Breast cancer 3 (1,304/1,612) 1.02 ( ) ( ) ( ) ( ) Skin cancer 4 (3,098/3,138) 0.86 ( ) ( ) ( ) ( ) Colorectal cancer 4 (762/1,267) 0.96 ( ) ( ) ( ) ( ) Other cancers 13 (3,025/4,656) 0.88 ( ) ( ) ( ) ( ) Source of control HB 13 (3,289/4,041) 0.95 ( ) ( ) ( ) ( ) PB 23 (8,411/10,992) 0.90 ( ) ( ) ( ) ( ) Ethnicity European 23 (7,990/10,609) 0.86 ( ) ( ) ( ) ( ) Mixed 3 (1,263/1,301) 1.01 ( ) ( ) ( ) ( ) Asian 9 (2,366/3,056) 1.04 ( ) ( ) ( ) ( ) HB, hospital-based; PB, population-based.

6 Ding et al. 493 Table 3. Overall meta-analysis for XPA A-allele in the additive model on lung cancer risk Cases Controls Weight Odds ratiom-h, References A-allele G-allele A-allele G-allele (%) fixed, 95% CI ( ) ( ) ( ) ( ) ( ) ( ) ( ) , ( ) ( ) ( ) ( ) ( ) Total (95% CI) 7,022 8, % 1.08 ( ) Heterogeneity: v 2 ¼ 15.9, d.f. ¼ 11, p ¼ Test of overall effect: Z ¼ 2.36, p ¼ Odds ratiom-h, fixed, 95% CI Table 4. Stratified analysis of the XPA A-allele and G-allele carrier on lung cancer risk A-allele carrier versus G-allele carrier on lung cancer risk N a OR 95% p het I 2 (%) Total studies Design of control HB PB Smoking status Smokers Nonsmokers Histological type AD b SQ c Sex Male Female a Number of studies. b Adenocarcinoma. c Squamous cell carcinoma. p het : p value for heterogeneity; HB hospital-based; PB population-based. in an increased steady state level of XPA protein. And results of a functional study indicated that the G-allele had 13% higher DNA repair capacity than the variant A-allele. 33 Interestingly, in the stratified analysis by cancer type, we observed that the XPA 4G>A polymorphism was associated with a reduced risk of skin cancer. And this contrast is consistent with prior studies of DNA repair polymorphisms where the variant alleles are risk factors for certain cancers Table 5. Stratified analysis of the XPA A-allele and G-allele in the additive model on cancer risk A-allele carrier versus G-allele carrier N a OR 95% p het I 2 (%) Total studies Cancer types Lung cancer Breast cancer Skin cancer Colorectal cancer Other cancer Design of control HB PB a Number of studies. p het : p value for heterogeneity; HB hospital-based; PB population-based. but are associated with a relative risk below the null for skin studies. 46 Inconsistent results might be due to a different role of XPA in different cell types or tissues. And another explanation for the different findings may be based onthegreaterapoptoticresponseofcasesofskincancersto DNA damage, leading to apoptosis prior to cell division and presenting in epidemiologic studies as relative risks below the null for skin cancers. There was no evidence for the association between XPA 4G>A polymorphism and cancer risk in subgroup analyses based on source of controls in all genetic models. And in the stratified analysis by

7 494 XPA 4G>A polymorphism and cancer risk Figure 1. Begg s funnel plot for publication bias test. AA versus GG. Each point represents a separate study for the indicated association. Log (OR), natural logarithm of OR. Horizontal line, mean effect size. ethnicity, individuals carrying the A-allele were not significantly associated with increased risk to cancer in European populations and Mixed populations compared with G-allele carriers. But we observed a significantly elevated cancer risk among Asian populations. It should be considered that the apparent inconsistency of these results may underlie differences in ethnicity, lifestyleanddiseaseprevalenceaswellaspossiblelimitations due to the relatively small sample size. The current knowledge of carcinogenesis indicates a multi-factorial and multi-step process that involves various genetic alterations and several biological pathways. Thus, it is unlikely that risk factors of cancer work in isolation from each other. And the same polymorphisms may play different roles in cancer susceptibility, because cancer is a complicated multi-genetic disease, and different genetic backgrounds may contribute to the discrepancy. And even more importantly, the low penetrance genetic effects of single polymorphism may largely depend on interaction with other polymorphisms and/or a particular environmental exposure. Some previous studies showed a dose response relationship between cancer risk and the number of variant alleles in both NER and BER. 33 In the study of Tse et al. 47 an increased risk of esophageal adenocarcinoma was observed with the number of variant alleles. And Hu et al. 48 also reported rising lung cancer risk associated with a combination of several variant alleles. Thus, it is plausible that the effects of DNA repair function on cancer risk may be modified by multiple genetic polymorphisms. Although cigarette smoking is the major cause of lung cancer, only a fraction of smokers develop smoking-related lung cancer, suggesting that there may be differences in individual susceptibility and possible gene environment interactions. No statistically significant interactions between the XPA 4G>A polymorphism and smoking were detected in our meta-analysis. In contrast to our finding, two previous studies concerning the association between the XPA 4G>A polymorphism and lung cancer found a higher risk of lung cancer among A-allele carriers when more exposed to tobacco smoke. 31,34 The discrepancy could be attributed to the potential problem of misclassification of smoking history. Many of the included studies explored the combined effect of XPA 4G>A polymorphism and tobacco use. However, some of the studies did not report how tobacco use was defined and categorized. Possible misclassification in exposure measurement and heterogeneity in definition of tobacco use may partly explain the high inconsistency of the findings. And chance findings should also be considered as a possible reason for the different findings. Although we have put considerable efforts and resources into testing possible association between XPA 4G>A polymorphism and cancer risk, there are still some limitations inherited from the published studies. First, our results were based on single-factor estimates without adjustment for other risk factors including alcohol usage, environmental factors and other lifestyle. At lower levels of alcohol consumption, the difference in cancer risk between the various gene carriers was less striking. And higher levels of alcohol consumption result in production of more acetaldehyde which then can exert its carcinogenic effect. 49 Second, the controls were not uniformly defined. Some studies used a healthy population as the reference group, whereas others selected hospital patients without organic cancer as the reference group. Therefore, non-differential misclassification bias is possible because these studies may have included the control groups who have different risks of developing cancer of various organs. Our meta-analysis also has several strengths. First, a systematic review of the association of XPA 4G>A polymorphism with cancer risk is statistically more powerful than any single study. Second, the quality of eligible studies included in current meta-analysis was satisfactory and met our inclusion criterion. Third, we did not detect any publication bias indicating that the whole pooled results should be unbiased. In conclusion, our meta-analysis suggests that the XPA 4G>A polymorphism may contribute to genetic susceptibility of lung cancer. And the results support that the minor A- allele of the XPA 4G>A polymorphism is associated with a reduced risk of skin cancers. However, it is necessary to conduct large sample studies using standardized unbiased genotyping methods, homogeneous cancer patients and wellmatched controls. Moreover, further studies estimating the effect of gene gene and gene environment interactions may eventually lead to our better, comprehensive understanding of the association between the XPA 4G>A polymorphism in the NER pathway and cancer risk. Acknowledgements The authors thank Ms. Jiangmei Liu (Department of Statistics, Southern Medical University, Guangzhou, China) for scientific editing.

8 Ding et al. 495 References 1. Wood RD, Mitchell M, Sgouros J, Lindahl T. Human DNA repair genes. Science 2001;291: Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 2004;73: Rademakers S, Volker M, Hoogstraten D, Nigg AL, Mone MJ, Van Zeeland AA, Hoeijmakers JH, Houtsmuller AB, Vermeulen W. Xeroderma pigmentosum group A protein loads as a separate factor onto DNA lesions. Mol Cell Biol 2003;23: Batty DP, Wood RD. Damage recognition in nucleotide excision repair of DNA. Gene 2000; 241: Kozak M. Interpreting cdna sequences: some insights from studies on translation. Mamm Genome 1996;7: Qian B, Zhang H, Zhang L, Zhou X, Yu H, Chen K. Association of genetic polymorphisms in DNA repair pathway genes with non-small cell lung cancer risk. Lung Cancer 2011;73: Palli D, Polidoro S, D Errico M, Saieva C, Guarrera S, Calcagnile AS, Sera F, Allione A, Gemma S, Zanna I, Filomena A, Testai E, et al. Polymorphic DNA repair and metabolic genes: a multigenic study on gastric cancer. Mutagenesis 2010;25: Jelonek K, Gdowicz-Klosok A, Pietrowska M, Borkowska M, Korfanty J, Rzeszowska-Wolny J, Widlak P. Association between single-nucleotide polymorphisms of selected genes involved in the response to DNA damage and risk of colon, head and neck, and breast cancers in a Polish population. J Appl Genet 2010;51: Hsieh YY, Chang CC, Wang YK, Hsu KH, Chen CP, Hsu CM, Tsai FJ. Insulin-like growth factors II exon 9 and E-cadherin-Pml I but not myeloperoxidase promoter-463, urokinase-apal I nor xeroderma pigmentosum polymorphisms are associated with higher susceptibility to leiomyoma. Anticancer Res 2010;30: Abbasi R, Ramroth H, Becher H, Dietz A, Schmezer P, Popanda O. Laryngeal cancer risk associated with smoking and alcohol consumption is modified by genetic polymorphisms in ERCC5, ERCC6 and RAD23B but not by polymorphisms in five other nucleotide excision repair genes. Int J Cancer 2009;125: Pan J, Lin J, Izzo JG, Liu Y, Xing J, Huang M, Ajani JA, Wu X. Genetic susceptibility to esophageal cancer: the role of the nucleotide excision repair pathway. Carcinogenesis 2009;30: Joshi AD, Corral R, Siegmund KD, Haile RW, Le Marchand L, Martinez ME, Ahnen DJ, Sandler RS, Lance P, Stern MC. Red meat and poultry intake, polymorphisms in the nucleotide excision repair and mismatch repair pathways and colorectal cancer risk. Carcinogenesis 2009;30: Raaschou-Nielsen O, Sorensen M, Overvad K, Tjonneland A, Vogel U. Polymorphisms in nucleotide excision repair genes, smoking and intake of fruit and vegetables in relation to lung cancer. Lung Cancer-J Iaslc 2008;59: Guo W, Zhou RM, Wan LL, Wang N, Li Y, Zhang XJ, Dong XJ. Polymorphisms of the DNA repair gene xeroderma pigmentosum groups A and C and risk of esophageal squamous cell carcinoma in a population of high incidence region of North China. J Cancer Res Clin Oncol 2008;134: Feng XX, Duan PF, Wang LB, Zhang JB, Lu ZX. [Study on the relationship between polymorphisms of XPA gene and susceptibility of esophageal cancer]. Zhonghua Liu Xing Bing Xue Za Zhi 2008;29: Lin J, Pu X, Wang W, Matin S, Tannir NM, Wood CG, Wu X. Case-control analysis of nucleotide excision repair pathway and the risk of renal cell carcinoma. Carcinogenesis 2008;29: Dong Z, Guo W, Zhou R, Wan L, Li Y, Wang N, Kuang G, Wang S. Polymorphisms of the DNA repair gene XPA and XPC and its correlation with gastric cardiac adenocarcinoma in a high incidence population in North China. J Clin Gastroenterol 2008;42: Crew KD, Gammon MD, Terry MB, Zhang FF, Zablotska LB, Agrawal M, Shen J, Long CM, Eng SM, Sagiv SK, Teitelbaum SL, Neugut AI, et al. Polymorphisms in nucleotide excision repair genes, polycyclic aromatic hydrocarbon-dna adducts, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 2007;16: Bau DT, Tsai MH, Huang CY, Lee CC, Tseng HC, Lo YL, Tsai Y, Tsai FJ. Relationship between polymorphisms of nucleotide excision repair genes and oral cancer risk in Taiwan: evidence for modification of smoking habit. Chin J Physiol 2007;50: Applebaum KM, Karagas MR, Hunter DJ, Catalano PJ, Byler SH, Morris S, Nelson HH. Polymorphisms in nucleotide excision repair genes, arsenic exposure, and non-melanoma skin cancer in New Hampshire. Environ Health Perspect 2007;115: Wang Y, Spitz MR, Lee JJ, Huang M, Lippman SM, Wu X. Nucleotide excision repair pathway genes and oral premalignant lesions. Clin Cancer Res 2007;13: De Ruyck K, Szaumkessel M, De Rudder I, Dehoorne A, Vral A, Claes K, Velghe A, Van Meerbeeck J, Thierens H. Polymorphisms in base-excision repair and nucleotide-excision repair genes in relation to lung cancer risk. Mutat Res 2007;631: Hansen RD, Sorensen M, Tjonneland A, Overvad K, Wallin H, Raaschou-Nielsen O, Vogel U. XPA A23G, XPC Lys939Gln, XPD Lys751Gln and XPD Asp312Asn polymorphisms, interactions with smoking, alcohol and dietary factors, and risk of colorectal cancer. Mutat Res 2007;619: Zienolddiny S, Campa D, Lind H, Ryberg D, Skaug V, Stangeland L, Phillips DH, Canzian F, Haugen A. Polymorphisms of DNA repair genes and risk of non-small cell lung cancer. Carcinogenesis 2006; 27: Sugimura T, Kumimoto H, Tohnai I, Fukui T, Matsuo K, Tsurusako S, Mitsudo K, Ueda M, Tajima K, Ishizaki K. Gene-environment interaction involved in oral carcinogenesis: molecular epidemiological study for metabolic and DNA repair gene polymorphisms. J Oral Pathol Med 2006;35: Shen J, Desai M, Agrawal M, Kennedy DO, Senie RT, Santella RM, Terry MB. Polymorphisms in nucleotide excision repair genes and DNA repair capacity phenotype in sisters discordant for breast cancer. Cancer Epidemiol Biomarkers Prev 2006;15: Miller KL, Karagas MR, Kraft P, Hunter DJ, Catalano PJ, Byler SH, Nelson HH. XPA, haplotypes, and risk of basal and squamous cell carcinoma. Carcinogenesis 2006;27: Weiss JM, Weiss NS, Ulrich CM, Doherty JA, Voigt LF, Chen C. Interindividual variation in nucleotide excision repair genes and risk of endometrial cancer. Cancer Epidemiol Biomarkers Prev 2005;14: Vogel U, Overvad K, Wallin H, Tjonneland A, Nexo BA, Raaschou-Nielsen O. Combinations of polymorphisms in XPD, XPC and XPA in relation to risk of lung cancer. Cancer Lett 2005; 222: Zhu JF, Hu ZB, Ma HX, Huo X, Xu L, Zhou JN, Shen HB, Chen YJ. Polymorphism of the DNA repair gene XPA and susceptibility to lung cancer. J Nanjing Medical University 2005;19: Butkiewicz D, Popanda O, Risch A, Edler L, Dienemann H, Schulz V, Kayser K, Drings P, Bartsch H, Schmezer P. Association between the risk for lung adenocarcinoma and a (-4) G-to-A polymorphism in the XPA gene. Cancer Epidemiol Biomarkers Prev 2004;13: Popanda O, Schattenberg T, Phong CT, Butkiewicz D, Risch A, Edler L, Kayser K, Dienemann H, Schulz V, Drings P, Bartsch H, Schmezer P. Specific combinations of DNA repair gene variants and increased risk for non-small cell lung cancer. Carcinogenesis 2004;25: Wu X, Zhao H, Wei Q, Amos CI, Zhang K, Guo Z, Qiao Y, Hong WK, Spitz MR. XPA polymorphism associated with reduced lung cancer risk and a modulating effect on nucleotide excision repair capacity. Carcinogenesis 2003; 24: Park JY, Park SH, Choi JE, Lee SY, Jeon HS, Cha SI, Kim CH, Park JH, Kam S, Park RW, Kim IS, Jung TH. Polymorphisms of the DNA repair gene xeroderma pigmentosum group A and risk of primary lung cancer. Cancer Epidemiol Biomarkers Prev 2002;11:993 7.

9 496 XPA 4G>A polymorphism and cancer risk 35. Judson R, Stephens JC, Windemuth A. The predictive power of haplotypes in clinical response. Pharmacogenomics 2000;1: Wan L, Zhou R, Wang N, Li Y, Guo W. Corrdation of XPA polymorphisms to the risk of squamous cell carcinoma and gastric cardia adenocarcinoma. Zhong Liu Fang Zhi Yan Jiu 2007;34: DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7: Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22: Egger M, Davey SG, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315: Monzo M, Brunet S, Urbano-Ispizua A, Navarro A, Perea G, Esteve J, Artells R, Granell M, Berlanga J, Ribera JM, Bueno J, Llorente A, et al. Genomic polymorphisms provide prognostic information in intermediate-risk acute myeloblastic leukemia. Blood 2006;107: Duell EJ, Bracci PM, Moore JH, Burk RD, Kelsey KT, Holly EA. Detecting pathway-based genegene and gene-environment interactions in pancreatic cancer. Cancer Epidemiol Biomarkers Prev 2008;17: Weiss JM, Weiss NS, Ulrich CM, Doherty JA, Chen C. Nucleotide excision repair genotype and the incidence of endometrial cancer: effect of other risk factors on the association. Gynecol Oncol 2006;103: Carles J, Monzo M, Amat M, Jansa S, Artells R, Navarro A, Foro P, Alameda F, Gayete A, Gel B, Miguel M, Albanell J, et al. Single-nucleotide polymorphisms in base excision repair, nucleotide excision repair, and double strand break genes as markers for response to radiotherapy in patients with Stage I to II head-and-neck cancer. Int J Radiat Oncol Biol Phys 2006;66: Feng J, Sun X, Sun N, Qin S, Li F, Cheng H, Chen B, Cao Y, Ma J, Cheng L, Lu Z, Ji J, et al. XPA A23G polymorphism is associated with the elevated response to platinum-based chemotherapy in advanced non-small cell lung cancer. Acta Biochim Biophys Sin (Shanghai) 2009;41: Larsen LK, Amri EZ, Mandrup S, Pacot C, Kristiansen K. Genomic organization of the mouse peroxisome proliferator-activated receptor beta/ delta gene: alternative promoter usage and splicing yield transcripts exhibiting differential translational efficiency. Biochem J 2002;366: Nelson HH, Christensen B, Karagas MR. The XPC poly-at polymorphism in non-melanoma skin cancer. Cancer Lett 2005;222: Tse D, Zhai R, Zhou W, Heist RS, Asomaning K, Su L, Lynch TJ, Wain JC, Christiani DC, Liu G. Polymorphisms of the NER pathway genes, ERCC1 and XPD are associated with esophageal adenocarcinoma risk. Cancer Causes Control 2008;19: Hu Z, Xu L, Shao M, Yuan J, Wang Y, Wang F, Yuan W, Qian J, Ma H, Wang Y, Liu H, Chen W, et al. Polymorphisms in the two helicases ERCC2/XPD and ERCC3/XPB of the transcription factor IIH complex and risk of lung cancer: a case-control analysis in a Chinese population. Cancer Epidemiol Biomarkers Prev 2006;15: Visapaa JP, Gotte K, Benesova M, Li J, Homann N, Conradt C, Inoue H, Tisch M, Horrmann K, Vakevainen S, Salaspuro M, Seitz HK. Increased cancer risk in heavy drinkers with the alcohol dehydrogenase 1C*1 allele, possibly due to salivary acetaldehyde. Gut 2004;53: